Publications by year
In Press
Lynam A, McDonald T, Hill A, Dennis J, Oram R, Pearson E, Weedon M, Hattersley A, Owen K, Shields B, et al (In Press). Development and validation of multivariable clinical diagnostic models to identify type 1 diabetes requiring rapid insulin therapy in adults aged 18 to 50. BMJ Open
Bailey SER, Abel GA, Atkins A, Byford R, Davies S-J, Mays J, McDonald TJ, Miller J, Neck C, Renninson J, et al (In Press). Diagnostic performance of the faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: a service evaluation in the South West of England.
Abstract:
Diagnostic performance of the faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: a service evaluation in the South West of England
AbstractObjectivesTo evaluate the faecal immunochemical test (FIT) for primary care clinicians to triage patients with low-risk symptoms of possible colorectal cancer, and to estimate its diagnostic performance.DesignService delivery evaluation.SettingAll primary and secondary care providers in the South West of England, approximate population 4 million.Participants3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer, following NICE NG12 and DG30, with a FIT (HM-JACKarc assay) analysed from 01/06/2018 to 31/12/2018.Main outcome measuresDiagnosis of colorectal cancer.Results618 (15.9%) patients tested positive at a threshold of 10μg Hb/g faeces (median 36μg Hb/g faeces (IQR 17 to 149)); 458 (74.1%) of these had an urgent referral to specialist lower gastrointestinal (GI) services within three months. 43 were diagnosed with colorectal cancer within 12 months. 3272 patients tested negative; 324 (9.9%) were referred on an urgent lower GI pathway in secondary care within three months. 8 were diagnosed with colorectal cancer within 12 months. The positive predictive value of FIT for colorectal cancer in the low-risk symptomatic population was 7.0% (95% CI 5.1% to 9.3%) and the negative predictive value was 99.8% (CI 99.5% to 99.9%). Sensitivity was 84.3% (CI 71.4% to 93.0%),and specificity 85.0% (CI 83.8% to 86.1%). The area under the ROC curve was 0.92 (CI 0.86 to 0.96). A threshold of 37μg Hb/g faeces would identify patients with an individual 3% risk of cancer.ConclusionsFIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care. The threshold value of 10μg Hb/g faeces represents a risk of cancer below 3% used in current NICE guidance; however, this lower value may be appropriate to meet the national aspiration of improving cancer diagnostics.
Abstract.
Koivula RW, Forgie IM, Kurbasic A, Viñuela A, Heggie A, Giordano GN, Hansen TH, Hudson M, Koopman A, Rutters F, et al (In Press). Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium.
Abstract:
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium
Abstract/SummaryBackground and aims:Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person’s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).Materials and methods:From a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.Results:Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].Conclusion:The epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.Abbreviations:ASATAbdominal subcutaneous adipose tissueDIRECTDiabetes Research on Patient StratificationEUEuropean UnionMMTTMixed-meal tolerance testMRIMagnetic resonance imaginghpfVMHigh-pass filtered vector magnitudeIAATIntra-abdominal adipose tissueIGRImpaired glucose regulationIMIInnovative Medicines InitiativeMEmultiechoNGRNormal glucose regulationOGTTOral glucose tolerance testPAPhysical activityTAATTotal abdominal adipose tissueT2DType 2 Diabetes
Abstract.
Clissold R, Fulford J, Hudson M, Shields B, McDonald T, Ellard S, Hattersley A, Bingham C (In Press). Exocrine pancreatic dysfunction is common in HNF1B-associated renal disease and can be symptomatic. Clinical Kidney Journal
Young KG, McDonald TJ, Shields BM (In Press). Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care.
Abstract:
Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care
AbstractData linkage of cohort or RCT data with routinely collected data is becoming increasingly commonplace, and this often involves combining biomarker measurements from different sources. However, sources may have different biases due to differences in assay method and calibration. Combining these measurements, or diagnoses based on these measurements, is therefore not always valid. We highlight an example using glycated haemoglobin A1c (HbA1c) test results from two different sources in UK Biobank data.
Abstract.
Sazonovs A, Kennedy N, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea C, Walker G, Perry MH, McDonald TJ, et al (In Press). HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy.
Abstract:
HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy
SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.
Abstract.
Jones AG, mcdonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA, Hattersley AT (In Press). Markers of beta cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes. Diabetes Care
Atabaki-Pasdar N, Ohlsson M, Viñuela A, Frau F, Pomares-Millan H, Haid M, Jones AG, Thomas EL, Koivula RW, Kurbasic A, et al (In Press). Predicting and elucidating the etiology of fatty liver disease using a machine learning-based approach: an IMI DIRECT study.
Abstract:
Predicting and elucidating the etiology of fatty liver disease using a machine learning-based approach: an IMI DIRECT study
ABSTRACTBackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in type 2 diabetes (T2D) and beyond. Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and ultimately hepatocellular carcinomas.Methods and FindingsUtilizing the baseline data from the IMI DIRECT participants (n=1514) we sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI image-derived liver fat content (<5% or ≥5%). We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and Random Forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operator characteristic area under the curve (ROCAUC) of 0.84 (95% confidence interval (CI)=0.82, 0.86), which compared with a ROCAUC of 0.82 (95% CI=0.81, 0.83) for a model including nine clinically-accessible variables. The IMI DIRECT prediction models out-performed existing non-invasive NAFLD prediction tools.ConclusionsWe have developed clinically useful liver fat prediction models (see:www.predictliverfat.org) and identified biological features that appear to affect liver fat accumulation.
Abstract.
Peters J, Anderson R, Shields B, Hudson M, Shepherd M, McDonald T, Hattersley A, Hyde C (In Press). Strategies to Identify Individuals with Monogenic Diabetes: Results of an Economic Evaluation. BMJ Open
Leete P, Oram R, McDonald T, Ziller C, Hattersley A, Richardson S, Morgan N (In Press). Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis. Diabetologia
Johnson M, Patel K, De Franco E, McDonald T, Hudson M, Dobbs R, Ellard S, Flanagan S, Hattersley A, Oram R, et al (In Press). Type 1 Diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta-cells. Diabetologia
2023
FUHRI SNETHAGE C, MCDONALD TJ, RAMPANELLI E, DE GROEN P, SCHIMMEL AWM, VAN RAALTE D, BROUWER CB, ORAM RA, ROEP BO, NIEUWDORP M, et al (2023). 27-OR: Residual Beta-Cell Function Associates with Lower Glycaemic Variability and More Time in Range in Individuals with Type 1 Diabetes. Diabetes, 72(Supplement_1).
Thomas NJ, Hill AV, Dayan CM, Oram RA, McDonald TJ, Shields BM, Jones AG, Simon G, Ramos A, Norris A, et al (2023). Age of Diagnosis Does Not Alter the Presentation or Progression of Robustly Defined Adult-Onset Type 1 Diabetes.
Diabetes Care,
46(6), 1156-1163.
Abstract:
Age of Diagnosis Does Not Alter the Presentation or Progression of Robustly Defined Adult-Onset Type 1 Diabetes
. OBJECTIVE
. To determine whether presentation, progression, and genetic susceptibility of robustly defined adult-onset type 1 diabetes (T1D) are altered by diagnosis age.
.
.
. RESEARCH DESIGN AND METHODS
. We compared the relationship between diagnosis age and presentation, C-peptide loss (annual change in urine C-peptide–creatinine ratio [UCPCR]), and genetic susceptibility (T1D genetic risk score [GRS]) in adults with confirmed T1D in the prospective StartRight study, 1,798 adults with new-onset diabetes. T1D was defined in two ways: two or more positive islet autoantibodies (of GAD antibody, IA-2 antigen, and ZnT8 autoantibody) irrespective of clinical diagnosis (n = 385) or one positive islet autoantibody and a clinical diagnosis of T1D (n = 180).
.
.
. RESULTS
. In continuous analysis, age of diagnosis was not associated with C-peptide loss for either definition of T1D (P &gt; 0.1), with mean (95% CI) annual C-peptide loss in those diagnosed before and after 35 years of age (median age of T1D defined by two or more positive autoantibodies): 39% (31–46) vs. 44% (38–50) with two or more positive islet autoantibodies and 43% (33–51) vs. 39% (31–46) with clinician diagnosis confirmed by one positive islet autoantibody (P &gt; 0.1). Baseline C-peptide and T1D GRS were unaffected by age of diagnosis or T1D definition (P &gt; 0.1). In T1D defined by two or more autoantibodies, presentation severity was similar in those diagnosed before and after 35 years of age: unintentional weight loss, 80% (95% CI 74–85) vs. 82% (76–87); ketoacidosis, 24% (18–30) vs. 19% (14–25); and presentation glucose, 21 mmol/L (19–22) vs. 21 mmol/L (20–22) (all P ≥ 0.1). Despite similar presentation, older adults were less likely to be diagnosed with T1D, insulin-treated, or admitted to hospital.
.
.
. CONCLUSIONS
. When adult-onset T1D is robustly defined, the presentation characteristics, progression, and T1D genetic susceptibility are not altered by age of diagnosis.
.
Abstract.
Allesøe RL, Lundgaard AT, Hernández Medina R, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, et al (2023). Author Correction: Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.
Nat Biotechnol,
41(7).
Author URL.
McDonald TJ (2023). Commentary on Abnormal Hb A1c Result from a Diabetic Patient Leads to Unexpected Diagnosis.
Clin Chem,
69(7), 688-689.
Author URL.
Allesøe RL, Lundgaard AT, Hernández Medina R, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, et al (2023). Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models.
Nature Biotechnology,
41(3), 399-408.
Abstract:
Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
AbstractThe application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
Abstract.
Bowman P, Patel KA, McDonald TJ, Holst JJ, Hartmann B, Leveridge M, Shields BM, Hammersley S, Spaull SR, Knight BA, et al (2023). Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulfonylurea-treated KCNJ11 neonatal diabetes.
J Diabetes InvestigAbstract:
Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulfonylurea-treated KCNJ11 neonatal diabetes.
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.
Abstract.
Author URL.
Happ HC, Sadleir LG, Zemel M, de Valles-Ibáñez G, Hildebrand MS, McConkie-Rosell A, McDonald M, May H, Sands T, Aggarwal V, et al (2023). Neurodevelopmental and Epilepsy Phenotypes in Individuals with Missense Variants in the Voltage-Sensing and Pore Domains of <i>KCNH5</i>.
Neurology,
100(6), e603-e615.
Abstract:
Neurodevelopmental and Epilepsy Phenotypes in Individuals with Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.
Background and objectivesKCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.
Abstract.
Liu Z, Le K, Zhou X, Alexander JL, Lin S, Bewshea C, Chanchlani N, Nice R, McDonald TJ, Lamb CA, et al (2023). Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.
Lancet Gastroenterol Hepatol,
8(2), 145-156.
Abstract:
Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.
BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p
Abstract.
Author URL.
Chanchlani N, Lin S, Hamilton B, Bewshea C, Thomas A, Smith R, Roberts C, Nice R, McDonald T, Goodhand J, et al (2023). O59 Understanding anti-TNF treatment failure: mechanisms and management of loss of response to anti-TNF therapy, three-year data from the PANTS study. Oral presentations.
Liu Z, Le K, Zhou X, Alexander J, Lin S, Bewshea C, Chanchlani N, Nice R, McDonald T, Lamb C, et al (2023). OP24 Neutralising antibody potency against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants in infliximab and vedolizumab treated patients with Inflammatory Bowel Disease after three doses of COVID-19 vaccine: a prospective multicentre cohort study. Journal of Crohn's and Colitis, 17(Supplement_1), i32-i34.
Smith R, Liu Z, Laskey K, Lin S, Chanchlani N, Nice R, Roberts C, Alexander J, McDonald TJ, Bewshea C, et al (2023). P115 Vitamin D concentrations are not associated with anti-SARS-CoV-2 antibody responses following mRNA COVID-19 vaccine in IBD patients treated with infliximab. Poster presentations.
Carbery I, Lin S, Chanchlani N, Janjua M, Nice R, McDonald TJ, Bewshea C, Kennedy NA, Ahmad T, Goodhand JR, et al (2023). P649 Does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn’s disease?. Journal of Crohn's and Colitis, 17(Supplement_1), i778-i778.
Lin S, Chanchlani N, Smith R, Roberts C, Nice R, McDonald TJ, Hamilton B, Bewshea C, Kennedy NA, Goodhand JR, et al (2023). P662 Pre-treatment vitamin D concentrations do not predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn’s disease. Journal of Crohn's and Colitis, 17(Supplement_1), i791-i793.
Chanchlani N, Lin S, Hamilton B, Bewshea C, Thomas A, Smith R, Roberts C, Nice R, McDonald TJ, Goodhand JR, et al (2023). P798 Understanding anti-TNF treatment failure: mechanisms and management of loss of response to anti-TNF therapy, three-year data from the PANTS study. Journal of Crohn's and Colitis, 17(Supplement_1), i928-i930.
Smith R, Lin S, Chanchlani N, Roberts C, Nice R, McDonald TJ, Hamilton B, Bewshea C, Kennedy NA, Goodhand JR, et al (2023). P82 Pre-treatment vitamin D concentrations do not predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn’s disease. Poster presentations.
Dawed AY, Mari A, Brown A, McDonald TJ, Li L, Wang S, Hong M-G, Sharma S, Robertson NR, Mahajan A, et al (2023). Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials. The Lancet Diabetes & Endocrinology, 11(1), 33-41.
Chanchlani N, Lin S, Smith R, Roberts C, Nice R, McDonald TJ, Hamilton B, Bishara M, Bewshea C, Kennedy NA, et al (2023). Pretreatment Vitamin D Concentrations Do Not Predict Therapeutic Outcome to Anti-TNF Therapies in Biologic-Naïve Patients with Active Luminal Crohn’s Disease.
Crohn's & Colitis 360,
5(3).
Abstract:
Pretreatment Vitamin D Concentrations Do Not Predict Therapeutic Outcome to Anti-TNF Therapies in Biologic-Naïve Patients with Active Luminal Crohn’s Disease
Abstract
.
. Background and Aims
. Vitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pretreatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pretreatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn’s disease.
.
.
. Methods
. 25-Hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study. Cut-offs for vitamin D were deficiency &lt;25 nmol/L, insufficiency 25–50 nmol/L, and adequacy/sufficiency &gt;50 nmol/L.
.
.
. Results
. About 17.1% (189/1107; 95% CI, 15.0–19.4) and 47.7% (528/1107; 95% CI, 44.8–50.6) of patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) of patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, and non-treatment with vitamin D supplementation were independently associated with lower vitamin D concentrations. Pretreatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab Ppnr =. 89, adalimumab Ppnr =. 18) or non-remission at week 54 (infliximab P =. 13, adalimumab P =. 58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab.
.
.
. Conclusions
. Vitamin D deficiency is common in patients with active Crohn’s disease. Unlike previous studies, pretreatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or nonremission at week 54.
.
Abstract.
Fuhri Snethlage CM, McDonald TJ, Oram RD, de Groen P, Rampanelli E, Schimmel AWM, Holleman F, Siegelaar S, Hoekstra J, Brouwer CB, et al (2023). Residual β-Cell Function is Associated with Longer Time in Range in Individuals with Type 1 Diabetes.
Diabetes CareAbstract:
Residual β-Cell Function is Associated with Longer Time in Range in Individuals with Type 1 Diabetes
. OBJECTIVE
. Little is known about the influence of residual islet function on glycemic control in type 1 diabetes (T1D). We investigated the associations between residual β-cell function and metrics of continuous glucose monitoring (CGM) in individuals with T1D.
.
.
. RESEARCH DESIGN AND METHODS
. In this cross-sectional cohort comprising 489 individuals (64% female, age 41.0 ± 14.0 years), T1D duration was 15.0 (interquartile range [IQR] 6.0–29.0) years. Individuals had a time in range (TIR) of 66% (IQR 52–80%) and a urinary C-peptide-to-creatinine ratio (UCPCR) of 0.01 (IQR 0.00–0.41) nmol/mmol. To assess β-cell function, we measured UCPCR (detectable &gt;0.01 nmol/mmol), and to assess α-cell function, fasting plasma glucagon/glucose ratios were measured. CGM was used to record TIR (3.9–10 mmol/L), time below range (TBR) (&lt;3.9 mmol/L), time above range (TAR) (&gt;10 mmol/L), and glucose coefficient of variance (CV). For CGM, 74.7% used FreeStyle Libre 2, 13.8% Medtronic Guardian, and 11.5% Dexcom G6 as their device.
.
.
. RESULTS
. The percentage of patients with T1D who had a detectable UCPCR was 49.4%. A higher UCPCR correlated with higher TIR (r = 0.330, P &lt; 0.05), lower TBR (r = −0.237, P &lt; 0.05), lower TAR (r = −0.302, P &lt; 0.05), and lower glucose CV (r = −0.356, P &lt; 0.05). A higher UCPCR correlated negatively with HbA1c levels (r = −0.183, P &lt; 0.05) and total daily insulin dose (r = −0.183, P &lt; 0.05). Glucagon/glucose ratios correlated with longer TIR (r = 0.234, P &lt; 0.05).
.
.
. CONCLUSIONS
. Significantly longer TIR, shorter TBR and TAR, and lower CV were observed in individuals with greater UCPCR-assessed β-cell function. Therefore, better CGM-derived metrics in individuals with preserved β-cell function may be a contributor to a lower risk of developing long-term complications.
.
Abstract.
Hall LA, McKay SC, Halle-Smith J, Soane J, Osei-Bordom D-C, Goodburn L, Magill L, Pinkney T, Radhakrishna G, Valle JW, et al (2023). The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.
British journal of cancer,
128(10), 1922-1932.
Abstract:
The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.
IntroductionCONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC).MethodsThe treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up.ResultsAmong 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093).ConclusionPathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.
Abstract.
Katte JC, McDonald TJ, Sobngwi E, Jones AG (2023). The phenotype of type 1 diabetes in sub-Saharan Africa.
Frontiers in Public Health,
11Abstract:
The phenotype of type 1 diabetes in sub-Saharan Africa
The phenotype of type 1 diabetes in Africa, especially sub-Saharan Africa, is poorly understood. Most previously conducted studies have suggested that type 1 diabetes may have a different phenotype from the classical form of the disease described in western literature. Making an accurate diagnosis of type 1 diabetes in Africa is challenging, given the predominance of atypical diabetes forms and limited resources. The peak age of onset of type 1 diabetes in sub-Saharan Africa seems to occur after 18–20 years. Multiple studies have reported lower rates of islet autoantibodies ranging from 20 to 60% amongst people with type 1 diabetes in African populations, lower than that reported in other populations. Some studies have reported much higher levels of retained endogenous insulin secretion than in type 1 diabetes elsewhere, with lower rates of type 1 diabetes genetic susceptibility and HLA haplotypes. The HLA DR3 appears to be the most predominant HLA haplotype amongst people with type 1 diabetes in sub-Saharan Africa than the HLA DR4 haplotype. Some type 1 diabetes studies in sub-Saharan Africa have been limited by small sample sizes and diverse methods employed. Robust studies close to diabetes onset are sparse. Large prospective studies with well-standardized methodologies in people at or close to diabetes diagnosis in different population groups will be paramount to provide further insight into the phenotype of type 1 diabetes in sub-Saharan Africa.
Abstract.
Kennedy NA, Janjua M, Chanchlani N, Lin S, Bewshea C, Nice R, McDonald TJ, Auckland C, Harries LW, Davies M, et al (2023). Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.
Gut,
72(2), 295-305.
Abstract:
Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.
OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p
Abstract.
Author URL.
2022
Hill AV, Bolt R, Aldred M, Tippett PW, Nice R, McDonald TJ, Jones AG (2022). A novel, patient-focused approach to home sample collection improves rate of return & sample quality and enables research to continue during the covid-19 pandemic.
Author URL.
Chanchlani N, Lin S, Chee D, Hamilton B, Nice R, Arkir Z, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, et al (2022). Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.
J Crohns Colitis,
16(3), 389-397.
Abstract:
Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.
BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. RESULTS: Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p
=
0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94-9.96] vs 5.02 [2.18-18.70], p
=
0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39-68.10, p
Abstract.
Author URL.
Thomas N, Hill A, Bolt R, Tippett P, Shields B, McDonald T, Jones A (2022). Age of onset does not affect progression of robustly defined adult onset type 1 diabetes.
Author URL.
Lin S, Kennedy NA, Saifuddin A, Sandoval DM, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin K-M, Butler DK, et al (2022). Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.
Nat Commun,
13(1).
Abstract:
Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.
Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p
Abstract.
Author URL.
Taylor GS, Shaw AC, Smith K, Wason J, McDonald TJ, Oram RA, Stevenson E, Shaw JAM, West DJ (2022). Capturing the real-world benefit of residual β-cell function during clinically important time-periods in established Type 1 diabetes.
Diabet Med,
39(5).
Abstract:
Capturing the real-world benefit of residual β-cell function during clinically important time-periods in established Type 1 diabetes.
AIMS: Many individuals with type 1 diabetes retain residual β-cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β-cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes. METHODS: Under free-living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C-peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpepund ), low (Cpeplow : 0.001-0.19 nmol/mmol) and high (Cpephigh : ≥0.2 nmol/mmol). RESULTS: Greater β-cell function was associated with incremental improvements in glycaemia. Cpephigh spent significantly greater time in normoglycaemia than Cpepund overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0-300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpepund had increased hyperglycaemia versus Cpeplow overnight and increased postprandial hypoglycaemic events compared with Cpephigh. For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner. CONCLUSIONS: Residual β-cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial.
Abstract.
Author URL.
Wesolowska-Andersen A, Brorsson CA, Bizzotto R, Mari A, Tura A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, et al (2022). Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: an IMI DIRECT study. Cell Reports Medicine, 3(1), 100477-100477.
Russon C, Vaughan N, Pulsford R, Andrews R, Allen M (2022). Glycaemic events during exercise can be effectively predicted with machine learning using only start glucose and duration. European Association for the Study of Diabetes (EASD). 19th - 23rd Sep 2022.
Abstract:
Glycaemic events during exercise can be effectively predicted with machine learning using only start glucose and duration
Abstract.
Chanchlani N, Lin S, Auth MK, Lee CL, Robbins H, Looi S, Murugesan SV, Riley T, Preston C, Stephenson S, et al (2022). Implications for sequencing of biologic therapy and choice of second <scp>anti‐TNF</scp> in patients with inflammatory bowel disease: results from the <scp>IMmunogenicity</scp> to Second <scp>Anti‐TNF</scp> therapy (<scp>IMSAT</scp>) therapeutic drug monitoring study.
Alimentary Pharmacology & Therapeutics,
56(8), 1250-1263.
Abstract:
Implications for sequencing of biologic therapy and choice of second anti‐TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti‐TNF therapy (IMSAT) therapeutic drug monitoring study
SummaryBackgroundAnti‐drug antibodies are associated with treatment failure to anti‐TNF agents in patients with inflammatory bowel disease (IBD).AimTo assess whether immunogenicity to a patient's first anti‐TNF agent would be associated with immunogenicity to the second, irrespective of drug sequenceMethodsWe conducted a UK‐wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti‐TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti‐TNF agent, defined at any timepoint as an anti‐TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.ResultsIn patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27–3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46–4.80, p < 0.001). For each 10‐fold increase in anti‐infliximab and anti‐adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38–2.17, p < 0.001) and 1.99 (95%CI 1.34–2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39–4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti‐TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.ConclusionIrrespective of drug sequence, immunogenicity to the first anti‐TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.
Abstract.
Brackley SM, Thomas N, Hill A, Shields B, Fox C, McDonald T, Huber J, Jones AG (2022). In adults with new onset type 1 diabetes baseline psychological resilience is prospectively associated with HbA1c.
Author URL.
Simpson VE, Thomas N, Hill AV, Deshmukh S, Shields BM, McDonald T, Jones AG (2022). In people with suspected type 1 diabetes or rapid progression to insulin, a single positive islet autoantibody confirms the genetic characteristics and progression of classical type 1 diabetes.
Author URL.
Grace SL, Bowden J, Walkey HC, Kaur A, Misra S, Shields BM, McKinley TJ, Oliver NS, McDonald TJ, Johnston DG, et al (2022). Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association with Genetic and Clinical Characteristics.
J Clin Endocrinol Metab,
107(12), e4341-e4349.
Abstract:
Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association with Genetic and Clinical Characteristics.
CONTEXT: the importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear. OBJECTIVE: We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D. METHODS: We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D. RESULTS: GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10-17), female sex (52% vs 37%, P = 1 × 10-8), other autoimmune diseases (13% vs 6%, P = 3 × 10-6), and HLA-DR3-DQ2 (58% vs 51%, P =. 006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10-7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10-6), and ZnT8A positivity (77% vs 52%, P = 1 × 10-15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays. CONCLUSION: Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis.
Abstract.
Author URL.
Liu Z, Le K, Zhou X, Alexander JL, Lin S, Bewshea C, Chanchlani N, Nice R, McDonald T, Lamb CA, et al (2022). Neutralising Antibody Potency Against SARS-CoV-2 Ancestral and Omicron BA.1 and BA.4/5 Variants in Patients with Inflammatory Bowel Disease after Three Doses of COVID-19 Vaccine: a Prospective Multicentre Cohort Study (CLARITY).
Lin S, Kennedy NA, Saifuddin A, Muñoz Sandoval D, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin KM, Butler DK, et al (2022). OP22 Antibody decay, T cell immunity and breakthrough infections following SARS-CoV-2 vaccination in infliximab- and vedolizumab-treated patients.
Journal of Crohn's & colitis,
16(Suppl 1), i023-i025.
Abstract:
OP22 Antibody decay, T cell immunity and breakthrough infections following SARS-CoV-2 vaccination in infliximab- and vedolizumab-treated patients
Abstract Background Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p
Abstract.
Nice R, Goodhand JR, Kennedy N, Ahmad T, Winyard P, McDonald TJ (2022). P196 Pre-treatment antibodies to infliximab and adalimumab are common but are not associated with anti-TNF treatment failure. Journal of Crohn's and Colitis, 16(Supplement_1), i256-i256.
Shields BM, Dennis JM, Angwin CD, Warren F, Henley WE, Farmer AJ, Sattar N, Holman RR, Jones AG, Pearson ER, et al (2022). Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study. Nature Medicine, 29(2), 376-383.
Chee D, Nice R, Hamilton B, Jones E, Hawkins S, Redstone C, Cairnes V, Pohl K, Chanchlani N, Lin S, et al (2022). Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for Therapeutic Drug Monitoring in patients with Inflammatory Bowel Disease.
J Crohns Colitis,
16(2), 190-198.
Abstract:
Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for Therapeutic Drug Monitoring in patients with Inflammatory Bowel Disease.
BACKGROUND AND AIMS: Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling [fingerPRICKS] compared to conventional venepuncture. METHODS: We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire. RESULTS: Therapeutic drug monitoring requests for adalimumab (96.5 [70.5-106] per week to 52 [33.5-57.0], p < 0.001) but not infliximab (184.5 [161.2-214.2] to 161 [135-197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding 6 months. Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab and ustekinumab drug, and anti-adalimumab and anti-infliximab antibody levels. The median [interquartile range] volume of serum obtained using intracapillary sampling was 195 µL [130-210]. More than 87% [90/103] of patients agreed that intracapillary testing was easy and 69% [71/103] preferred it to conventional venepuncture. In routine care, 75.3% [58/77] of patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring. CONCLUSIONS: Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.
Abstract.
Author URL.
Dawed AY, Mari A, McDonald TJ, Li L, Wang S, Hong M-G, Sharma S, Robertson NR, Mahajan A, Wang X, et al (2022). Pharmacogenomics of GLP-1 Receptor Agonists: a genome wide analysis of observational data and large randomized controlled trials.
Grace SL, Long AE, Gillespie KM, Williams AJK, Lampasona V, Achenbach P, Pearson ER, McDonald TJ, Jones AG (2022). Rapid insulin progression in glutamate decarboxylase autoantibody positive adult-onset diabetes can be better predicted by detecting autoantibodies to n-terminally truncated GAD(96-585).
Author URL.
Meek CL, Oram RA, McDonald TJ, Feig DS, Hattersley AT, Murphy HR (2022). Response to Comment on Meek et al. Reappearance of C-Peptide During the Third Trimester in Type 1 Diabetes Pregnancy: Pancreatic Regeneration or Fetal Hyperinsulinism? Diabetes Care 2021;44:1826-1834.
Diabetes Care,
45(2), e43-e44.
Author URL.
Eason RJ, Thomas NJ, Hill AV, Knight BA, Carr A, Hattersley AT, McDonald TJ, Shields BM, Jones AG, Grp SS, et al (2022). Routine islet autoantibody testing in clinically diagnosed adult-onset type 1 diabetes can help identify misclassification and guide successful insulin cessation.
DIABETOLOGIA,
65(SUPPL 1), S153-S154.
Author URL.
Eason RJ, Thomas NJ, Hill AV, Deshmukh S, Hattersley AT, Shields BM, McDonald TJ, Jones AG (2022). Routine islet autoantibody testing in newly diagnosed adult-onset type 1 diabetes can guide clinical reclassification and successful insulin cessation.
Author URL.
Katte JC, Sobngwi E, Dehayem MY, Deshmukh S, Patel KA, Shields BM, McDonald TJ, Jones AG (2022). The majority of young people diagnosed with type 1 diabetes in Cameroon do not have evidence of islet autoimmunity: Results from the Young-Onset Diabetes in sub-Saharan Africa (YODA) study.
Author URL.
Taylor GS, Shaw A, Scragg JH, Smith K, Campbell MD, McDonald TJ, Shaw JA, Ross MD, West DJ (2022). Type 1 Diabetes Patients with Different Residual Beta-Cell Function but Similar Age, HBA1c, and Cardiorespiratory Fitness Have Differing Exercise-Induced Angiogenic Cell Mobilisation.
Frontiers in Endocrinology,
13Abstract:
Type 1 Diabetes Patients with Different Residual Beta-Cell Function but Similar Age, HBA1c, and Cardiorespiratory Fitness Have Differing Exercise-Induced Angiogenic Cell Mobilisation
Background: Many individuals with type 1 diabetes retain residual beta-cell function. Sustained endogenous insulin and C-peptide secretion is associated with reduced diabetes related complications, but underlying mechanisms remain unclear. Lower circulating numbers of endothelial and hematopoietic progenitor cells (EPCs and HPCs), and the inability to increase the count of these cells in response to exercise, are also associated with increased diabetes complications and cardiovascular disease. It is unknown whether residual beta-cell function influences HPCs and EPCs. Thus, this study examined the influence of residual beta-cell function in type 1 diabetes upon exercise-induced changes in haematopoietic (HPCs) and endothelial progenitor cells (EPCs). Methods: Participants with undetectable stimulated C-peptide (n=11; Cpepund), 10 high C-peptide (Cpephigh; >200 pmol/L), and 11 non-diabetes controls took part in this observational exercise study, completing 45 minutes of intensive walking at 60% (Formula presented.). Clinically significant HPCs (CD34+) and EPCs (CD34+VEGFR2+) phenotypes for predicting future adverse cardiovascular outcomes, and subsequent cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), were enumerated at rest and immediately post-exercise by flow cytometry. Results: Exercise increased HPCs and EPCs phenotypes similarly in the Cpephigh and control groups (+34-121% across phenotypes, p
Abstract.
Lin S, Chanchlani N, Carbery I, Janjua M, Nice R, McDonald TJ, Bewshea C, Kennedy NA, Ahmad T, Selinger CP, et al (2022). Understanding <scp>anti‐TNF</scp> treatment failure: does serum triiodothyronine‐to‐thyroxine (<scp>T3</scp>/<scp>T4</scp>) ratio predict therapeutic outcome to <scp>anti‐TNF</scp> therapies in biologic‐naïve patients with active luminal Crohn's disease?.
Alimentary Pharmacology & Therapeutics,
56(5), 783-793.
Abstract:
Understanding anti‐TNF treatment failure: does serum triiodothyronine‐to‐thyroxine (T3/T4) ratio predict therapeutic outcome to anti‐TNF therapies in biologic‐naïve patients with active luminal Crohn's disease?
SummaryBackgroundDuring illness, adaptations of the hypothalamic–pituitary‐thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine‐to‐thyroxine (fT3/fT4) ratio has been linked to non‐response to treatment in a range of diseases, including in biologic‐treated patients with inflammatory bowel disease.AimTo assess whether baseline serum fT3/fT4 ratio predicted primary non‐response (PNR) and non‐remission to infliximab and adalimumab in patients with Crohn's diseaseMethodsThyroid function tests were undertaken in stored serum from biologic‐naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti‐TNF Therapy in Crohn's Disease study (PANTS).ResultsBaseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27–0.34] vs 0.32 [0.28–0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25–0.33] vs. 0.32 [0.29–0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31–0.85, p = 0.009), but not non‐remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54–0.61], sensitivity 0.62 [95% CI 0.41–0.74], and specificity 0.53 [95% CI 0.42–0.73]).ConclusionsLower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti‐TNF treatment at week 14, but not non‐remission at week 54.
Abstract.
2021
(2021). 57<sup>th</sup> EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia, 64(Suppl 1), 1-380.
Chee D, Nice R, Hamilton B, Jones E, Hawkins S, Redstone C, Cairnes V, Pohl K, Kennedy N, Ahmad T, et al (2021). 855 PATIENT-LED REMOTE INTRACAPILLARY PHARMACOKINETIC SAMPLING (FINGERPRICKS): VALIDATION AND ACCEPTABILITY FOR HOME THERAPEUTIC DRUG MONITORING IN PATIENTS WITH IBD IN THE COVID-19 PANDEMIC. Gastroenterology, 160(6), s-173.
MEEK CL, ORAM RA, MCDONALD TJ, FEIG D, HATTERSLEY AT, MURPHY HR (2021). 94-OR: Reappearance of C-Peptide during the Third Trimester in Type 1 Diabetes Pregnancy: Pancreatic Regeneration or Fetal Hyperinsulinism?. Diabetes, 70(Supplement_1).
Kennedy NA, Goodhand JR, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft NM, et al (2021). Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.
Gut,
70(5), 865-875.
Abstract:
Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab
ObjectiveAntitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.DesignAntibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.ResultsRates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2–5.6) vs 37.0 (15.2–76.1), p<0.0001).ConclusionsInfliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.Trial registration numberISRCTN45176516.
Abstract.
Kennedy NA, Goodhand J, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft N, et al (2021). Anti-SARS-CoV2 antibody responses are attenuated in patients with Inflammatory Bowel Disease treated with infliximab.
Author URL.
Lin S, Kennedy NA, Saifuddin A, Sandoval DM, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin K-M, Butler DK, et al (2021). Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients.
Greiner R, Nyirenda M, Rodgers L, Asiki G, Banda L, Shields B, Hattersley A, Crampin A, Newton R, Jones A, et al (2021). Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies.
BMJ Global Health,
6(5), e005222-e005222.
Abstract:
Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies
IntroductionLow high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, although this relationship is not causal and is likely mediated through associations with other risk factors. Low HDL is extremely common in sub-Saharan African populations, and this has often been interpreted to indicate that these populations will have increased cardiovascular risk. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK.MethodsWe compared data from adults living in Uganda and Malawi (n=26 216) and in the UK (n=8747). We examined unadjusted and adjusted levels of HDL and applied the WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors.ResultsHDL was substantially lower in the African than in the European studies (geometric mean 0.9–1.2 mmol/L vs 1.3–1.8 mmol/L), with African prevalence of low HDL as high as 77%. Total cholesterol was also substantially lower (geometric mean 3.3–3.9 mmol/L vs 4.6–5.4 mmol/L). In comparison with European studies the relationship between HDL and adiposity (body mass index, waist to hip ratio) was greatly attenuated in African studies and the relationship with non-HDL cholesterol reversed: in African studies low HDL was associated with lower non-HDL cholesterol. The association between sex and HDL was also different; using the WHO sex-specific definitions, low HDL was substantially more common among women (69%–77%) than men (41%–59%) in Uganda/Malawi.ConclusionThe relationship between HDL and sex, adiposity and non-HDL cholesterol in sub-Saharan Africa is different from European populations. In sub-Saharan Africans low HDL is a marker of low overall cholesterol and sex differences are markedly attenuated. Therefore low HDL in isolation is unlikely to indicate raised cardiovascular risk and the WHO sex-based cut-offs are inappropriate.
Abstract.
Rodgers LR, Hill AV, Dennis JM, Craig Z, May B, Hattersley AT, McDonald TJ, Andrews RC, Jones A, Shields BM, et al (2021). Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study.
BMC Medicine,
19(1).
Abstract:
Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study
Abstract
. Background
. Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D.
.
. Methods
. We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model.
.
. Results
. The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%).
.
. Conclusions
. A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.
.
Abstract.
Obura M, Beulens JWJ, Slieker R, Koopman ADM, Hoekstra T, Nijpels G, Elders P, Dekker JM, Koivula RW, Kurbasic A, et al (2021). Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: an IMI-DIRECT study.
Diabet Med,
38(2).
Abstract:
Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: an IMI-DIRECT study.
AIM: to examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: at baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (β = 0.36, 95% CI 0.13-0.58), Subgroup 3 (β = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (β = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.
Abstract.
Author URL.
Koivula RW, Atabaki-Pasdar N, Giordano GN, White T, Adamski J, Bell JD, Beulens J, Brage S, Brunak S, De Masi F, et al (2021). Correction to: the role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study (Diabetologia, (2020), 63, 4, (744-756), 10.1007/s00125-019-05083-6).
Diabetologia,
64(1), 260-261.
Abstract:
Correction to: the role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study (Diabetologia, (2020), 63, 4, (744-756), 10.1007/s00125-019-05083-6)
Unfortunately, ‘Present address’ was omitted from one of the addresses provided for Mark I. McCarthy (#26).The corrected address details are given on the following page.
Abstract.
Lin S, Kennedy NA, Saifuddin A, Sandoval DM, Reynolds C, Seoane RC, Kottoor S, Pieper F, Lin K-M, Butler DK, et al (2021). Covid-19 vaccine-induced antibodies are attenuated and decay rapidly in infliximab treated patients.
Bailey SER, Abel GA, Atkins A, Byford R, Davies S-J, Mays J, McDonald TJ, Miller J, Neck C, Renninson J, et al (2021). Diagnostic performance of a faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: an evaluation in the South West of England.
Br J Cancer,
124(7), 1231-1236.
Abstract:
Diagnostic performance of a faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: an evaluation in the South West of England.
BACKGROUND: the faecal immunochemical test (FIT) was introduced to triage patients with low-risk symptoms of possible colorectal cancer in English primary care in 2017, underpinned by little primary care evidence. METHODS: all healthcare providers in the South West of England (population 4 million) participated in this evaluation. 3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer had a FIT from 01/06/2018 to 31/12/2018. A threshold of 10 μg Hb/g faeces defined a positive test. RESULTS: Six hundred and eighteen (15.9%) patients tested positive; 458 (74.1%) had an urgent referral to specialist lower gastrointestinal (GI) services within three months. Forty-three were diagnosed with colorectal cancer within 12 months. 3272 tested negative; 324 (9.9%) had an urgent referral within three months. Eight were diagnosed with colorectal cancer within 12 months. Positive predictive value was 7.0% (95% CI 5.1-9.3%). Negative predictive value was 99.8% (CI 99.5-99.9%). Sensitivity was 84.3% (CI 71.4-93.0%), specificity 85.0% (CI 83.8-86.1%). The area under the ROC curve was 0.92 (CI 0.86-0.96). A threshold of 37 μg Hb/g faeces would identify patients with an individual 3% risk of cancer. CONCLUSIONS: FIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care; a higher threshold may be appropriate in the wake of the COVID-19 crisis.
Abstract.
Author URL.
Tikhonova IA, Yang H, Bello S, Salmon A, Robinson S, Hemami MR, Dodman S, Kharechko A, Haigh RC, Jani M, et al (2021). Enzyme-linked immunosorbent assays for monitoring TNF-alpha inhibitors and antibody levels in people with rheumatoid arthritis: a systematic review and economic evaluation.
Health Technol Assess,
25(8), 1-248.
Abstract:
Enzyme-linked immunosorbent assays for monitoring TNF-alpha inhibitors and antibody levels in people with rheumatoid arthritis: a systematic review and economic evaluation.
BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response. METHODS: Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc. North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc. New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk of Bias in Non-randomised Studies - of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost-utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses. RESULTS: Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols-Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost-utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care. LIMITATIONS: There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS. CONCLUSIONS: Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales. FUTURE WORK: Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018105195. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.
Abstract.
Author URL.
(2021). Erratum to: Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications (Diabetes Care 2021; 44: 390–398).
Diabetes Care,
44(4).
Abstract:
Erratum to: Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications (Diabetes Care 2021; 44: 390–398)
The authors report that the following errors occurred in transcribing the results of the statistical computations into the abstract and text. In the Abstract, “insulin dose at baseline, 27% lower (P 5 2 3 10239)” should be “insulin dose at baseline, 9% lower (P 5 2310217).” in the Results, under the section C-Peptide Association with Insulin Dose, “(ratio of geometric means 0.91, P 5 2 3 10239)” should be “(ratio of geometric means 0.91, P 5 2 3 10217).” the authors apologize for the errors. The online version of the article (https://doi.org/10.2337/dc20-0567) has been corrected.
Abstract.
Jeyam A, Colhoun H, McGurnaghan S, Blackbourn L, McDonald TJ, Palmer CNA, McKnight JA, Strachan MWJ, Patrick AW, Chalmers J, et al (2021). Erratum. Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications. Diabetes Care 2021;44:390-398. Diabetes Care
Grace SL, Walkey HC, Kaur A, Misra S, Oliver NS, McDonald TJ, Johnston DG, Jones G, Patel KA (2021). Glutamate decarboxylase and islet antigen-2 autoantibody titres at diagnosis in people with type 1 diabetes showed bimodal distribution and an association with age at diagnosis and HLA genotype.
Author URL.
Niwaha AJ, Rodgers LR, Greiner R, Balungi PA, Mwebaze R, McDonald TJ, Hattersley AT, Shields BM, Nyirenda MJ, Jones AG, et al (2021). HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study.
BMJ Open Diabetes Research & Care,
9(1), e002350-e002350.
Abstract:
HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study
IntroductionThe utility of HbA1c (glycosylated hemoglobin) to estimate glycemic control in populations of African and other low-resource countries has been questioned because of high prevalence of other medical conditions that may affect its reliability. Using continuous glucose monitoring (CGM), we aimed to determine the comparative performance of HbA1c, fasting plasma glucose (FPG) (within 5 hours of a meal) and random non-fasting glucose (RPG) in assessing glycemic burden.Research design and methodsWe assessed the performance of HbA1c, FPG and RPG in comparison to CGM mean glucose in 192 Ugandan participants with type 2 diabetes. Analysis was undertaken in all participants, and in subgroups with and without medical conditions reported to affect HbA1c reliability. We then assessed the performance of FPG and RPG, and optimal thresholds, in comparison to HbA1c in participants without medical conditions thought to alter HbA1c reliability.Results32.8% (63/192) of participants had medical conditions that may affect HbA1c reliability: anemia 9.4% (18/192), sickle cell trait and/or hemoglobin C (HbC) 22.4% (43/192), or renal impairment 6.3% (12/192). Despite high prevalence of medical conditions thought to affect HbA1c reliability, HbA1c had the strongest correlation with CGM measured glucose in day-to-day living (0.88, 95% CI 0.84 to 0.91), followed by FPG (0.82, 95% CI 0.76 to 0.86) and RPG (0.76, 95% CI 0.69 to 0.81). Among participants without conditions thought to affect HbA1c reliability, FPG and RPG had a similar diagnostic performance in identifying poor glycemic control defined by a range of HbA1c thresholds. FPG of ≥7.1 mmol/L and RPG of ≥10.5 mmol/L correctly identified 78.2% and 78.8%, respectively, of patients with an HbA1c of ≥7.0%.ConclusionsHbA1c is the optimal test for monitoring glucose control even in low-income and middle-income countries where medical conditions that may alter its reliability are prevalent; FPG and RPG are valuable alternatives where HbA1c is not available.
Abstract.
Bowman P, Patel KA, McDonald TJ, Holst JJ, Hartmann B, Leveridge M, Knight BA, Shepherd MH, Andrews RC, Hattersley AT, et al (2021). Incretin hormone responses to carbohydrate and protein/fat are preserved in adults with sulphonylurea-treated KCNJ11 neonatal diabetes, when compared with healthy controls.
Author URL.
Atabaki-Pasdar N, Pomares-Millan H, Koivula RW, Tura A, Brown A, Viñuela A, Agudelo L, Coral D, van Oort S, Allin K, et al (2021). Inferring causal pathways between metabolic processes and liver fat accumulation: an IMI DIRECT study.
Kennedy NA, Lin S, Goodhand JR, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Cummings F, Fraser A, et al (2021). Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines.
Kennedy NA, Lin S, Goodhand JR, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Cummings JF, Fraser A, et al (2021). Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.
Gut,
70(10), 1884-1893.
Abstract:
Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.
OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p
Abstract.
Author URL.
Grace SL, Bowden J, Walkey HC, Kaur A, Misra S, Shields BM, McKinley TJ, Oliver NS, McDonald T, Johnston DG, et al (2021). Islet autoantibody level distributions in type 1 diabetes and their association with genetic and clinical characteristics.
Jones AG, McDonald TJ, Shields BM, Hagopian W, Hattersley AT (2021). Latent Autoimmune Diabetes of Adults (LADA) is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes.
Diabetes Care,
44(6), 1243-1251.
Abstract:
Latent Autoimmune Diabetes of Adults (LADA) is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes
Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.
Abstract.
Carr A, Oram R, Narendran P, Andrews R (2021). MEASUREMENT OF C-PEPTIDE AT DIAGNOSIS INFORMS GLYCEMIC CONTROL BUT NOT HYPOGLYCEMIC RISK IN TYPE 1 DIABETES.
Author URL.
Meek CL, Oram R, McDonald T, Feig DS, Hattersley AT, Murphy HR (2021). Maternal C-peptide reappearance in type 1 diabetes pregnancy: Evidence of beta cell regeneration or fetal hyperinsulinism?.
Author URL.
Katte JC, Lemdjo G, Dehayem MY, Jones AG, McDonald TJ, Sobngwi E, Mbanya JC (2021). Mortality amongst children and adolescents with type 1 diabetes in. <scp>sub‐Saharan</scp>. Africa: the case study of the Changing Diabetes in Children program in Cameroon. Pediatric Diabetes, 23(1), 33-37.
Kennedy NA, Goodhand J, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft N, et al (2021). OP03 Anti-SARS-CoV2 antibody responses are attenuated in patients with Inflammatory Bowel Disease treated with infliximab.
Journal of Crohn's & colitis,
15(Suppl 1), S002-S004.
Abstract:
OP03 Anti-SARS-CoV2 antibody responses are attenuated in patients with Inflammatory Bowel Disease treated with infliximab
Abstract Background Anti-TNF drugs increase the risk of serious respiratory infections and impair protective immunity following pneumococcal, influenza, and viral hepatitis vaccinations. Therefore, we sought to determine whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses following SARS-CoV-2 infection. Methods CLARITY IBD is a multicentre, prospective observational cohort study. Antibody responses in participants treated with infliximab were compared to a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22nd September and 23rd December 2020. Nucleocapsid anti-SARS-CoV2 antibodies were measured using the Roche Elecsys assay. Clinical data and serum were collected every 8 weeks. Durability was defined as nonreduction in antibody level by at least 50% from baseline. Results at baseline, rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab- than vedolizumab-treated patients (3.4% [161/4685], vs 6.0% [134/2250], p
Abstract.
Nice R, Chanchlani N, Kennedy NA, Green HD, Lin S, Gordon C, Chee D, Hamilton B, Bewshea C, Goodhand J, et al (2021). POSITIVITY THRESHOLDS OF TOTAL INFLIXIMAB AND ADALIMUMAB ANTI-DRUG ANTIBODY ASSAYS AND IMPACT IN CLINICAL PRACTICE.
Author URL.
Tura A, Grespan E, Göbl CS, Koivula RW, Franks PW, Pearson ER, Walker M, Forgie IM, Giordano GN, Pavo I, et al (2021). Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: an IMI DIRECT Study.
Diabetes,
70(9), 2092-2106.
Abstract:
Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: an IMI DIRECT Study.
Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). β-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P < 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P < 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, P < 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence.
Abstract.
Author URL.
Meek CL, Oram RA, McDonald TJ, Feig DS, Hattersley AT, Murphy HR, CONCEPTT Collaborative Group (2021). Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?.
Diabetes Care,
44(8), 1826-1834.
Abstract:
Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?
OBJECTIVE: We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of β-cell regeneration in pregnancy with type 1 diabetes. RESEARCH DESIGN AND METHODS: C-peptide was measured on maternal serum samples from 127 participants (12, 24, and 34 weeks) and cord blood during the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay. RESULTS: Three discrete patterns of maternal C-peptide trajectory were identified: pattern 1, undetectable throughout pregnancy, n = 74 (58%; maternal C-peptide
Abstract.
Author URL.
Eason R, Hill A, Shields B, Tippett P, McDonald T, Hattersley A, Oram R, Knight B, Thomas N, Jones A, et al (2021). The absence of islet autoantibodies when routinely tested in adult-onset type 1 diabetes is associated with a high prevalence of treatment change and successful insulin cessation.
Author URL.
Shaw AC, Taylor GS, McDonald TJ, Oram RA, Shaw JAM, West DJ (2021). The influence of residual beta cell function upon free-living postprandial and nocturnal glycaemic control in individuals with type 1 diabetes.
Author URL.
Nice R, Chanchlani N, Green H, Bewshea C, Ahmad T, Goodhand JR, McDonald TJ, Perry MH, Kennedy NA (2021). Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays.
Aliment Pharmacol Ther,
53(1), 128-137.
Abstract:
Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays.
BACKGROUND: When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. AIM: to validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays. METHODS: We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. RESULTS: the 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and -adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P
Abstract.
Author URL.
Grace SL, Cooper A, Jones AG, McDonald TJ (2021). Zinc transporter 8 autoantibody testing requires age-related cut-offs.
BMJ Open Diabetes Research & Care,
9(1), e002296-e002296.
Abstract:
Zinc transporter 8 autoantibody testing requires age-related cut-offs
IntroductionZinc transporter 8 autoantibodies (ZnT8A) are biomarkers of beta cell autoimmunity in type 1 diabetes that have become more widely available to clinicians in recent years. Robust control population-defined thresholds are essential to ensure high clinical specificity in islet autoantibody testing. We aimed to determine the optimal cut-offs for ZnT8A testing.Research design and methods97.5th and 99th centile cut-offs were determined using residual clinical sera from 1559 controls aged between 0 and 83 years with no history of diabetes and a hemoglobin A1c level of less than 6.0% (<42 mmol/mol). ZnT8A were measured by ELISA (RSR, Cardiff, UK) on a Dynex DS2 ELISA robot (Dynex, Preston, UK). We assessed the impact of age-related cut-offs in comparison with the manufacturer’s recommended threshold in a mixed cohort of young-onset (<age 30) diabetes (UNITED study (Using pharmacogeNetics to Improve Treatment in Early-onset Diabetes), n=145).ResultsUsing the manufacturer’s limit of detection, 6 WHO U/mL, 16.2% of people in the control cohort had detectable levels of ZnT8A and those who had detectable ZnT8A were much more likely to be younger (p<0.0001). The 97.5th and 99th centile thresholds were substantially higher in younger participants: 18 and 127 WHO U/mL (tested under 30 years) in comparison with 9 and 21 WHO U/mL (tested 30 years and over). In the UNITED cohort some of those found to be ZnT8A-positive by the manufacturer’s threshold but negative using the appropriate 99% centile cut-off (127 WHO U/mL) displayed characteristics suggestive of type 2 diabetes.ConclusionsAge-related thresholds are needed for ZnT8A testing. In those aged <30 years, use of manufacturers’ recommended cut-offs may result in low test specificity and potentially high rates of false positive test results in patients who do not have autoimmune diabetes.
Abstract.
2020
(2020). 56th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia, 63(S1), 1-485.
TAYLOR GS, SMITH K, SCRAGG J, BASHIR A, FLATT A, STEVENSON EJ, MCDONALD TJ, ORAM RA, SHAW JA, ROSS MD, et al (2020). 680-P: Residual ß-Cell Function in Long-Term Type 1 Diabetes is Associated with a Fivefold Greater Mobilization of Endothelial Progenitor Cells after Exercise. Diabetes, 69(Supplement_1).
Tippett PW, Hill AV, Bolt R, Lynam AL, Carr ALJ, Hattersley AT, McDonald TJ, Oram RA, Shields BM, Jones AG, et al (2020). A clinical prediction model combining clinical features and type 1 diabetes genetic risk has high accuracy for classification of adult onset diabetes at diagnosis.
Author URL.
Bar N, Korem T, Weissbrod O, Zeevi D, Rothschild D, Leviatan S, Kosower N, Lotan-Pompan M, Weinberger A, Le Roy CI, et al (2020). A reference map of potential determinants for the human serum metabolome.
Nature,
588(7836), 135-140.
Abstract:
A reference map of potential determinants for the human serum metabolome
The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
Abstract.
Shields BM, Baptist A, Bandopadhyay S, Phatak S, Bhat D, Kamat R, Hudson M, McDonald TJ, Hattersley AT, Yajnik CS, et al (2020). C-peptide decline follows a similar biphasic pattern in both UK and Indian type 1 diabetes patients.
Author URL.
Jeyam A, Colhoun H, McGurnaghan S, Blackbourn L, McDonald TJ, Palmer CNA, McKnight JA, Strachan MWJ, Patrick AW, Chalmers J, et al (2020). Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications.
Diabetes Care,
44(2), 390-398.
Abstract:
Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications
. OBJECTIVE
. To quantify the relationship of residual C-peptide secretion to glycemic outcomes and microvascular complications in type 1 diabetes.
.
.
. RESEARCH DESIGN AND METHODS
. C-peptide was measured in an untimed blood sample in the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) cohort of 6,076 people with type 1 diabetes monitored for an average of 5.2 years.
.
.
. RESULTS
. In regression models adjusted for age at onset and duration, effect sizes for C-peptide ≥200 vs. &lt;5 pmol/L were as follows: insulin dose at baseline, 9% lower (P = 2 × 10−17); HbA1c during follow-up, 4.9 mmol/mol lower (P = 3 × 10−13); hazard ratio for hospital admission for diabetic ketoacidosis during follow-up, 0.44 (P = 0.0001); odds ratio for incident retinopathy, 0.51 (P = 0.0003). Effects on the risk of serious hypoglycemic episodes were detectable at lower levels of C-peptide, and the form of the relationship was continuous down to the limit of detection (3 pmol/L). In regression models contrasting C-peptide 30 to &lt;200 pmol/L with &lt;5 pmol/L, the odds ratio for self-report of at least one serious hypoglycemic episode in the last year was 0.56 (P = 6 × 10−8), and the hazard ratio for hospital admission for hypoglycemia during follow-up was 0.52 (P = 0.03).
.
.
. CONCLUSIONS
. These results in a large representative cohort suggest that even minimal residual C-peptide secretion could have clinical benefit in type 1 diabetes, in contrast to a follow-up study of the Diabetes Control and Complications Trial (DCCT) intensively treated cohort where an effect on hypoglycemia was seen only at C-peptide levels ≥130 pmol/L. This has obvious implications for the design and evaluation of trials of interventions to preserve or restore pancreatic islet function in type 1 diabetes.
.
Abstract.
(2020). Clinical care and other categories posters: Type 1 diabetes.
Eriksen R, Perez IG, Posma JM, Haid M, Sharma S, Prehn C, Thomas LE, Koivula RW, Bizzotto R, Prehn C, et al (2020). Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: an IMI DIRECT study. EBioMedicine, 58, 102932-102932.
Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea CM, Chanchlani N, Walker GJ, Perry MH, et al (2020). HLA-DQA1*05 Carriage Associated with Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients with Crohn's Disease.
Gastroenterology,
158(1), 189-199.
Abstract:
HLA-DQA1*05 Carriage Associated with Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients with Crohn's Disease.
BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: the HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: in an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.
Abstract.
Author URL.
Greiner RS, Hill A, Knight BA, McDonald T, Shields B, Jones AG, Rodgers LR (2020). HbA(1c) thresholds have substantial impact in screening procedures for those at risk of developing type 2 diabetes.
Author URL.
Frayling TM, Pitt A, Hudson M, Knight B, Nice R, McDonald T, Jones A, Hattersley AT (2020). In vivo estimates of beta cellmass in 251 normoglycaemic individuals are strongly associated with BMI and insulin resistance.
Author URL.
Shepherd MH, Knight BA, Laskey K, McDonald TJ (2020). Newborn screening for glucose: 'An absolutely fantastic idea'.
Author URL.
Nice R, Chanchlani N, Green H, Bewshea C, Kennedy N, Ahmad T, Goodhand J, McDonald T, Perry M (2020). OP21 Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: the prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service. Journal of Crohn's and Colitis, 14(Supplement_1), s018-s019.
Tikhonova IA, Bello S, Salmon A, Robinson S, Hemami MR, Haigh RC, Jani M, McDonald TJ, Hoyle M (2020). PMS68 PROMONITOR FOR THERAPEUTIC DRUG MONITORING IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS TREATED WITH ADALIMUMAB IN ENGLAND AND WALES. Value in Health, 23
Tikhonova IA, Bello S, Salmon A, Robinson S, Hemami RM, Haigh RC, Jani M, McDonald TJ, Hoyle M (2020). PROMONITOR FOR THERAPEUTIC DRUG MONITORING IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS TREATED WITH ADALIMUMAB IN ENGLAND AND WALES.
Author URL.
Shepherd M, Knight BA, Laskey K, McDonald TJ (2020). Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study.
BMJ Open,
10(11).
Abstract:
Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study
Neonatal diabetes presents
Abstract.
Chee D, Nice R, Hamilton B, Jones E, Hawkins S, Redstone C, Cairnes V, Pohl K, Kennedy NA, Ahmad T, et al (2020). Patient-Led Remote Intracapillary Pharmacokinetic Sampling (Fingerpricks): Validation and Acceptability for Home Therapeutic Drug Monitoring in Patients with Ibd in the COVID-19 Pandemic.
Thomas N, Hill A, Tippett P, McDonald T, Knight B, Carr A, Oram R, Hattersley A, Weedon M, Jones A, et al (2020). Patterns of autoimmunity of genetically defined adult onset type 1 diabetes are different above and below 30 years of age, without impacting on clinical presentation.
Author URL.
P B, TJ M, BA K, SE F, M L, SR S, BM S, S H, MH S, RC A, et al (2020). Patterns of post-meal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways.
Greiner R, Hill A, Knight BA, McDonald T, Shields BM, Jones AG, Rodgers L (2020). Performance and implications of NICE-recommended screening for identifying those at risk of type 2 diabetes: Results from a UK population cohort.
Author URL.
Nice R, Chanchlani N, Green H, Bewshea C, Kennedy N, Ahmad T, Goodhand J, McDonald T, Perry M (2020). Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: the prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service.
Author URL.
Obura M, Beulens JWJ, Slieker R, Koopman ADM, Hoekstra T, Nijpels G, Elders P, Koivula RW, Kurbasic A, Laakso M, et al (2020). Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: an IMI-DIRECT study.
PLoS ONE,
15(11 November).
Abstract:
Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: an IMI-DIRECT study
Aim Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. Methods the study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. Results at baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1–3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18–1.92) for subgroup 2 and 1.88 (-0.08–3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. Conclusions Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.
Abstract.
Katte J-C, Poka-Mayap V, Niwaha A, Nakanga W, Jones A, McDonald TJ, Sobgnwi E (2020). Post-meal Urinary C-peptide creatinine ratio is a moderate measure of insulin secretion in diabetes patients in Cameroon: results from a cross-sectional study. PAMJ Clinical Medicine, 3
Taylor GS, Smith K, Capper TE, Scragg JH, Bashir A, Flatt A, Stevenson EJ, McDonald TJ, Oram RA, Shaw JA, et al (2020). Postexercise Glycemic Control in Type 1 Diabetes is Associated with Residual β-Cell Function.
Diabetes Care,
43(10), 2362-2370.
Abstract:
Postexercise Glycemic Control in Type 1 Diabetes is Associated with Residual β-Cell Function
. OBJECTIVE
. To investigate the impact of residual β-cell function on continuous glucose monitoring (CGM) outcomes following acute exercise in people with type 1 diabetes (T1D).
.
.
. RESEARCH DESIGN AND METHODS
. Thirty participants with T1D for ≥3 years were recruited. First, participants wore a blinded CGM unit for 7 days of free-living data capture. Second, a 3-h mixed-meal test assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund &lt;3 pmol/L), low (Cpeplow 3–200 pmol/L), or high (Cpephigh &gt;200 pmol/L) C-peptide groups. Finally, participants completed 45 min of incline treadmill walking at 60% VO2peak followed by a further 48-h CGM capture.
.
.
. RESULTS
. CGM parameters were comparable across groups during the free-living observation week. In the 12- and 24-h postexercise periods (12 h and 24 h), the Cpephigh group had a significantly greater amount of time spent with glucose 3.9–10 mmol/L (12 h, 73.5 ± 27.6%; 24 h, 76.3 ± 19.2%) compared with Cpeplow (12 h, 43.6 ± 26.1%, P = 0.027; 24 h, 52.3 ± 25.0%, P = 0.067) or Cpepund (12 h, 40.6 ± 17.0%, P = 0.010; 24 h, 51.3 ± 22.3%, P = 0.041). Time spent in hyperglycemia (12 h and 24 h glucose &gt;10 and &gt;13.9 mmol/L, P &lt; 0.05) and glycemic variability (12 h and 24 h SD, P &lt; 0.01) were significantly lower in the Cpephigh group compared with Cpepund and Cpeplow. Change in CGM outcomes from pre-exercise to 24-h postexercise was divergent: Cpepund and Cpeplow experienced worsening (glucose 3.9–10 mmol/L: −9.1% and −16.2%, respectively), with Cpephigh experiencing improvement (+12.1%) (P = 0.017).
.
.
. CONCLUSIONS
. Residual β-cell function may partially explain the interindividual variation in the acute glycemic benefits of exercise in individuals with T1D. Quantifying C-peptide could aid in providing personalized and targeted support for exercising patients.
.
Abstract.
Atabaki-Pasdar N, Ohlsson M, Viñuela A, Frau F, Pomares-Millan H, Haid M, Jones AG, Thomas EL, Koivula RW, Kurbasic A, et al (2020). Predicting and elucidating the etiology of fatty liver disease: a machine learning modeling and validation study in the IMI DIRECT cohorts. PLOS Medicine, 17(6), e1003149-e1003149.
Flatt AJS, Little SA, Speight J, Leelarathna L, Walkinshaw E, Tan HK, Bowes A, Lubina-Solomon A, Holmes-Truscott E, Chadwick TJ, et al (2020). Predictors of Recurrent Severe Hypoglycemia in Adults with Type 1 Diabetes and Impaired Awareness of Hypoglycemia During the HypoCOMPaSS Study.
Diabetes Care,
43(1), 44-52.
Abstract:
Predictors of Recurrent Severe Hypoglycemia in Adults with Type 1 Diabetes and Impaired Awareness of Hypoglycemia During the HypoCOMPaSS Study.
OBJECTIVE: the HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years' follow-up. RESEARCH DESIGN AND METHODS: a total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months' follow-up. RESULTS: There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy. CONCLUSIONS: Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy.
Abstract.
Author URL.
Walker GJ, Chanchlani N, Thomas A, Lin S, Moore L, Heerasing NM, Hendy P, Abdelrahim M, Mole S, Perry MH, et al (2020). Primary care faecal calprotectin testing in children with suspected inflammatory bowel disease: a diagnostic accuracy study.
Arch Dis Child,
105(10), 957-963.
Abstract:
Primary care faecal calprotectin testing in children with suspected inflammatory bowel disease: a diagnostic accuracy study.
OBJECTIVE: to determine the diagnostic accuracy of calprotectin to diagnose inflammatory bowel disease (IBD) in children in whom general practitioners (GPs) suspected IBD. DESIGN: Prospective observational cohort study of a new calprotectin-based primary care referral pathway. SETTING: 48 GP practices and gastroenterology secondary care services at the Royal Devon and Exeter NHS Foundation Trust in the South-West of England, UK. PATIENTS: 195 children aged between 4 and 18 years referred on the pathway between January 2014 and August 2017 for investigation of gastrointestinal symptoms were included. INTERVENTIONS: Primary-care-driven faecal calprotectin testing. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. MAIN OUTCOME MEASURES: Diagnostic accuracy of calprotectin testing to detect IBD. RESULTS: 7% (13/195) tested patients were diagnosed with IBD. Using our prespecified cut-off of 100 µg/g, calprotectin had a diagnostic accuracy of 91% (95% CI 86% to 95%) with a sensitivity for distinguishing IBD from non-IBD of 100% (95% CI 75% to 100%), a specificity of 91% (95% CI 85% to 94%), a positive predictive value of 43% (95% CI 25% to 63%) and a negative predictive value of 100% (95% CI 98% to 100%). Calprotectin testing had no effect on the time to diagnosis, but a negative test contributed to saved referrals and was associated with fewer diagnostic tests in secondary care. CONCLUSIONS: Calprotectin testing of children with suspected IBD in primary care accurately distinguishes IBD from a functional gut disorder, reduces secondary care referrals and associated diagnostic healthcare utilisation.
Abstract.
Author URL.
Bizzotto R, Jennison C, Jones AG, Kurbasic A, Tura A, Kennedy G, Bell JD, Thomas EL, Frost G, Eriksen R, et al (2020). Processes Underlying Glycemic Deterioration in Type 2 Diabetes: an IMI DIRECT Study.
Diabetes Care,
44(2), 511-518.
Abstract:
Processes Underlying Glycemic Deterioration in Type 2 Diabetes: an IMI DIRECT Study
. OBJECTIVE
. We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D).
.
.
. RESEARCH DESIGN AND METHODS
. A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression.
.
.
. RESULTS
. Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8–10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07–0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role.
.
.
. CONCLUSIONS
. Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
.
Abstract.
Taylor GS, Smith K, Scragg J, Bashir A, McDonald T, Oram R, Stevenson EJ, Shaw JA, West DJ (2020). Stimulated c-peptide, but not glucagon, is associated with improved glycaemic control after exercise in individuals with type 1 diabetes.
Author URL.
Elyas S, Allen G, Mcdonald T (2020). THE IDENTIFICATION OF STROKE BIO-MARKERS TO DISTINGUISH STROKE FROM STROKE MIMICS, a PILOT STUDY AND CONCEPT.
Author URL.
Jones AG, Shields BM, Dennis JM, Hattersley AT, McDonald TJ, Thomas NJ (2020). The challenge of diagnosing type 1 diabetes in older adults.
Diabet Med,
37(10), 1781-1782.
Author URL.
Koivula RW, Atabaki-Pasdar N, Giordano GN, White T, Adamski J, Bell JD, Beulens J, Brage S, Brunak S, De Masi F, et al (2020). The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.
Diabetologia,
63(4), 744-756.
Abstract:
The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.
AIMS/HYPOTHESIS: it is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS: the TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.
Abstract.
Author URL.
Gudmundsdottir V, Pedersen HK, Mazzoni G, Allin KH, Artati A, Beulens JW, Banasik K, Brorsson C, Cederberg H, Chabanova E, et al (2020). Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.
Genome Medicine,
12(1).
Abstract:
Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study
AbstractBackgroundThe rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.MethodsClusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.ResultsWe identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.ConclusionsOur results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
Abstract.
Grace SL, Cooper A, Jones AG, McDonald TJ (2020). Zinc transporter 8 autoantibody testing requires age-specific cut-offs.
Author URL.
2019
TAYLOR GS, SMITH K, SCRAGG J, BASHIR A, ORAM RA, MCDONALD TJ, STEVENSON EJ, SHAW JA, WEST DJ (2019). 294-OR: Type 1 Diabetes Patients with Residual Beta-Cell Function Display Improved Time in Euglycemia and Less Glycaemic Fluctuation after Exercise. Diabetes, 68(Supplement_1).
Koivula RW, Forgie IM, Kurbasic A, Viñuela A, Heggie A, Giordano GN, Hansen TH, Hudson M, Koopman ADM, Rutters F, et al (2019). Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.
Diabetologia,
62(9), 1601-1615.
Abstract:
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.
AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: from a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: the IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
Abstract.
Author URL.
Myngheer N, Allegaert K, Hattersley A, McDonald T, Kramer H, Ashcroft FM, Verhaeghe J, Mathieu C, Casteels K (2019). Erratum: Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes (Diabetes Care (2014) 37 (3333–3335) DOI: 10.2337/dc14-1247).
Diabetes Care,
42(7).
Abstract:
Erratum: Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes (Diabetes Care (2014) 37 (3333–3335) DOI: 10.2337/dc14-1247)
On page 3335 of the article cited above, funding information was added for author Frances M. Ashcroft. The following sentence was inserted at the end of the Funding section: "F.M.A. is supported by the European Research Council (grant 322620).".The online version of the article (https://doi.org/10.2337/dc14-1247) has been corrected to reflect this change.
Abstract.
Wilman HR, Parisinos CA, Atabaki-Pasdar N, Kelly M, Thomas EL, Neubauer S, Jennison C, Ehrhardt B, Baum P, Schoelsch C, et al (2019). Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration.
Journal of Hepatology,
71(3), 594-602.
Abstract:
Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p
Abstract.
Shields B, McDonald T, Owen K, Malecki M, Jones A, Colclough K, Hattersley A (2019). Improving the MODY calculator for use in insulin treated patients with the addition of C-peptide and islet autoantibodies.
Author URL.
Long AE, Wilson IV, Aitken RJ, McDonald TJ, Wong FS, Williams AJK, Gillespie KM (2019). Insulin autoantibody level at diagnosis predicts long-term residual beta cell function.
Author URL.
Lampasona V, Pittman DL, Williams AJ, Achenbach P, Schlosser M, Akolkar B, Winter WE, Watson K, Weets I, Tao Y, et al (2019). Islet Autoantibody Standardization Program 2018 Workshop: Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance.
CLINICAL CHEMISTRY,
65(9), 1141-1152.
Author URL.
Hill AV, Tippett P, McDonald TJ, Knight BA, Hattersley AT, Jones AG (2019). No single clinical feature can robustly classify diabetes at diagnosis, but approaches that integrate clinical features have high diagnostic accuracy.
Author URL.
Bowman P, McDonald TJ, Knight BA, Flanagan SE, Leveridge M, Spaull SR, Shields BM, Hammersley S, Shepherd MH, Andrews RC, et al (2019). Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways.
BMJ Open Diabetes Research and Care,
7(1).
Abstract:
Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-K ATP -channel pathways
Objective Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-K ATP -channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM. Research design and methods 5 adults with sulfonylurea-treated KCNJ11 PNDM and five age, sex and body mass index-matched controls without diabetes had a high-carbohydrate and high-protein/fat meal on two separate mornings. Insulin(i) and glucose(g) were measured at baseline then regularly over 4 hours after the meal. Total area under the curve (tAUC) for insulin and glucose was calculated over 4 hours and compared between meals in controls and KCNJ11 cases. Results in controls, glucose values after carbohydrate and protein/fat were similar (median glucose tAUC 0-4h 21.4 vs 19.7 mmol/L, p=0.08). In KCNJ11 cases glucose levels were higher after carbohydrate than after protein/fat (median glucose tAUC 0-4h 58.1 vs 31.3 mmol/L, p=0.04). These different glycemic responses reflected different patterns of insulin secretion: in controls, insulin secretion was greatly increased after carbohydrate versus protein/fat (median insulin tAUC 0-4h 727 vs 335 pmol/L, p=0.04), but in KCNJ11 cases insulin secretion was similar after carbohydrate and protein/fat (median insulin tAUC 0-4h 327 vs 378 pmol/L, p=0.50). Conclusions Individuals with sulfonylurea-treated KCNJ11 PNDM produce similar levels of insulin in response to both carbohydrate and protein/fat meals despite carbohydrate resulting in much higher glucose levels and protein/fat resulting in relatively low glucose levels. This suggests in an inability to modulate insulin secretion in response to glucose levels, consistent with a dependence on non-K ATP pathways for insulin secretion. Trial registration number NCT02921906.
Abstract.
Marren SM, Hammersley S, McDonald TJ, Shields BM, Knight BA, Hill A, Bolt R, Tree TI, Roep BO, Hattersley AT, et al (2019). Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?.
Diabet Med,
36(9), 1092-1099.
Abstract:
Persistent C-peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?
AIMS: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c , hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C-peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. METHODS: We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA1c , insulin dose and microvascular complications (n = 140) in those with preserved and low C-peptide. RESULTS: Stimulated median (IQR) C-peptide was 114 (43, 273) pmol/l and
Abstract.
Author URL.
McKeigue PM, Spiliopoulou A, McGurnaghan S, Colombo M, Blackbourn L, McDonald TJ, Onengut-Gomuscu S, Rich SS, a Palmer CN, McKnight JA, et al (2019). Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes.
BMC Med,
17(1).
Abstract:
Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes.
BACKGROUND: the objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. METHODS: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. RESULTS: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. CONCLUSIONS: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.
Abstract.
Author URL.
Bowman P, Patel KA, McDonald TJ, Knight BA, Leveridge M, Flanagan SE, Hammersley S, Shepherd MH, Andrews RC, Hattersley AT, et al (2019). Physiological assessment of individuals with sulphonylurea-treated KCNJ11 permanent neonatal diabetes following carbohydrate and protein meals shows markedly reduced KATP mediated insulin secretion but relatively intact non-KATP pathways.
Author URL.
Bewshea CM, Ahmad T, Kennedy N, Goodhand J, McDonald T, Green H (2019). Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterology and Hepatology
Chapman DP, Gooding KM, McDonald TJ, Shore AC (2019). Stability of urinary albumin and creatinine after 12 months storage at -20 °C and -80 °C.
Pract Lab Med,
15Abstract:
Stability of urinary albumin and creatinine after 12 months storage at -20 °C and -80 °C.
BACKGROUND: Increasing albumin to creatinine ratio (ACR) within the normal range is a risk factor for cardiovascular disease in the general population. Clinical and epidemiological studies often store urine samples for long durations prior to ACR assessment. The stability of ACR at the lowest urinary albumin concentrations during prolonged storage has not been previously studied because routine clinical assays can't quantify very low concentrations of albumin. AIM: to determine the stability of urinary albumin and creatinine over 12 months in samples stored at -20 °C and -80 °C using an assay which enables assessment of previously undetectable levels of albumin and to investigate if additives can be used to prevent urinary albumin degradation. METHOD: ACR was measured in 30 urine samples from healthy subjects on the day of collection. Each sample was divided into 5 portions, each receiving a different treatment; alkalisation, protease inhibiter, boric acid, low protein binding tubes and no treatment (control). Samples were stored at -20 °C and -80 °C and ACR was analysed again after 12 months. RESULTS: Mean (95% CI) percent change in ACR was -34.3% (-47.2 to -21.4; p
Abstract.
Author URL.
Koopman ADM, Beulens JW, Voerman E, Rauh SP, van der Heijden AA, McDonald TJ, Langendoen-Gort M, Rutters F (2019). The association between GAD65 antibody levels and incident Type 2 Diabetes Mellitus in an adult population: a meta-analysis.
Metabolism,
95, 1-7.
Abstract:
The association between GAD65 antibody levels and incident Type 2 Diabetes Mellitus in an adult population: a meta-analysis.
CONTEXT: Antibodies to the 65 kD isoform of glutamic acid decarboxylase (GAD65) have been associated with incident Type 2 Diabetes Mellitus, however results are inconsistent. OBJECTIVE: to assess the association between GAD65 antibody positivity and incident Type 2 Diabetes Mellitus in a non-diabetic adult (≥18 years) population, in a systematic review and meta-analysis. DATA SOURCES: a systematic literature search was conducted in Pubmed (MEDLINE) and Embase until January 14th, 2019. STUDY SELECTION: Included studies were 1) prospective studies on the association between GAD65 antibodies and incident Type 2 Diabetes Mellitus; 2) in a non-diabetic adult (≥18 years) population. To strengthen the review, unpublished data from 1302 Hoorn Study participants were included. DATA EXTRACTION: Data extraction and quality assessment were performed independently by two observers. Ten studies were rated for methodological quality and seven were pooled using a random-effects meta-analysis, of which 2 strong, 2 moderate and 3 of low methodological quality. DATA SYNTHESIS: the pooled risk estimate of incident Type 2 Diabetes Mellitus for GAD65 antibody positivity, compared to GAD65 antibody negativity was 3.36 (95% CI: 1.9-5.9). This result was robust to sensitivity analyses. Heterogeneity between studies was significant with I2 statistic of 79% (p
Abstract.
Author URL.
Jones AG, Hill AV, Trippett PW, Hattersley AT, McDonald TJ, Shields BM (2019). The utility of clinical features and glycaemia at diagnosis in classifying young adult onset diabetes.
Author URL.
Tikhonova I, Yang H, Salmon A, Bello S, Peters J, Robinson S, Coelho H, Kharechko A, Haigh R, Jani M, et al (2019). Therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis.
Rodgers LR, Hill AV, Hattersley AT, McDonald TJ, Jones A, Shields BM (2019). Time to revise HbA(1c) thresholds for diabetes risk? Evidence from a prospective study of 4010 participants.
Author URL.
Yaghootkar H, Abbasi F, Ghaemi N, Rabbani A, Wakeling MN, Eshraghi P, Enayati S, Vakili S, Heidari S, Patel K, et al (2019). Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population.
Diabet Med,
36(12), 1694-1702.
Abstract:
Type 1 diabetes genetic risk score discriminates between monogenic and Type 1 diabetes in children diagnosed at the age of <5 years in the Iranian population.
AIM: to examine the extent to which discriminatory testing using antibodies and Type 1 diabetes genetic risk score, validated in European populations, is applicable in a non-European population. METHODS: We recruited 127 unrelated children with diabetes diagnosed between 9 months and 5 years from two centres in Iran. All children underwent targeted next-generation sequencing of 35 monogenic diabetes genes. We measured three islet autoantibodies (islet antigen 2, glutamic acid decarboxylase and zinc transporter 8) and generated a Type 1 diabetes genetic risk score in all children. RESULTS: We identified six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n=3), SLC19A2 and SLC29A3, and a heterozygous mutation in GCK. All clinical features were similar in children with monogenic diabetes (n=6) and in the rest of the cohort (n=121). The Type 1 diabetes genetic risk score discriminated children with monogenic from Type 1 diabetes [area under the receiver-operating characteristic curve 0.90 (95% CI 0.83-0.97)]. All children with monogenic diabetes were autoantibody-negative. In children with no mutation, 59 were positive to glutamic acid decarboxylase, 39 to islet antigen 2 and 31 to zinc transporter 8. Measuring zinc transporter 8 increased the number of autoantibody-positive individuals by eight. CONCLUSIONS: the present study provides the first evidence that Type 1 diabetes genetic risk score can be used to distinguish monogenic from Type 1 diabetes in an Iranian population with a large number of consanguineous unions. This test can be used to identify children with a higher probability of having monogenic diabetes who could then undergo genetic testing. Identification of these individuals would reduce the cost of treatment and improve the management of their clinical course.
Abstract.
Author URL.
Hattersley A, McDonald T, Shepherd M, Hudson M, Colclough K, Ellard S, Pearson E, Shields B (2019). Use of the MODY probability calculator in the real-world setting.
Author URL.
Dawed AY, Zhou K, van Leeuwen N, Mahajan A, Robertson N, Koivula R, Elders PJM, Rauh SP, Jones AG, Holl RW, et al (2019). Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: an IMI DIRECT Study.
Diabetes Care,
42(6), 1027-1033.
Abstract:
Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: an IMI DIRECT Study.
OBJECTIVE: Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS: the study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS: Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS: These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.
Abstract.
Author URL.
Niwaha A, Nakanga W, Katte J-C, Shields B, Jones A, Nyirenda M, McDonald T (2019). When there is no haemolysis, plasma C-peptide levels are stable up to 5 days at 4 degrees C.
Author URL.
Patel KA, Weedon MN, Shields BM, Pearson ER, Hattersley AT, McDonald TJ, UNITED study team (2019). Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score can Exclude Individuals with Type 1 Diabetes from Inappropriate Genetic Testing for Monogenic Diabetes.
Diabetes Care,
42(2), e16-e17.
Author URL.
2018
Grubb A, McDonald T, Rutters F, Donnelly L, Hattersley A, Oram R, Palmer C, van der Heijden A, Carr F, Elders P, et al (2018). A Type 1 Diabetes Genetic Risk Score can Identify Patients with GAD65 Autoantibody–Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy. Diabetes Care
Johnson MBJ, Patel K, De Franco E, Houghton J, McDonald T, Ellard S, Flanagan S, Hattersley A (2018). A Type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early onset clustering of polygenic autoimmunity with diabetes. Diabetologia
Grubb AL, Donnelly LA, Slieker RC, McDonald TJ, Rutters F, 't Hart LM, Pearson ER, Hattersley AT, Shields BM, Jones AG, et al (2018). A Type 1 diabetes genetic risk score can identify patients with glutamic acid decarboxylase (GAD) antibody-positive Type 2 diabetes with and without rapid progression to insulin therapy.
Author URL.
Knight AR, Taylor EL, Lukaszewski R, Winyard PG (2018). A high-sensitivity electrochemiluminescence-based ELISA for the measurement of the oxidative stress biomarker, 3-nitrotyrosine, in human blood serum and cells. Free Radical Biology and Medicine
Shields B, McDonald T, Oram R, Hill A, Hudson M, Leete P, Pearson E, Richardson S, Morgan N, Hattersley A, et al (2018). C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care
Jones AG, McDonald TJ (2018). Comment on: "Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): a post-hoc analysis of the AWARD-2, -4 and -5 trials".
Diabetes Obes Metab,
20(6), 1549-1550.
Author URL.
Dawed AY, Mari A, McDonald TJ, Robertson NR, Mahajan A, Walker M, Gough S, Zhou K, Forgie I, Ruetten H, et al (2018). Common variants in the GLP-1 receptor are associated with glycaemic response to GLP-1 receptor agonists in observational and large RCT data: an IMI-DIRECT study.
Author URL.
Grubb AL, Patel K, Oram RA, Hill AV, Angwin C, McDonald TJ, Weedon MN, Hattersley AT, Owen KR, Shields BM, et al (2018). Development and validation of a clinical prediction model to identify adult patients (aged 18-50) with type 1 diabetes requiring early insulin therapy.
Author URL.
Mcdonald TJ, Flanagan SE, Knight B (2018). Differential diagnosis of hyperglycaemia at day five of life: Implications for a new born screening programme.
Author URL.
Bowman P, Shepherd MH, McDonald TJ, Andrews RC, Spaull SR, Statton S, Hammersley S, Leveridge M, Shields BM, Flanagan SE, et al (2018). Excess insulin secretion with a high protein meal in sulphonylurea treated KCNJ11 neonatal diabetes patients shows the limitations of amplifying insulin secretion pathways.
Author URL.
Clissold RL, Fulford J, Hudson M, Shields BM, McDonald TJ, Ellard S, Hattersley AT, Bingham C (2018). Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic.
Clin Kidney J,
11(4), 453-458.
Abstract:
Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic.
BACKGROUND: Heterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. METHODS: Faecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 μg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n = 6) underwent pancreatic imaging. RESULTS: Faecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at
Abstract.
Author URL.
Walker GJ, Moore L, Heerasing N, Hendy P, Perry MH, McDonald TJ, Debenham T, Bethune R, Bewshea C, Hyde C, et al (2018). Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study.
Aliment Pharmacol Ther,
47(8), 1103-1116.
Abstract:
Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study.
BACKGROUND: Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms. AIMS: We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs. METHODS: We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of ≥100 μg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. RESULTS: Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and £160 per patient. CONCLUSIONS: Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs.
Abstract.
Author URL.
Dawed AY, Mari A, McDonald TJ, Hong M-G, Sharma S, Robertson NR, Mahajan A, Walker M, Gough S, Zhou K, et al (2018). GLP-1 RECEPTOR VARIANTS MARKEDLY DIFFERENTIATE GLYCAEMIC RESPONSE TO GLP-1 RECEPTOR AGONISTS: a DIRECT STUDY.
Author URL.
MCKEIGUE P, SPILIOPOULOU A, MCGURNAGHAN S, COLOMBO M, MCDONALD TJ, COLHOUN H (2018). Genotypic Associations with C-Peptide Persistence in People with Type 1 Diabetes. Diabetes, 67(Supplement_1).
Perry MH, McDonald TJ (2018). Method Comparison Between ELISAs Suggests Therapeutic Ranges for Infliximab Should be Assay-Specific.
J Appl Lab Med,
3(3), 515-517.
Author URL.
Oram RA, McDonald TJ, Sabbah S, Bloem S, Shields B, Hill A, Bolt R, Begom S, Khatri L, Tree T, et al (2018). Older age of diagnosis is the major feature of persistent long term endogenous insulin secretion in type 1 diabetes.
Author URL.
Dennis J, Shields B, Hill A, Knight B, McDonald T, Rodgers L, Weedon M, Henley W, Sattar N, Holman R, et al (2018). Precision medicine in Type 2 diabetes: Clinical markers of insulin resistance are associated with altered short- and long-term glycemic response to DPP-4 inhibitor therapy. Diabetes Care
Shakweh EY, Shields BM, Angwin CD, Rodgers LR, McDonald TJ, Pearson ER, Hattersley AT, Jones AG, Consortium M (2018). Precision medicine in Type 2 diabetes: is variation in response to sitagliptin and gliclazide therapy related to drug levels?.
Author URL.
Marren SM, Hammersley S, Knight B, Bolt R, Hill A, Hattersley AT, McDonald TJ, Jones AG, Oram RA (2018). Preserved beta cell function in long-duration Type 1 diabetes is associated with markedly lower hypoglycaemia and insulin dose but no improvements in HbA1c, suggesting the need to intensify therapy.
Author URL.
Tippett PW, Hill AV, McDonald TJ, Hattersley AT, Jones AG (2018). Prevalence and clinical associations of ZnT8 islet autoantibodies in the first year of adult diabetes.
Author URL.
Oram RA, Hammersley S, Knight BA, Bolt R, Hill A, Jones AG, Hattersley AT, McDonald TJ (2018). Proinsulin measurement suggests persistent beta cells even in those with undetectable c-peptide in long-duration Type 1 diabetes: Evidence for disordered insulin processing.
Author URL.
Huber JW, Fox C, Hill A, McDonald T, Shields B, Jones A (2018). Psychological resilience in Type 1 diabetes carries independent benefits for blood glucose control.
Author URL.
Colombo M, McDonald TJ, McKeigue PM, Colhoun HM, Investigators SDRNTBIO (2018). Relationship of C-peptide persistence and HbA(1c) in type 1 diabetes.
Author URL.
Leete P, Oram R, McDonald TJ, Ziller C, Shields B, Hattersley AT, Richardson SJ, Morgan NG, Team TTS, Team TTS, et al (2018). Studies of insulin-related peptides in pancreas and plasma support the existence of two distinct aetiological subtypes of type 1 diabetes associated with age at diagnosis.
Author URL.
Teare HJA, de Masi F, Banasik K, Barnett A, Herrgard S, Jablonka B, Postma JWM, McDonald TJ, Forgie I, Chmura PJ, et al (2018). The governance structure for data access in the DIRECT consortium: an innovative medicines initiative (IMI) project.
Life Sci Soc Policy,
14(1).
Abstract:
The governance structure for data access in the DIRECT consortium: an innovative medicines initiative (IMI) project.
Biomedical research projects involving multiple partners from public and private sectors require coherent internal governance mechanisms to engender good working relationships. The DIRECT project is an example of such a venture, funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU). This paper describes the data access policy that was developed within DIRECT to support data access and sharing, via the establishment of a 3-tiered Data Access Committee. The process was intended to allow quick access to data, whilst enabling strong oversight of how data were being accessed and by whom, and any subsequent analyses, to contribute to the overall objectives of the consortium.
Abstract.
Author URL.
Yaghootkar H, Patel K, Colclough K, Moleirinho A, Ghaemi N, Heidari S, Vakili S, Enayati S, Rabbani A, Abbasi F, et al (2018). Type 1 diabetes genetic risk score discriminates between monogenic and type 1 diabetes in patients with diabetes presented below five years of age in Iranian population.
Author URL.
Thomas N, Grubb A, McDonald T, Hill A, Weedon M, Oram R, Hattersley A, Jones A (2018). Type 1 diabetes leading to severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes in clinical practice.
DIABETOLOGIA,
61, S152-S152.
Author URL.
Chan TYH, Patel K, Colclough K, Hattersley AT, McDonald TJ (2018). Zinc transporter 8 autoantibody is comparable to established autoantibodies in excluding patients for genetic analysis in Maturity Onset Diabetes of the Young (MODY).
Author URL.
2017
Hammersley SE, Bolt RL, Hill AV, McDonald TJ, Oram RA, Hattersley AT (2017). A novel patient focused approach enables study participation and aids recruitment rate in Type 1 diabetes research.
Author URL.
McDonald T (2017). AIDS to correct genetic diagnosis in mody: being smarter with laboratory medicine. Pathology, 49
Oram RA, Leete P, Shields B, Richardson S, Hill A, McDonald T, Morgan N, Hattersley A (2017). C-peptide measurements support the existence of two distinct subtypes of Type 1 diabetes as defined by pancreatic immunopathology.
Author URL.
Dennis JM, Shields BM, Henley WE, Knight BA, McDonald TJ, Hill AV, Weedon MN, Rodgers LR, Hattersley AT, Jones AG, et al (2017). Clinical markers of insulin resistance predict reduced glycaemic response with DPP4-inhibitors: a MASTERMIND stratified medicine study.
Author URL.
Shields B, Richardson S, Oram R, Leete P, Hill A, McDonald T, Morgan N, Hattersley A (2017). Cross-sectional c-peptide data and histological analysis of pancreas samples suggest two phases of beta cell decline in Type 1 diabetes.
Author URL.
Chakera AJ, McDonald TJ, Knight BA, Vaidya B, Jones AG (2017). Current laboratory requirements for adrenocorticotropic hormone and renin/aldosterone sample handling are unnecessarily restrictive.
Clin Med (Lond),
17(1), 18-21.
Abstract:
Current laboratory requirements for adrenocorticotropic hormone and renin/aldosterone sample handling are unnecessarily restrictive.
Samples for adrenocorticotropic hormone (ACTH) and aldosterone/renin analysis usually require rapid transport to the receiving laboratory for immediate separation and freezing. In practice, this means assessment is limited to hospital settings and many samples are rejected. We examined whether these requirements are necessary by assessing the stability of ACTH, aldosterone and renin over 48 hours in whole blood collected in serum gel and EDTA plasma from 31 participants. Our results show that ACTH collected into EDTA plasma is stable at room temperature for at least 6 hours, mean change at 6 hours -2.6% (95% CI -9.7 to 4.5). Both aldosterone and renin were stable collected on serum gel at room temperature for at least 6 hours: mean change aldosterone +0.2% (95% CI -3.6 to 4.0), renin -1.9% (95% CI -7.0 to3.2). Therefore, by using appropriate preservatives, ACTH and aldosterone/renin can be measured on samples collected at room temperature and processed within 6 hours. This would facilitate outpatient and emergency room assessment of these analytes.
Abstract.
Author URL.
Grubb AL, Patel KA, Oram RA, Hill AV, Angwin C, McDonald TJ, Weedon MN, Hattersley AT, Shields BV, Jones AG, et al (2017). Development of a risk calculator to identify patients with Type 1 diabetes who will require early insulin therapy.
Author URL.
Dawed AY, Mari A, McDonald TJ, Hong MG, Sharma S, Robertson NR, Mahajan A, Walker M, Gough S, Zhou K, et al (2017). GLP-1 receptor variants markedly differentiate glycaemic response to GLP-1 receptor agonists: a DIRECT study.
Author URL.
McDonald T (2017). Heterogeneity of type 1 diabetes. Pathology, 49
McDonald T (2017). Neonatal biochemistry: advances in neonatal diabetes. Pathology, 49
Shields B, Shepherd M, Hudson M, McDonald T, Colclough K, Peters J, Knight B, Hyde C, Ellard S, Pearson E, et al (2017). Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients. Diabetes Care
Davidson J, McDonald T, Sutherland C, Mostazir M, VanAalten L, Wilkin T (2017). Proinsulin is stable at room temperature for 24 hours in EDTA: a clinical laboratory analysis (adAPT 3).
PLoS One,
12(4).
Abstract:
Proinsulin is stable at room temperature for 24 hours in EDTA: a clinical laboratory analysis (adAPT 3).
AIMS: Reference laboratories advise immediate separation and freezing of samples for the assay of proinsulin, which limit its practicability for smaller centres. Following the demonstration that insulin and C-peptide are stable in EDTA at room temperature for at least 24hours, we undertook simple stability studies to establish whether the same might apply to proinsulin. METHODS: Venous blood samples were drawn from six adult women, some fasting, some not, aliquoted and assayed immediately and after storage at either 4°C or ambient temperature for periods from 2h to 24h. RESULTS: There was no significant variation or difference with storage time or storage condition in either individual or group analysis. CONCLUSION: Proinsulin appears to be stable at room temperature in EDTA for at least 24h. Immediate separation and storage on ice of samples for proinsulin assay is not necessary, which will simplify sample transport, particularly for multicentre trials.
Abstract.
Author URL.
Hope SV, Knight BA, Shields BM, Hill A, Choudhary P, Strain WD, Hattersley AT, McDonald TJ, Jones G (2017). RANDOM NON-FASTING C-PEPTIDE CAN BE USED AS a RISK ASSESSMENT TOOL FOR HYPOGLYCAEMIA IN ELDERLY NSULIN-TREATED PATIENTS WITH TYPE 2 DIABETES.
Author URL.
Hope SV, Knight BA, Shields BM, Hill AV, Choudhary P, Strain WD, McDonald TJ, Jones AG (2017). Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia. Diabetologia
McDonald TJ, Besser RE, Perry M, Babiker T, Knight BA, Shepherd MH, Ellard S, Flanagan SE, Hattersley AT (2017). Screening for neonatal diabetes at day 5 of life using dried blood spot glucose measurement.
Diabetologia,
60(11), 2168-2173.
Abstract:
Screening for neonatal diabetes at day 5 of life using dried blood spot glucose measurement
Aims/hypothesis: the majority of infants with neonatal diabetes mellitus present with severe ketoacidosis at a median of 6 weeks. The treatment is very challenging and can result in severe neurological sequelae or death. The genetic defects that cause neonatal diabetes are present from birth. We aimed to assess if neonatal diabetes could be diagnosed earlier by measuring glucose in a dried blood spot collected on day 5 of life. Methods: in this retrospective case–control study we retrieved blood spot cards from 11 infants with genetically confirmed neonatal diabetes (median age of diagnosis 6 [range 2–112] days). For each case we also obtained one (n = 5) or two (n = 6) control blood spot cards collected on the same day. Glucose was measured on case and control blood spot cards. We established a normal range for random glucose at day 5 of life in 687 non-diabetic neonates. Results: all 11 neonates with diabetes had hyperglycaemia present on day 5 of life, with blood glucose levels ranging from 10.2 mmol/l to >30 mmol/l (normal range 3.2–6.0 mmol/l). In six of these neonates the diagnosis of diabetes was made after screening at day 5, with the latest diagnosis made at 16 weeks. Conclusions/interpretation: Neonatal diabetes can be detected on day 5 of life, preceding conventional diagnosis in most cases. Earlier diagnosis by systematic screening could lead to prompt genetic diagnosis and targeted treatment, thereby avoiding the most severe sequelae of hyperglycaemia in neonates.
Abstract.
Shepherd M, Colclough K, McDonald TJ (2017). Tests aiding diagnosis of monogenic diabetes. Practical Diabetes, 34(6), 217-220a.
McDonald T (2017). The sequencer will see you now: getting the correct genetic diagnosis in maturity onset diabetes of the young. Pathology, 49
2016
Oram RA, Patel K, Hill A, Shields B, McDonald TJ, Jones A, Hattersley AT, Weedon MN (2016). A Type 1 Diabetes Genetic Risk Score can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.
Diabetes Care,
39(3), 337-344.
Abstract:
A Type 1 Diabetes Genetic Risk Score can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.
OBJECTIVE: with rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes. RESEARCH DESIGN AND METHODS: We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency 0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (
Abstract.
Author URL.
Perry M, O'Connor J, James AJ, Cudmore AP, Lewis AV, Salzmann MB, McDonald TJ (2016). A cautionary tale: Unforeseen consequences of lean processing in a blood sciences laboratory.
Clin Biochem,
49(16-17), 1311-1312.
Author URL.
Juszczak A, James TJ, McDonald TJ, Vaxillaire M, Klimes I, Malecki MT, Hansen T, Njolstad PR, Tuomi T, Gloyn AL, et al (2016). Assessing the likely function of HNF1A missense variants using CRP and allele frequency data.
Author URL.
Williams GM, Long AE, Wilson IV, Aitken RJ, Wyatt RC, McDonald TJ, Wong FS, Hattersley AT, Williams AJK, Bingley PJ, et al (2016). Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes.
Diabetologia,
59(12), 2722-2726.
Abstract:
Beta cell function and ongoing autoimmunity in long-standing, childhood onset type 1 diabetes.
AIMS/HYPOTHESIS: This study aimed to determine the frequency of residual beta cell function in individuals with long-standing type 1 diabetes who were recruited at diagnosis, and relate this to baseline and current islet autoantibody profile. METHODS: Two hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants (median age at diagnosis: 11.7 years; 47% male), a median of 23 years (range 12-29 years) after diagnosis. UCPCR thresholds equivalent to mixed meal-stimulated serum C-peptide >0.001 nmol/l, ≥0.03 nmol/l and ≥0.2 nmol/l were used to define 'detectable', 'minimal' and 'residual/preserved') endogenous insulin secretion, respectively. Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were measured by radioimmunoassay. RESULTS: Endogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%). In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%). The level of UCPCR was related to age at diagnosis (p = 0.002) and was independent of diabetes duration, and baseline or current islet autoantibody status. CONCLUSIONS/INTERPRETATION: There is evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes. Endogenous insulin secretion continues for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5. These findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.
Abstract.
Author URL.
Patel KA, Oram RA, Mcdonald TJ, Hudson M, Colclough K, Ellard S, Weedon MN, Pearson EZ, Hattersley AT (2016). Classifying the unclassified using Type 1 diabetes genetic risk score: patients with young onset diabetes who are islet autoantibody negative and have preserved c-peptide.
Author URL.
McDonald TJ, Perry MH (2016). Detection of C-Peptide in Urine as a Measure of Ongoing Beta Cell Function.
Methods Mol Biol,
1433, 93-102.
Abstract:
Detection of C-Peptide in Urine as a Measure of Ongoing Beta Cell Function.
C-peptide is a protein secreted by the pancreatic beta cells in equimolar quantities with insulin, following the cleavage of proinsulin into insulin. Measurement of C-peptide is used as a surrogate marker of endogenous insulin secretory capacity. Assessing C-peptide levels can be useful in classifying the subtype of diabetes as well as assessing potential treatment choices in the management of diabetes.Standard measures of C-peptide involve blood samples collected either fasted or, most often, after a fixed stimulus (such as oral glucose, mixed meal, or IV glucagon). Despite the established clinical utility of blood C-peptide measurement, its widespread use is limited. In many instances this is due to perceived practical restrictions associated with sample collection.Urine C-peptide measurement is an attractive noninvasive alternative to blood measures of beta-cell function. Urine C-peptide creatinine ratio measured in a single post stimulated sample has been shown to be a robust, reproducible measure of endogenous C-peptide which is stable for three days at room temperature when collected in boric acid. Modern high sensitivity immunoassay technologies have facilitated measurement of C-peptide down to single picomolar concentrations.
Abstract.
Author URL.
Dawed AY, Jones AG, McDonald TJ, Walker M, Mari A, Franks PW, Pearson ER, Project IMI-DIRECT (2016). Determinants of glucagon secretion in prediabetes and recently diagnosed type 2 diabetes: an IMI-DIRECT study.
Author URL.
Seelig E, Timper K, Falconnier C, Stoeckli R, Bilz S, Oram R, McDonald TJ, Donath MY (2016). Interleukin-1 antagonism in type 1 diabetes of long duration.
Diabetes Metab,
42(6), 453-456.
Author URL.
Oram RA, Hammersley S, Hill A, Shields B, Hattersley A, McDonald T (2016). Longitudinal study of extremely low c-peptide: evidence for persistent beta cells in all people with Type 1 diabetes.
Author URL.
Johnson MB, Flanagan SE, Martins TB, Hill HR, Hattersley AT, McDonald TJ (2016). Low IgE is a Useful Tool to Identify STAT3 Gain-of-Function Mutations.
Clin Chem,
62(11), 1536-1538.
Author URL.
McDonald TJ, Besser REJ, Perry MH, Babiker T, Hattersley AT (2016). Newborn screening by blood spot glucose can diagnose neonatal diabetes at day 5 of life.
DIABETIC MEDICINE,
33, 73-73.
Author URL.
Hope SV, Knight BA, Shields BM, Hattersley AT, McDonald TJ, Jones AG (2016). Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic.
Diabet Med,
33(11), 1554-1558.
Abstract:
Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic.
BACKGROUND: Measuring endogenous insulin secretion using C-peptide can assist diabetes management, but standard stimulation tests are impractical for clinical use. Random non-fasting C-peptide assessment would allow testing when a patient is seen in clinic. METHODS: We compared C-peptide at 90 min in the mixed meal tolerance test (sCP) with random non-fasting blood C-peptide (rCP) and random non-fasting urine C-peptide creatinine ratio (rUCPCR) in 41 participants with insulin-treated diabetes [median age 72 (interquartile range 68-78); diabetes duration 21 (14-31) years]. We assessed sensitivity and specificity for previously reported optimal mixed meal test thresholds for severe insulin deficiency (sCP < 200 pmol//l) and Type 1 diabetes/inability to withdraw insulin (< 600 pmol//l), and assessed the impact of concurrent glucose. RESULTS: rCP and sCP levels were similar (median 546 and 487 pmol//l, P = 0.92). rCP was highly correlated with sCP, r = 0.91, P < 0.0001, improving to r = 0.96 when excluding samples with concurrent glucose < 8 mmol//l. An rCP cut-off of 200 pmol//l gave 100% sensitivity and 93% specificity for detecting severe insulin deficiency, with area under the receiver operating characteristic curve of 0.99. rCP < 600 pmol//l gave 87% sensitivity and 83% specificity to detect sCP < 600 pmol//l. Specificity improved to 100% when excluding samples with concurrent glucose < 8 mmol//l. rUCPCR (0.52 nmol/mmol) was also well-correlated with sCP, r = 0.82, P < 0.0001. A rUCPCR cut-off of < 0.2 nmol/ mmol gave sensitivity and specificity of 83% and 93% to detect severe insulin deficiency, with area under the receiver operating characteristic curve of 0.98. CONCLUSIONS: Random non-fasting C-peptide measures are strongly correlated with mixed meal C-peptide, and have high sensitivity and specificity for identifying clinically relevant thresholds. These tests allow assessment of C-peptide at the point patients are seen for clinical care.
Abstract.
Author URL.
Hope SV, Knight BA, Shields BM, Hattersley AT, McDonald TJ, Jones AG (2016). Random non-fasting c-peptide provides an accurate measure of endogenous insulin secretion for clinical practice.
Author URL.
Umapathysivam MM, McDonald T, Humphreys S, Neville M, Gloyn AL, McCarthy MI, Hattersley AT, Karpe F, Frayling TM (2016). Strategies for improving statistical power for detailed physiological characterisation of individuals with type 2 diabetes-associated variants.
Author URL.
Peters JL, Anderson R, Shields BM, King S, Hudson M, Shepherd M, McDonald TJ, Pearson E, Hattersley AT, Hyde C, et al (2016). Strategies to identify individuals with MODY: results of a health economic model.
Author URL.
Shepherd M, Shields B, Hammersley S, Hudson M, McDonald TJ, Colclough K, Oram RA, Knight B, Hyde C, Cox J, et al (2016). Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population with Monogenic Diabetes.
Diabetes Care,
39(11), 1879-1888.
Abstract:
Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population with Monogenic Diabetes.
OBJECTIVE: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing. RESEARCH DESIGN AND METHODS: We studied 808 patients (79.5% of the eligible population)
Abstract.
Author URL.
Craig ZV, Hill AV, McDonald TJ, Hattersley AT, Jones AG, Shields BM (2016). Time to change the HbA1c cut-off for prediabetes.
Author URL.
2015
Oram RA, Hill A, Mcdonald TJ, Patel KA, Jones AG, Hattersley AT, Weedon MN (2015). 3. A Novel, Inexpensive Test can Discriminate between Type 1 and Type 2 Diabetes (1745-P). Nederlands Tijdschrift voor Diabetologie, 13(3), 57-57.
Weedon MN, Hill AV, McDonald TJ, Patel KA, Jones A, Hattersley AT, Oram R (2015). A novel inexpensive test can discriminate between Type 1 and Type 2 diabetes.
Author URL.
Parfitt C, Church D, Armston A, Couchman L, Evans C, Wark G, McDonald TJ (2015). Commercial insulin immunoassays fail to detect commonly prescribed insulin analogues.
CLINICAL BIOCHEMISTRY,
48(18), 1354-1357.
Author URL.
Mcdonald TJ, Parfitt C, Armston A, Church D, Couchman L, Evans C, Wark G (2015). Commercial insulin immunoassays fail to detect commonly prescribed insulin analogues.
Author URL.
Veale DA, McCulloch RW, McDonald TJ, Cudmore A, Parfitt C, O'Connor J, Kerr JP (2015). Current use of nephelometric quantification of serum free light chains (FLCs) in the management of plasma cell dyscrasias, and the potential benefits of point-of-care testing.
Author URL.
Perry M, Bewshea C, Brown R, So K, Ahmad T, McDonald T (2015). Infliximab and adalimumab are stable in whole blood clotted samples for seven days at room temperature.
Ann Clin Biochem,
52(Pt 6), 672-674.
Abstract:
Infliximab and adalimumab are stable in whole blood clotted samples for seven days at room temperature.
INTRODUCTION: the biologic anti-tumour necrosis factor alpha (anti-TNFα) agents infliximab and adalimumab are monoclonal antibodies with binding specificity to TNFα, which are used for the treatment of Crohn's disease. Clinical response is varied from complete with mucosal healing, to primary non-response, loss of response and adverse drug reactions. Measuring trough blood levels of infliximab and adalimumab may guide clinical management. The sample handling requirements for infliximab and adalimumab were previously unknown. AIM: the aim of this study was to determine the in vitro stability of infliximab and adalimumab in samples stored for up to seven days at room temperature. METHODS: Samples were stored as clotted whole blood or serum at room temperature for up to seven days, before being frozen (-20℃) and analysed as a batch for either infliximab or adalimumab. RESULTS: No significant difference between the concentration of infliximab and adalimumab measured in samples stored as serum or whole blood for seven days at room temperature, as compared to baseline was found (t-test; infliximab: P = .35 [serum], P = .38 [whole blood]; adalimumab: P = .12 [serum], P = .49 [whole blood]). CONCLUSION: the stability of infliximab and adalimumab at room temperature for seven days allows samples to be posted direct from clinics and research centres to the analysing laboratory.
Abstract.
Author URL.
Jones AG, Hill AV, Bolt R, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2015). Insulin resistance and high fasting glucose are associated with reduced glycaemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy.
Author URL.
McDonald TJ, Oram RA, Vaidya B (2015). Investigating hyperkalaemia in adults.
BMJ,
351 Author URL.
Hope SV, McDonald TJ, Hill AV, Strain WD, Hattersley AT (2015). Low c-peptide is associated in insulin-treated patients with hypoglycaemia unawareness as well as hypoglycaemia frequency.
Author URL.
Oram RA, McDonald TJ, Shields BM, Hudson MM, Shepherd MH, Hammersley S, Pearson ER, Hattersley AT, UNITED Team (2015). Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors.
Diabetes Care,
38(2), 323-328.
Abstract:
Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors.
OBJECTIVE: Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS: We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS: Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS: This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment.
Abstract.
Author URL.
McDonald TJ, Oram RA, Vaidya B (2015). RATIONAL TESTING Investigating hyperkalaemia in adults.
BMJ-BRITISH MEDICAL JOURNAL,
351 Author URL.
Rodgers LR, Pearson ER, Angwin CD, Hammersley S, McDonald TJ, Shields BM, Hattersley AT, Jones AG, Consortium M (2015). Response to glucose lowering therapy can be assessed by a brief period of treatment withdrawal: a MASTERMIND study.
Author URL.
Espeland MA, Probstfield J, Hire D, Redmon JB, Evans GW, Coday M, Lewis CE, Johnson KC, Wilmoth S, Bahnson J, et al (2015). Systolic blood pressure control among individuals with type 2 diabetes: a comparative effectiveness analysis of three interventions.
American Journal of Hypertension,
28(8), 995-1009.
Abstract:
Systolic blood pressure control among individuals with type 2 diabetes: a comparative effectiveness analysis of three interventions
BACKGROUND the relative effectiveness of 3 approaches to blood pressure control- (i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. METHODS Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) 30 kg/m2, while frequent goal-based monitoring with medication management may be more effective among individuals with lower body mass index (interaction P = 0.047). CONCLUSIONS Among overweight and obese adults with type 2 diabetes, both ILI and frequent goal-based monitoring with pharmacological management can be successful strategies for blood pressure control. clinical trials registry clinicaltrials.gov identifiers NCT00017953 (Look AHEAD) and NCT00000620 (ACCORD).
Abstract.
Chapman DP, Gooding KM, McDonald TJ, Anning CM, Pamphilon N, Ball C, Casanova F, Shore AC (2015). Using clinical characteristics to account for variation of urinary creatinine excretion improves the accuracy of the albumin to creatinine ratio (ACR) to identify individuals with microalbuminuria.
Author URL.
2014
Oram RA, McDonald TJ, Shields BM, Pearson ER, Hattersley AT, Team UNITEDR (2014). A large, population-based study demonstrates that most people with long duration Type 1 diabetes are insulin microsecretors and produce their own endogenous insulin.
Author URL.
Flanagan SE, Haapaniemi E, Russell MA, McDonald TJ, Barton J, Murphy NP, Seppanen M, Milenkovic T, Heiskanen K, Lernmark A, et al (2014). A novel syndrome of early-onset type 1 diabetes and multi-organ autoimmunity caused by activating germline mutations in STAT3.
Author URL.
Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, McDonald TJ, Rajala H, Ramelius A, Barton J, et al (2014). Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Nat Genet,
46(8), 812-814.
Abstract:
Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.
Abstract.
Author URL.
Shields BM, Hudson M, Shepherd M, Oram R, McDonald TJ, Ellard S, Pearson ER, Hattersley AT, Team UNITED (2014). Comparison of screening using clinical criteria and biomarkers to identify maturity-onset diabetes of the young (MODY) in a community based setting.
Author URL.
Jones AG, Shields BM, Hill AV, McDonald TJ, Knight BA, Hattersley AT (2014). Defining good response to glucose lowering therapy: different definitions identify different individuals and associated characteristics.
Author URL.
McDonald TJ, Warren RE (2014). Diagnostic confusion? Repeat HbA1c for the diagnosis of diabetes.
DIABETIC MEDICINE,
31, 72-72.
Author URL.
McDonald TJ, Warren R (2014). Diagnostic confusion? Repeat HbA1c for the diagnosis of diabetes.
Author URL.
Koivula RW, Heggie A, Barnett A, Cederberg H, Hansen TH, Koopman AD, Ridderstråle M, Rutters F, Vestergaard H, Gupta R, et al (2014). Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: Rationale and design of the epidemiological studies within the IMI DIRECT Consortium.
Diabetologia,
57(6), 1132-1142.
Abstract:
Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: Rationale and design of the epidemiological studies within the IMI DIRECT Consortium
Aims/hypothesis: the DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT. Methods: Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires. Conclusions/interpretation: DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes. © 2014 the Author(s).
Abstract.
Koivula RW, Heggie A, Barnett A, Cederberg H, Hansen TH, Koopman AD, Ridderstråle M, Rutters F, Vestergaard H, Gupta R, et al (2014). Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium. Diabetologia
Jones AG, McDonald TJ, Hattersley AT, Shields BM (2014). Effect of the holiday season in patients with diabetes: Glycemia and lipids increase postholiday, but the effect is small and transient. Diabetes Care, 37(5).
Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ (2014). Erratum to: the majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells.
Diabetologia,
57(1).
Author URL.
Myngheer N, Allegaert K, Hattersley A, McDonald T, Kramer H, Ashcroft FM, Verhaeghe J, Mathieu C, Casteels K (2014). Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes.
Diabetes Care,
37(12), 3333-3335.
Abstract:
Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes.
OBJECTIVE: Sulfonylureas (SUs) are effective at controlling glycemia in permanent neonatal diabetes mellitus (PNDM) caused by KCNJ11 (Kir6.2) mutations. RESEARCH DESIGN AND METHODS: We report the case of a woman with PNDM who continued high doses of glibenclamide (85 mg/day) during her pregnancy. The baby was born preterm, and presented with macrosomia and severe hyperinsulinemic hypoglycemia requiring high-rate intravenous glucose infusion. RESULTS: Postnatal genetic testing excluded a KCNJ11 mutation in the baby. Glibenclamide was detected in both the baby's blood and the maternal milk. CONCLUSIONS: We hypothesize that high doses of glibenclamide in the mother led to transplacental passage of the drug and overstimulation of fetal β-cells, which resulted in severe hyperinsulinemic hypoglycemia in the neonate (who did not carry the mutation) and contributed to fetal macrosomia. We suggest that glibenclamide (and other SUs) should be avoided in mothers with PNDM if the baby does not carry the mutation or if prenatal screening has not been performed, while glibenclamide may be beneficial when the fetus is a PNDM carrier.
Abstract.
Author URL.
Babiker T, Perry M, McDonald T, Brooke A, O'Connor J (2014). High testosterone? Look again!. Endocrine Abstracts
Oram RA, Brooks AM, Forbes S, Eckoldt S, Smith RM, Choudhary P, Rosenthal MJ, Johnson P, Rutter MK, Burling KA, et al (2014). Home urine C-peptide creatinine ratio can be used to monitor islet transplant function.
Diabetes Care,
37(6), 1737-1740.
Abstract:
Home urine C-peptide creatinine ratio can be used to monitor islet transplant function.
OBJECTIVE: Islet graft function is defined by serum C-peptide in a standardized challenge test. We assessed whether urine C-peptide creatinine ratio (UCPCR) sent from home could provide a viable alternative. RESEARCH DESIGN AND METHODS: Seventeen islet recipients provided 90-min serum C-peptide (sCP90) and 120-min UCPCR (UCPCR120) samples during 68 interval posttransplant mixed-meal tolerance tests, also posting from home a 120-min postbreakfast UCPCR sample every 2 weeks. UCPCR was compared with a clinical score of islet function, derived from HbA1c and insulin dose. RESULTS: UCPCR120 and mean home postmeal UCPCR were strongly correlated with sCP90 (r(s) = 0.73, P < 0.001; and rs = 0.73, P < 0.01, respectively). Mean home UCPCR increased with clinical score (r(s) = 0.75; P < 0.001) and with graft function defined both by sCP90 >200 pmol/L and insulin independence. UCPCR cutoffs to detect insulin independence and poor graft function were sensitive and specific. CONCLUSIONS: Home UCPCR provides a valid measure of C-peptide production in islet transplant recipients.
Abstract.
Author URL.
Jones AG, McDonald TJ, Hill AV, Stewart J, Shields BM, Knight BA, Hattersley AT (2014). Markers of beta cell failure are associated with reduced glycaemic response to GLP-1 agonists in Type 2 diabetes.
Author URL.
McDonald TJ, Oram R, Shields B, Pearson E, Hattersley A (2014). Most people with long duration of type 1 diabetes are insulin microsecretors and produce their own endogenous insulin.
Author URL.
Shepherd M, Shields B, Knight B, Weinand-Barnett S, Fox CJ, McDonald TJ, Hattersley AT (2014). Patients with Type 2 diabetes treated with analogue insulin require 40% more insulin to achieve the same level of HbA1c than those on non-analogue insulin.
Author URL.
Aitken RJ, Wilson IV, Long AE, Williams AJK, McDonald TJ, Gillespie KM, Wong FS, Hattersley AT, Bingley PJ (2014). Residual beta cell function in long-standing childhood onset Type 1 diabetes.
DIABETIC MEDICINE,
31, 19-20.
Author URL.
Bingley PJ, Aitken RJ, Wilson IV, Long AE, Williams AJK, McDonald T, Wong S, Hattersley AT, Gillespie KM (2014). Residual beta cell function in long-standing childhood onset type 1 diabetes.
Author URL.
Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, Oram RA, Shields BM, Shepherd M, Inward CD, et al (2014). The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
J Med Genet,
51(3), 165-169.
Abstract:
The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
BACKGROUND: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. METHODS AND RESULTS: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. CONCLUSIONS: the HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
Abstract.
Author URL.
Thong KY, Mcdonald TJ, Hattersley AT, Blann AD, Ramtoola S, Duncan C, Carr S, Adamson K, Nayak AU, Khurana R, et al (2014). The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study.
Diabetic Medicine,
31(4), 403-411.
Abstract:
The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study
Aims: the response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous β-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response. Methods: a single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 → 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown. Results: One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, r = -0.17, P = 0.17 and r = -0.20, P = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change (P = 0.048 and P = 0.040, respectively). Mean (sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) (P = 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) (P = 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) (P = 0.002) and -12±17 mmol/mol (-1.1±1.6%) (P=0.016), respectively. Conclusions: Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response. © 2013 Diabetes UK.
Abstract.
Oram RA, Jones AG, Besser REJ, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ (2014). The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells.
Diabetologia,
57(1), 187-191.
Abstract:
The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells
Aims/hypothesis: Classically, type 1 diabetes is thought to proceed to absolute insulin deficiency. Recently developed ultrasensitive assays capable of detecting C-peptide under 5 pmol/l now allow very low levels of C-peptide to be detected in patients with long-standing type 1 diabetes. It is not known whether this low-level endogenous insulin secretion responds to physiological stimuli. We aimed to assess how commonly low-level detectable C-peptide occurs in long-duration type 1 diabetes and whether it responds to a meal stimulus. Methods: We performed a mixed-meal tolerance test in 74 volunteers with long-duration (>5 years) type 1 diabetes, i.e. with age at diagnosis 16 (9-23) years (median [interquartile range]) and diabetes duration of 30 (19-41) years. We assessed fasting and stimulated serum C-peptide levels using an electrochemiluminescence assay (detection limit 3.3 pmol/l), and also the urinary C-peptide:creatinine ratio (UCPCR). Results: Post-stimulation serum C-peptide was detectable at very low levels (>3.3 pmol/l) in 54 of 74 (73%) patients. In all patients with detectable serum C-peptide, C-peptide either increased (n = 43, 80%) or stayed the same (n = 11) in response to a meal, with no indication of levels falling (p < 0.0001). With increasing disease duration, absolute C-peptide levels fell although the numbers with detectable C-peptide remained high (68%, i.e. 25 of 37 patients with >30 years duration). Similar results were obtained for UCPCR. Conclusions/interpretation: Most patients with long-duration type 1 diabetes continue to secrete very low levels of endogenous insulin, which increase after meals. This is consistent with the presence of a small number of still functional beta cells and implies that beta cells are either escaping immune attack or undergoing regeneration. © 2013 the Author(s).
Abstract.
2013
Hudson MM, Shepherd M, Oram RA, McDonald TJ, Ellard S, Shields BM, Hattersley AT, Team UR (2013). A population-based approach to genetic testing defines the prevalence of maturity onset diabetes of the young (MODY) in patients with diabetes diagnosed under 30 years as 3%.
Author URL.
Jones AG, Hill AV, Stewart J, Githens-Mazer G, Shields BM, McDonald TJ, Knight BA, Hattersley AT (2013). Baseline HbA1c is the major clinical predictor of glycaemic response to incretin based agents in Type 2 diabetes.
Author URL.
Nowak N, Szopa M, Thanabalasingham G, McDonald TJ, Colclough K, Skupien J, James TJ, Kiec-Wilk B, Kozek E, Mlynarski W, et al (2013). Cystatin C is not a good candidate biomarker for HNF1A-MODY.
ACTA DIABETOLOGICA,
50(5), 815-820.
Author URL.
Clark P, McDonald T (2013). Diabetes Mellitus. In (Ed) The Immunoassay Handbook, 783-794.
Oram RA, Jones AG, Besser REJ, Knight BA, Shields BM, Brown RJ, Hattersley AT, McDonald TJ (2013). Erratum to: the majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia, 57(1), 262-262.
Besser REJ, Shields BM, Hammersley SE, Colclough K, McDonald TJ, Gray Z, Heywood JJN, Barrett TG, Hattersley AT (2013). Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.
Pediatr Diabetes,
14(3), 181-188.
Abstract:
Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.
BACKGROUND: Making the correct diabetes diagnosis in children is crucial for lifelong management. Type 2 diabetes and maturity onset diabetes of the young (MODY) are seen in the pediatric setting, and can be difficult to discriminate from type 1 diabetes. Postprandial urinary C-peptide creatinine ratio (UCPCR) is a non-invasive measure of endogenous insulin secretion that has not been tested as a diagnostic tool in children or in patients with diabetes duration
Abstract.
Author URL.
Flanagan SE, MacKay DJG, Greeley SAW, McDonald TJ, Mericq V, Hassing J, Richmond EJ, Martin WR, Acerini C, Kaulfers AM, et al (2013). Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: Expanding the clinical phenotype. Diabetologia, 56(1), 218-221.
Flanagan SE, Mackay DJG, Greeley SAW, McDonald TJ, Mericq V, Hassing J, Richmond EJ, Martin WR, Acerini C, Kaulfers AM, et al (2013). Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype.
Diabetologia,
56(1), 218-221.
Author URL.
Oram RA, McDonald TJ, Vaidya B (2013). Investigating hypokalaemia.
BMJ,
347 Author URL.
Jones AG, Hill AV, Stewart J, Shields BM, McDonald TJ, Knight BA, Hattersley AT (2013). Markers of insulin resistance and beta cell function do not predict response to incretin based treatments in type 2 diabetes.
Author URL.
McDonald TJ, Ellard S (2013). Maturity onset diabetes of the young: identification and diagnosis.
Ann Clin Biochem,
50(Pt 5), 403-415.
Abstract:
Maturity onset diabetes of the young: identification and diagnosis.
Maturity-onset diabetes of the young (MODY) is a monogenic disorder that results in a familial, young-onset non-insulin dependent form of diabetes, typically presenting in lean young adults before 25 years. Approximately 1% of diabetes has a monogenic cause but this is frequently misdiagnosed as Type 1 or Type 2 diabetes. A correct genetic diagnosis is important as it often leads to improved treatment for those affected with diabetes and enables predictive genetic testing for their asymptomatic relatives. An early diagnosis together with appropriate treatment is essential for reducing the risk of diabetic complications in later life. Mutations in the GCK and HNF1A/4 A genes account for up to 80% of all MODY cases. Mutations in the GCK gene cause a mild, asymptomatic and non-progressive fasting hyperglycaemia from birth usually requiring no treatment. In contrast, mutations in the genes encoding the transcription factors HNF1A and HNF4A cause a progressive insulin secretory defect and hyperglycaemia that can lead to vascular complications. The diabetes in these patients is usually well controlled with sulphonylurea tablets although insulin treatment may be required in later life. In this review, we outline the key clinical and laboratory characteristics of the common and rarer causes of MODY with the aim of raising awareness of this condition amongst health-care scientists.
Abstract.
Author URL.
Steele AM, Wensley KJ, Brewer E, Shields BM, Hattersley AT, McDonald TJ (2013). Preanalytical sample handling of venous blood: How to ensure your glucose measurement is accurate and reliable.
Practical Diabetes,
30(3), 128-131.
Abstract:
Preanalytical sample handling of venous blood: How to ensure your glucose measurement is accurate and reliable
Measurement of blood glucose is a standard biochemical test requiring optimum preanalytical sample handling. Glucose measured in plasma from tubes containing sodium fluoride is recommended but serum from serum-gel tubes may be used in research situations. To help inform best practice, we assessed glucose stability in plasma and serum samples subjected to different preanalytical conditions. Fasting samples were taken from 10 non-diabetic volunteers into fluoride/EDTA and serum-gel tubes. Whole blood samples were pipetted into aliquots, placed on crushed ice or left at room temperature. Aliquots were centrifuged at 0, 2, 12, 24, and 48 hours. When neither ice nor centrifuge were available, plasma glucose was stable for 48 hours (96% of baseline); serum glucose degraded to 8% of baseline. When centrifuged and left at room temperature, plasma glucose was stable for 48 hours (101% of baseline) but, by 24 hours, serum glucose had fallen (94% of baseline). The result of un-centrifuged plasma on ice was stable (96% of baseline) at 48 hours; serum glucose had dropped to 92% of baseline by 12 hours. Plasma glucose and serum glucose were constant for 48 hours when separated and placed on ice within 2 hours: plasma glucose 101% of baseline; serum glucose 100% of baseline. Separated serum resting on the serum plug fell to 94% of baseline by 12 hours at room temperature and to 92% of baseline by 48 hours on ice. Clinically, we recommend that glucose is measured on plasma taken from fluoride tubes. Analysis should be undertaken as soon as practicable. In the research setting, glucose can be measured on plasma or serum but samples must be centrifuged and chilled soon after venepuncture and analysed within 48 hours. Copyright © 2013 John Wiley & Sons.
Abstract.
Hammersley S, Oram R, Shepherd M, Moudiotis C, Fraser B, Mallam K, Cox J, Smith B, McDonald TJ, Besser REJ, et al (2013). Prevalence of non-Type 1 diabetes in paediatric diabetes.
Author URL.
Thong KY, Mcdonald TJ, Hattersley AT, Blann AD, Ramtoola S, Duncan C, Carr S, Adamson K, Nayak AU, Khurana R, et al (2013). The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study. Diabetic Medicine
Oram RA, McDonald TJ, Jones AG, Besser REJ, Hattersley AT (2013). The majority of patients with over five years of Type 1 diabetes are insulin microsecretors and have functioning beta cells.
Author URL.
Hope SV, Jones AG, Goodchild E, Shepherd M, Besser REJ, Shields B, Mcdonald T, Knight BA, Hattersley A (2013). Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
Diabetic Medicine,
30(11), 1342-1348.
Abstract:
Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes
Aims: to determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. Methods: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. Results: a total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide 0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m2, P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. Conclusions: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion. © 2013 the Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.
Abstract.
Hope SV, Jones AG, Goodchild E, Shepherd M, Besser REJ, Shields B, McDonald T, Knight BA, Hattersley A (2013). Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
Diabet Med,
30(11), 1342-1348.
Abstract:
Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes.
AIMS: to determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. METHODS: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. RESULTS: a total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide 0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m(2) , P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. CONCLUSIONS: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion.
Abstract.
Author URL.
Hope SV, Jones AG, Shepherd M, Shields B, Strain D, McDonald T, Knight BA, Hattersley AT (2013). Urinary C-peptide creatinine ratio to detect absolute insulin deficiency in type 2 diabetes.
Author URL.
Oram RA, Rawlingson A, Shields BM, Bingham C, Besser REJ, McDonald TJ, Knight BA, Hattersley AT (2013). Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study.
BMJ Open,
3(12).
Abstract:
Urine C-peptide creatinine ratio can be used to assess insulin resistance and insulin production in people without diabetes: an observational study.
OBJECTIVES: the current assessment of insulin resistance (IR) in epidemiology studies relies on the blood measurement of C-peptide or insulin. A urine C-peptide creatinine ratio (UCPCR) can be posted from home unaided. It is validated against serum measures of the insulin in people with diabetes. We tested whether UCPCR could be a surrogate measure of IR by examining the correlation of UCPCR with serum insulin, C-peptide and HOMA2 (Homeostasis Model Assessment 2)-IR in participants without diabetes and with chronic kidney disease (CKD). DESIGN: Observational study. SETTING: Single-centre clinical research facility. PARTICIPANTS: 37 healthy volunteers and 30 patients with CKD (glomerular filtration rate 15-60) were recruited. PRIMARY AND SECONDARY ENDPOINTS: Serum insulin, C-peptide and glucose at fasting (0), 30, 60, 90 and 120 min were measured during an oral glucose tolerance test (OGTT). Second-void fasting UCPCR and 120 min post-OGTT UCPCR were collected. HOMA2-IR was calculated using fasting insulin and glucose. The associations between UCPCR and serum measures were assessed using Spearman's correlations. RESULTS: in healthy volunteers, fasting second-void UCPCR strongly correlated with serum insulin (rs=0.69, p
Abstract.
Author URL.
Oram RA, Brooks AMS, Smith R, Rutter MK, Johnson PR, Choudhary P, Rosenthal M, Forbes S, McDonald TJ, Hattersley AT, et al (2013). Urine c-peptide creatinine ratio can be used for home monitoring of islet transplant function.
DIABETIC MEDICINE,
30, 87-87.
Author URL.
2012
Jones AG, Besser REJ, Shields BM, McDonald TJ, Hope SV, Knight BA, Hattersley AT (2012). Assessment of endogenous insulin secretion in insulin treated diabetes predicts postprandial glucose and treatment response to prandial insulin.
BMC Endocrine Disorders,
12Abstract:
Assessment of endogenous insulin secretion in insulin treated diabetes predicts postprandial glucose and treatment response to prandial insulin
Background: in patients with both Type 1 and Type 2 diabetes endogenous insulin secretion falls with time which changes treatment requirements, however direct measurement of endogenous insulin secretion is rarely performed. We aimed to assess the impact of endogenous insulin secretion on postprandial glucose increase and the effectiveness of prandial exogenous insulin.Methods: We assessed endogenous insulin secretion in 102 participants with insulin treated diabetes (58 Type 1) following a standardised mixed meal without exogenous insulin. We tested the relationship between endogenous insulin secretion and post meal hyperglycaemia. In 80 participants treated with fast acting breakfast insulin we repeated the mixed meal with participants' usual insulin given and assessed the impact of endogenous insulin secretion on response to exogenous prandial insulin.Results: Post meal glucose increment (90 minute - fasting) was inversely correlated with endogenous insulin secretion (90 minute C-peptide) (Spearman's r = -0.70, p < 0.001). Similar doses of exogenous prandial insulin lowered glucose increment more when patients had less endogenous insulin; by 6.4(4.2-11.1) verses 1.2(0.03-2.88) mmol/L (p < 0.001) for patients in the lowest verses highest tertiles of endogenous insulin.Conclusions: in insulin treated patients the measurement of endogenous insulin secretion may help predict the degree of postprandial hyperglycaemia and the likely response to prandial insulin. © 2012 Jones et al.; licensee BioMed Central Ltd.
Abstract.
McDonald TJ, Perry MH, Peake RWA, Pullan NJ, O'Connor J, Shields BM, Knight BA, Hattersley AT (2012). EDTA improves stability of whole blood C-peptide and insulin to over 24 hours at room temperature.
PLoS One,
7(7).
Abstract:
EDTA improves stability of whole blood C-peptide and insulin to over 24 hours at room temperature.
INTRODUCTION: C-peptide and insulin measurements in blood provide useful information regarding endogenous insulin secretion. Conflicting evidence on sample stability and handling procedures continue to limit the widespread clinical use of these tests. We assessed the factors that altered the stability of insulin and C-peptide in blood. METHODS: We investigated the impact of preservative type, time to centrifugation, storage conditions and duration of storage on the stability of C-peptide and insulin on three different analytical platforms. RESULTS: C-peptide was stable for at least 24 hours at room temperature in both centrifuged and whole blood collected in K(+)-EDTA and serum gel tubes, with the exception of whole blood serum gel, which decreased to 78% of baseline at 24 hours, (p = 0.008). Insulin was stable at room temperature for 24 hours in both centrifuged and whole blood collected in K(+)-EDTA tubes. In contrast insulin levels decreased in serum gel tubes both centrifuged and whole blood (66% of baseline, p = 0.01 and 76% of baseline p = 0.01, by 24 hours respectively). C-peptide and insulin remained stable after 6 freeze-thaw cycles. CONCLUSIONS: the stability of C-peptide and insulin in whole blood K(+)-EDTA tubes negates the need to conform to strict sample handling procedures for these assays, greatly increasing their clinical utility.
Abstract.
Author URL.
Shields BM, McDonald TJ, Owen KR, Malecki MT, Besser REJ, Jones AG, Ellard S, Hattersley AT (2012). Integration of biomarkers and clinical characteristics provides the best method for identifying patients with MODY.
Author URL.
McDonald TJ, McEneny J, Pearson ER, Thanabalasingham G, Szopa M, Shields BM, Ellard S, Owen KR, Malecki MT, Hattersley AT, et al (2012). Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes.
Clinica Chimica Acta,
413(9-10), 927-932.
Abstract:
Lipoprotein composition in HNF1A-MODY: Differentiating between HNF1A-MODY and Type 2 diabetes
Introduction: the young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia.We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. Methods: 1)14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups.2)HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. Results: 1)In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93mmol/l, p=0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15mmol/l, p=0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33mmol/L, p=0.04 and 1.10 vs. 0.83mmol/L, p=0.019, respectively), but were similar to controls (1.59 vs. 1.45mmol/L, p=0.35 and 1.10 vs. 1.21mmol/L, p=0.19, respectively).2)A plasma-HDL-cholesterol >1.12mmol/L was 75% sensitive and 64% specific (ROC AUC=0.76) at discriminating HNF1A-MODY from Type 2 diabetes. Conclusion: the plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. © 2012 Elsevier B.V.
Abstract.
McDonald TJ, McEneny J, Pearson ER, Thanabalasingham G, Szopa M, Shields BM, Ellard S, Owen KR, Malecki MT, Hattersley AT, et al (2012). Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
Clin Chim Acta,
413(9-10), 927-932.
Abstract:
Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
INTRODUCTION: the young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. METHODS: 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. RESULTS: 1) in HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) a plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. CONCLUSION: the plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY.
Abstract.
Author URL.
Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT (2012). The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.
Diabetologia,
55(5), 1265-1272.
Abstract:
The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.
AIMS/HYPOTHESIS: Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. METHODS: We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. RESULTS: the models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis
Abstract.
Author URL.
Thomas NJ, Shields BM, Besser REJ, Jones AG, Rawlingson A, Goodchild E, Leighton C, Bowman P, Shepherd M, Knight BA, et al (2012). The impact of gender on urine C-peptide creatinine ratio interpretation.
Ann Clin Biochem,
49(Pt 4), 363-368.
Abstract:
The impact of gender on urine C-peptide creatinine ratio interpretation.
BACKGROUND: Urinary C-peptide creatinine ratio (UCPCR) is a non-invasive and convenient way of assessing endogenous insulin production. Adjusting for urine creatinine levels allows for differences in urine concentration. Creatinine excretion is known to be higher in men due to gender differences in muscle mass. We investigated the impact of gender on UCPCR. METHODS: One hundred and seventy-six subjects underwent a mixed meal tolerance test (MMTT). We looked at the relationship between UCPCR on urine C-peptide and creatinine excretion rates using timed post-meal urine samples. A further 415 subjects had two-hour post-meal UCPCR measurements in order to derive gender-specific percentiles for different diabetes subgroups and controls. RESULTS: UCPCR was 1.48-fold higher in women (n=78) than men (n=98), median (interquartile range [IQR]): 1.88 (0.49-3.49) men versus 2.88 (1.58-4.91) nmol mmol(-1) women, P=0.01. This reflects a gender difference in creatinine excretion rates (11.5 [8.3-13.7] men versus 8.2 [5.6-9.1] women μmol min(-1) P
Abstract.
Author URL.
Besser REJ, Jones AG, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2012). The impact of insulin administration during the mixed meal tolerance test.
Diabet Med,
29(10), 1279-1284.
Abstract:
The impact of insulin administration during the mixed meal tolerance test.
AIMS: the mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. METHODS: Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. RESULTS: the 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l). CONCLUSIONS: Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients.
Abstract.
Author URL.
Oram RA, Shepherd MH, Hudson M, Sanders T, Tiley S, Hammersley S, Shields B, McDonald TJ, Knight BA, Besser REJ, et al (2012). The prevalence of endogenous insulin production in a cohort of adults with type 1 diabetes.
Author URL.
Besser REJ, Jones J, McDonald TJ, Smith R, Shepherd MH, Hattersley AT (2012). Using highly sensitive C-reactive protein measurement to diagnose MODY in a family with suspected type 2 diabetes.
BMJ Case ReportsAbstract:
Using highly sensitive C-reactive protein measurement to diagnose MODY in a family with suspected type 2 diabetes
The authors report an adolescent who was found to have diabetes on routine blood testing. The initial diagnosis was type 2 diabetes because she was obese, did not have type 1 diabetes antibodies and both parents had diabetes. Highly sensitive C-reactive protein (hsCRP) was low in the proband and her father (≤0.1 mg/l) indicating that type 2 diabetes was unlikely, and that hepatocyte nuclear factor 1-α-iquest;-maturity onset diabetes of the young (HNF1A-MODY) was the most likely diagnosis. Following a genetic diagnosis of HNF1A-MODY in the proband and her father, both patients were treated with gliclazide, with improvement in HbA1c. This case highlights the challenges of making a correct diagnosis of MODY in young onset diabetes. The authors report the first case where hsCRP, an easily available biomarker, has been used on an individual level to determine appropriate genetic testing of MODY in a family whose main differential diagnosis was familial type 2 diabetes.
Abstract.
Besser REJ, Jones J, McDonald TJ, Smith R, Shepherd MH, Hattersley AT (2012). Using highly sensitive C-reactive protein measurement to diagnose MODY in a family with suspected type 2 diabetes.
BMJ case reports,
2012Abstract:
Using highly sensitive C-reactive protein measurement to diagnose MODY in a family with suspected type 2 diabetes.
The authors report an adolescent who was found to have diabetes on routine blood testing. The initial diagnosis was type 2 diabetes because she was obese, did not have type 1 diabetes antibodies and both parents had diabetes. Highly sensitive C-reactive protein (hsCRP) was low in the proband and her father (≤0.1 mg/l) indicating that type 2 diabetes was unlikely, and that hepatocyte nuclear factor 1-α-maturity onset diabetes of the young (HNF1A-MODY) was the most likely diagnosis. Following a genetic diagnosis of HNF1A-MODY in the proband and her father, both patients were treated with gliclazide, with improvement in HbA1c. This case highlights the challenges of making a correct diagnosis of MODY in young onset diabetes. The authors report the first case where hsCRP, an easily available biomarker, has been used on an individual level to determine appropriate genetic testing of MODY in a family whose main differential diagnosis was familial type 2 diabetes.
Abstract.
Bowman P, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2012). Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with Type 2 diabetes.
Diabet Med,
29(1), 90-93.
Abstract:
Validation of a single-sample urinary C-peptide creatinine ratio as a reproducible alternative to serum C-peptide in patients with Type 2 diabetes.
AIMS: Serum C-peptide can be used in Type 2 diabetes as a measure of endogenous insulin secretion, but practicalities of collection limit its routine clinical use. Urine C-peptide creatinine ratio is a non-invasive alternative that is stable for at least 3 days at room temperature in boric acid preservative. We aimed to assess the utility of urine C-peptide creatinine ratio in individuals with Type 2 diabetes as an alternative to serum C-peptide. METHODS: We assessed, in 77 individuals with Type 2 diabetes, the reproducibility of, and correlations between, fasting and postprandial urine C-peptide creatinine ratio and serum C-peptide, and the impact of renal impairment (estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2)) on these correlations. RESULTS: Urine C-peptide creatinine ratio was at least as reproducible as serum C-peptide [fasting coefficient of variation mean (95% CI): 28 (21-35)% vs. 38 (26-59)% and 2-h post-meal 26 (18-33)% vs. 27 (20-34)%. Urine C-peptide creatinine ratio 2 h post-meal was correlated with stimulated serum C-peptide, both the 2-h value (r = 0.64, P < 0.001) and the 2-h area under the C-peptide curve (r = 0.63, P < 0.001). The association seen was similar in patients with and without moderate renal impairment (P = 0.6). CONCLUSIONS: in patients with Type 2 diabetes, a single urine C-peptide creatinine ratio is a stable, reproducible measure that is well correlated with serum C-peptide following meal stimulation, even if there is moderate renal impairment. Urine C-peptide creatinine ratio therefore has potential for use in clinical practice in the assessment of Type 2 diabetes.
Abstract.
Author URL.
2011
McDonald TJ, Perry MH, Jones AG, Donohoe M, Salzmann MB, O'Connor J (2011). A novel case of a raised testosterone and LH in a young man.
Clinica Chimica Acta,
412(21-22), 1999-2001.
Abstract:
A novel case of a raised testosterone and LH in a young man
A 19. year old male attended his GP with a history of "fluid retention", lack of libido and erectile dysfunction. He was found to have a high serum testosterone, and a raised luteinising hormone. After further investigations, the patient admitted to taking a supplement called ActivaTe Xtreme™, obtained from an internet source, to address his low libido.ActivaTe Xtreme™ contains active ingredients which increase serum testosterone levels by several independent mechanisms that are not associated with luteinising hormone suppression. Urine analyses for synthetic anabolic steroids were negative, and urinary testosterone, epitestosterone and other androgens were normal. This biochemical pattern is not the same as that seen with anabolic steroids (i.e. raised testosterone, suppressed luteinising hormone and abnormal urine steroid profile).The issue of self medication with performance enhancing compounds needs to be carefully considered in order to avoid expensive and invasive investigations, missing an underlying pathology or misdiagnosing a patient. This case also raises the spectre of yet another "performance enhancing" product that may cause difficulty for those trying to ensure that sport remains on a "hormonally" equal basis. © 2011.
Abstract.
Nowak N, Szopa M, Thanabalasingham G, McDonald TJ, James TJ, Skupien J, Kiec-Wilk B, Mlynarski W, Hattersley AT, Owen KR, et al (2011). Cystatin C is not a good candidate biomarker for HNF1A MODY.
Author URL.
McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S, Hattersley AT (2011). High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.
Diabetes Care,
34(8), 1860-1862.
Abstract:
High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.
OBJECTIVE: Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. RESEARCH DESIGN AND METHODS: hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). RESULTS: hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP
Abstract.
Author URL.
McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, Williams A, Hattersley AT, Ellard S (2011). Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.
Diabet Med,
28(9), 1028-1033.
Abstract:
Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.
AIM: Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. METHODS: We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects. RESULTS: GAD and/or IA-2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity-onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA-2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA-2 only in 19.4%. All five patients with maturity-onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA-2 antibodies. CONCLUSION: the prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA-2 antibodies, makes the diagnosis of maturity-onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing.
Abstract.
Author URL.
Jones AG, Besser REJ, McDonald TJ, Shields BM, Hope SV, Bowman PA, Oram RA, Knight BA, Hattersley AT (2011). Measuring endogenous insulin secretion: does it matter in insulin treated patients?. Diabetes UK Annual Professional Conference 2011. 30th Mar - 1st Apr 2011.
Jones AG, Besser REJ, Shields BM, McDonald TJ, Hope SV, Oram RA, Knight BA, Hattersley AT (2011). Practical alternatives to the mixed meal tolerance test in insulin treated diabetes. Diabetes UK Annual Professional Conference 2011. 30th Mar - 1st Apr 2011.
McDonald TJ, Owen KR, Gloyn AL, Hattersley AT (2011). Response to comment on: McDonald et al. High-Sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. Diabetes Care 2011;34: 1860-1862. Diabetes Care, 34(12).
Shields BM, McDonald TJ, Ellard S, Hyde C, Campbell M, Hattersley AT (2011). Should I test this patient for maturity onset diabetes of the young? a clinical prediction model to determine the probability of MODY.
Author URL.
Thomas NJM, Besser REJ, Jones AG, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2011). Simple and convenient alternatives to the mixed meal tolerance test.
Author URL.
Hope SV, Jones A, Goodchild E, Shepherd M, Besser REJ, Shields B, McDonald T, Knight BA, Hattersley A (2011). URINARY C-PEPTIDE CREATININE RATIO (UCPCR) CAN BE USED AS a SCREENING TOOL TO DETECT ABSOLUTE INSULIN DEFICIENCY IN PEOPLE WITH TYPE 2 DIABETES.
Author URL.
Hope SV, Jones AG, Goodchild E, Shepherd M, Besser REJ, Shields BM, McDonald TJ, Knight BA, Hattersley AT (2011). Urinary C-Peptide Creatinine Ratio (UCPCR) can be used as a screening tool to detect absolute insulin deficiency in type 2 diabetes. Diabetes UK Annual Professional Conference 2011. 30th Mar - 1st Apr 2011.
Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Ellard S, Hattersley AT (2011). Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the young from long-duration type 1 diabetes.
Diabetes Care,
34(2), 286-291.
Abstract:
Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the young from long-duration type 1 diabetes.
OBJECTIVE: Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with diabetes for ≥ 5 years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS: UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (
Abstract.
Author URL.
Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Hammersley S, Ellard S, Hattersley AT (2011). Urinary C-peptide creatinine ratio is a practical outpatient tool in identifying MODY from type 1 diabetes in children with diabetes.
Author URL.
Besser REJ, Ludvigsson J, Jones AG, McDonald TJ, Shields BM, Knight BA, Hattersley AT (2011). Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes.
Diabetes Care,
34(3), 607-609.
Abstract:
Urine C-peptide creatinine ratio is a noninvasive alternative to the mixed-meal tolerance test in children and adults with type 1 diabetes.
OBJECTIVE: Stimulated serum C-peptide (sCP) during a mixed-meal tolerance test (MMTT) is the gold standard measure of endogenous insulin secretion, but practical issues limit its use. We assessed urine C-peptide creatinine ratio (UCPCR) as an alternative. RESEARCH DESIGN AND METHODS: Seventy-two type 1 diabetic patients (age of diagnosis median 14 years [interquartile range 10-22]; diabetes duration 6.5 [2.3-32.7]) had an MMTT. sCP was collected at 90 min. Urine for UCPCR was collected at 120 min and following a home evening meal. RESULTS: MMTT 120-min UCPCR was highly correlated to 90-min sCP (r = 0.97; P < 0.0001). UCPCR ≥ 0.53 nmol/mmol had 94% sensitivity/100% specificity for significant endogenous insulin secretion (90-min sCP ≥ 0.2 nmol/L). The 120-min postprandial evening meal UCPCR was highly correlated to 90-min sCP (r = 0.91; P < 0.0001). UCPCR ≥ 0.37 nmol/mmol had 84% sensitivity/97% specificity for sCP ≥ 0.2 nmol/L. CONCLUSIONS: UCPCR testing is a sensitive and specific method for detecting insulin secretion. UCPCR may be a practical alternative to serum C-peptide testing, avoiding the need for inpatient investigation.
Abstract.
Author URL.
Jones AG, Besser REJ, McDonald TJ, Shields BM, Hope SV, Bowman P, Oram RA, Knight BA, Hattersley AT (2011). Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.
Diabet Med,
28(9), 1034-1038.
Abstract:
Urine C-peptide creatinine ratio is an alternative to stimulated serum C-peptide measurement in late-onset, insulin-treated diabetes.
AIMS: Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. METHODS: We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min(-1) 1.73 m(-2) ). RESULTS: Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio (r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home (r = 0.73) and urine C-peptide creatinine ratio after largest home meal (r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. CONCLUSION: in patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice.
Abstract.
Author URL.
2010
Rawlingson A, Knight BA, Oram R, McDonald TJ, Shields BM, Hattersley AT (2010). A novel method for the assessment of insulin physiology: urinary C-peptide creatinine ratio can be used to assess insulin sensitivity and beta cell function in non-diabetic subjects.
Author URL.
Jones AG, Hope SV, Shepherd M, Shields BM, Besser REJ, Wensley KJ, Githens-Mazer G, McDonald TJ, Knight BA, Hattersley AT, et al (2010). Do patients with Long-Standing Type 2 Diabetes Develop Absolute Insulin Deficiency?.
Author URL.
Brooks AM, Shields BM, Knight BA, McDonald TJ, Mills S, Smith J, Dyer R, Paisey R, Hattersley AT (2010). Is Intensive Carbohydrate Counting Education a Treatment Option in Patients with Atypical Characteristics for Type 1 Diabetes?.
Author URL.
Hope SV, Shepherd M, Shields BM, McDonald T, Knight BA, Hattersley AT (2010). Patients with long-standing type 2 diabetes can develop absolute insulin deficiency.
Author URL.
Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Colclough KJ, Githens-Mazer G, Wensley KJ, Knight BA, Ellard S, Hattersley AT, et al (2010). Postal Urinary C-Peptide Creatinine Ratio Discriminates Long Duration Type 1 Diabetes from HNF1A MODY.
Author URL.
Jones AG, Besser REJ, McDonald TJ, Wensley KJ, Githens-Mazer G, Shields BM, Knight BA, Hattersley AT (2010). Serum Measurement of Endogenous C-Peptide after a Mixed Meal can be Replaced with a Single Post Meal Urine C-Peptide Creatinine Ratio (UCPCR).
Author URL.
Shields BM, McDonald TJ, Bowman P, Jones AG, Besser REJ, Wensley KJ, Githens-Mazer G, Knight BA, Hattersley AT (2010). Urinary C-Peptide Creatinine Ratio (UCPCR) is a Reliable Measure of Endogenous Insulin Secretion, Even in Patients with Renal Impairment.
Author URL.
Besser REJ, Jones AG, McDonald TJ, Shields BM, Githens-Mazer G, Wensley K, Knight BA, Hattersley AT (2010). Urinary C-Peptide Creatinine Ratio is a Novel Non Invasive Alternative to the Inpatient Mixed Meal Tolerance Test in Young Onset Type 1 Diabetes.
Author URL.
2009
Musich S, McDonald T, Chapman LS (2009). Health promotion strategies for the "boomer" generation: Wellness for the mature worker. American Journal of Health Promotion, 23(3), 1-9.
McDonald TJ, Knight BA, Shields BM, Bowman P, Salzmann MB, Hattersley AT (2009). Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide.
Clin Chem,
55(11), 2035-2039.
Abstract:
Stability and reproducibility of a single-sample urinary C-peptide/creatinine ratio and its correlation with 24-h urinary C-peptide.
INTRODUCTION: C-peptide measurement in blood or 24-h urine samples provides useful information regarding endogenous insulin secretion, but problems related to the rapid degradation of C-peptide in blood and difficulty of 24-h urine collection have limited widespread routine clinical use of this test. We assessed the feasibility of measuring urinary C-peptide (UCP) with correction for creatinine concentration in single urine samples. METHODS: We analyzed UCP using a routine electrochemiluminescence immunoassay in samples from 21 healthy volunteers. We investigated the stability of UCP with different preservatives and storage conditions and compared the reproducibility of urinary C-peptide/creatinine ratio (UCPCR) in first- and second-void fasting urines, then assessed correlations with 24-h collections. RESULTS: UCPCR was unchanged at room temperature for 24 h and at 4 degrees C for 72 h even in the absence of preservative. UCPCR collected in boric acid was stable at room temperature for 72 h. UCPCR remained stable after 7 freeze-thaw cycles but decreased with freezer storage time and dropped to 82%-84% of baseline by 90 days at -20 degrees C. Second-void fasting UCPCRs were lower than first-void (median 0.78 vs 1.31, P = 0.0003) and showed less variation (CV 33% vs 52%), as second-void UCPCRs were not influenced by evening food-related insulin secretion. Second-void fasting UCPCR was highly correlated with 24-h UCP (r = 0.8, P = 0.00006). CONCLUSIONS: Second-void fasting UCPCR is a reproducible measure that correlates well with 24-h UCP in normal samples. The 3-day stability of UCPCR at room temperature greatly increases its potential clinical utility.
Abstract.
Author URL.
2008
Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, et al (2008). Effects of intensive glucose lowering in type 2 diabetes.
New England Journal of Medicine,
358(24), 2545-2559.
Abstract:
Effects of intensive glucose lowering in type 2 diabetes
Background Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. Methods in this randomized study, 10,250 patients (mean age, 60.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). of these patients, 37% were women, and 7% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. Results at 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 70 patients in the intensive-therapy group, as compared with 359 in the standard-therapy group (hazard ratio, 0.88; 92% confidence interval [CI], 0.76 to 1.04; P = 0.16). At the same time, 255 patients in the intensive-therapy group died, as compared with 203 patients in the standardtherapy group (hazard ratio, 1.22; 92% CI, 1.01 to 1.45; P = 0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P
Abstract.
2006
Wang F, McDonald T, Bender J, Reffitt B, Miller A, Edington DW (2006). Association of healthcare costs with per unit body mass index increase.
Journal of Occupational and Environmental Medicine,
48(7), 668-674.
Abstract:
Association of healthcare costs with per unit body mass index increase
OBJECTIVE: the objective of this study was to quantify the healthcare costs per unit increase in body mass index (BMI). METHODS: This cross-sectional study included 35,932 employees and spouses in a manufacturing company who participated in an indemnity/PPO plan and one health risk appraisal during 2001 and 2002. RESULTS: Within the BMI range of 25 to 45 kg/m, medical costs and pharmaceutical costs increased $119.7 (4%) and $82.6 (7%) per BMI unit, respectively, adjusted for age and gender. The adjusted medical costs related to diabetes and heart disease increased by $6.2 and $20.3 per BMI unit. The likelihood of having any medical claim increased 11.6% per BMI unit for diabetes and 5.2% for heart disease. CONCLUSIONS: Each unit increase in BMI is associated with higher healthcare costs and increased likelihood of having claims for most major diagnostic codes and for diabetes and heart diseases. Copyright © 2006 by American College of Occupational and Environmental Medicine.
Abstract.
Yen L, Schultz AB, McDonald T, Champagne L, Edington DW (2006). Participation in employer-sponsored wellness programs before and after retirement.
American Journal of Health Behavior,
30(1), 27-38.
Abstract:
Participation in employer-sponsored wellness programs before and after retirement
Objectives: to evaluate wellness program participation before and after retirement. Methods: This retrospective cohort design compares 3 groups of employees: 1998-1999 retirees (N=6065), 1994-1995 retirees (N=5862), and 21, 176 employees who were still active as of 2002. Participation was compared over 2 time periods for high-intensity and low-intensity programs. Results: Significantly different participation rates were found among the 3 groups specific to program intensity. Participation before retirement is associated with higher participation after retirement regardless of program intensity (OR=3.8 for overall participation). Conclusions: Wellness programs can attract retirees, especially if they participated before retirement and are offered a variety of programs.
Abstract.
2005
Wang F, McDonald T, Reffitt B, Edington DW (2005). BMI, physical activity, and health care utilization/costs among medicare retirees.
Obesity Research,
13(8), 1450-1457.
Abstract:
BMI, physical activity, and health care utilization/costs among medicare retirees
Objective: to examine the influence of physical activity (PA) and BMI on health care utilization and costs among Medicare retirees. Research Methods and Procedures: This cross-sectional study was based on 42,520 Medicare retirees in a U.S.-wide manufacturing corporation who participated in indemnity/ perferred provider and one health risk appraisal during the years 2001 and 2002. Participants were assigned into one of the three weight groups: normal weight, overweight, and obese. PA behavior was classified into three levels: sedentary (0 time/wk), moderately active (1 to 3 times/wk), and very active (4+ times/wk). Results: Generalized linear models revealed that the moderately active retirees had $1456, $1731, and $177 lower total health care charges than their sedentary counterparts in the normal-weight, overweight, and obese groups, respectively (p < 0.01). The very active retirees had $1823, $581, and $1379 lower costs than the moderately active retirees. Health care utilization and specific costs showed similar trends with PA levels for all BMI groups. The total health care charges were lower with higher PA level for all age groups (p < 0.01). Discussion: Regular PA has strong dose-response effects on both health care utilization and costs for overweight/obese as well as normal-weight people. Promoting active lifestyle in this Medicare population, especially overweight and obese groups, could potentially improve their well-being and save a substantial amount of health care expenditures. Because those Medicare retirees are hard to reach in general, more creative approaches should be launched to address their needs and interests as well as help reduce the usage of health care system. Copyright © 2005 NAASO.
Abstract.
2004
Musich S, Lu C, McDonald T, Champagne LJ, Edington DW (2004). Association of Additional Health Risks on Medical Charges and Prevalence of Diabetes Within Body Mass Index Categories.
American Journal of Health Promotion,
18(3), 264-268.
Abstract:
Association of Additional Health Risks on Medical Charges and Prevalence of Diabetes Within Body Mass Index Categories
Purpose. The prevalence of obesity and diabetes continues to increase among employee populations. Although medical costs and the prevalence of diabetes have been studied across increasing body mass index (BMI) categories, little attention has been given to the association of additional health risks within those categories. The purpose of this study was to examine the association of health risk levels on medical charges and prevalence of diabetes across BMI categories within an employee population. Methods. A cross-sectional study design utilized health risk appraisal data (30% response rate) to measure BMI levels, self-reported diabetes status, and selected additional health risks among 38,841 active employees under age 65 of the General Motors Corporation. Associated average annual medical charges from 1996 to 2000 were calculated for defined health risk levels across five BMI categories (
Abstract.
Wright D, Adams L, Beard MJ, Burton WM, Hirschland D, McDonald T, Napier D, Galante S, Smith T, Edington DW, et al (2004). Comparing excess costs across multiple corporate populations.
Journal of Occupational and Environmental Medicine,
46(9), 937-945.
Abstract:
Comparing excess costs across multiple corporate populations
The purpose of this study was to examine the relationship of health risk level to charged medical costs and determine the excess cost of higher risk individuals compared to low risk. Two years of medical claims from six corporations were used to determine costs of health risk assessment (HRA) participants and nonparticipants. A total of 165,770 employees, 21,124 of which took an HRA, were used for the study. Costs increased as risk level increased. There were no significant differences within a risk level between companies for the cost ratio. Percent of medical costs due to excess risk ranged from 15.0-30.8% for HRA participants and 23.8-38.3% for the study population. Cost patterns were consistent across companies. Excess cost as the result of increased risk level accounted for a substantial portion of the cost at each company. These results can be used to justify the need for a health-promotion program and to estimate potential savings as the result of excess risk. Even without the use of an HRA, health practitioners should feel confident stating that excess risk accounts for at least 25% to 30% of medical costs per year across a wide variety of companies, regardless of industry or demographics. The numbers can be used as a realistic estimate for any health promotion program financial proposal.
Abstract.
Wang F, McDonald T, Champagne LJ, Edington DW (2004). Relationship of Body Mass Index and Physical Activity to Health Care Costs among Employees.
Journal of Occupational and Environmental Medicine,
46(5), 428-436.
Abstract:
Relationship of Body Mass Index and Physical Activity to Health Care Costs among Employees
This study examined the relationship between physical activity and health care costs by different weight groups. The study sample consisted of 23,490 active employees grouped into normal weight, overweight, and obese categories. After adjustment for covariates, physically moderately active (1 to 2 times/week) and very active (3+ times/week) employees had approximately $250 less paid health care costs annually than sedentary employees (0 time/week) across all weight categories. The difference was approximately $450 in the obese subpopulation. The maximum possible savings was estimated to be 1.5% of the total health care costs if all obese sedentary employees would adapt a physically active lifestyle. As a strategy to control escalating health care costs, wellness programs should facilitate engagement in moderate physical activity of at least 1 to 2 times a week among sedentary obese people and help them to maintain this more active lifestyle.
Abstract.
2003
Yen L, McDonald T, Hirschland D, Edington DW (2003). Association Between Wellness Score from a Health Risk Appraisal and Prospective Medical Claims Costs.
Journal of Occupational and Environmental Medicine,
45(10), 1049-1057.
Abstract:
Association Between Wellness Score from a Health Risk Appraisal and Prospective Medical Claims Costs
This study examines how wellness scores generated from the Health Risk Appraisal are associated with prospective medical claims costs, controlling for age, gender, and disease status. The study was conducted among 19,861 active employees who participated in the Health Risk Appraisal and selected indemnity or PPO medical plans from 1996 to 1998. A multiple regression model based on group averages of age, gender, disease status, and wellness score levels was developed among a randomly selected screening subsample (n = 10,172)from the study sample. Total medical claim costs of -$56, $88, and $3574 were estimated for one additional point on the wellness score, 1 year of additional age, and an existing major disease, respectively. No significant differences were found between the model predicted and actual medical claims costs for the individuals in both screening and calibration (n = 9689) subsamples.
Abstract.
Musich S, McDonald T, Hirschland D, Edington DW (2003). Erratum: Examination of risk status transitions among active employees in a comprehensive worksite health promotion program (Journal of Occupational and Environmental Medicine (April)). Journal of Occupational and Environmental Medicine, 45(6).
Musich S, McDonald T, Hirschland D, Edington DW (2003). Examination of risk status transitions among active employees in a comprehensive worksite health promotion program.
Journal of Occupational and Environmental Medicine,
45(4), 393-399.
Abstract:
Examination of risk status transitions among active employees in a comprehensive worksite health promotion program
Most worksite health promotion programs are designed to effect risk reduction. Net changes in the prevalence of health behaviors are a combination of individuals who reduce to low-risk and those who become high-risk. It is the purpose of this study to examine overall risk status transitions, between low-risk (0-2 risks); medium-risk (3-4 risks); and high-risk (5 or more risks), within a comprehensive worksite health promotion program over the first year of the program (short-term) and after 5 years (long-term). Significant increases were demonstrated in the numbers of individuals who transitioned to lower risk status. Nearly half (+ 5.0 percentage points) of the net reduction to low-risk status (+ 10.4 percentage points) occurred during the first year of the program. The design of health promotion programs may need to be adjusted from risk reduction in the short-term to programs that maximize retention of individuals within low-risk categories over the long-term. This program design would maximize the opportunity to obtain initial risk reduction during the first years of the program and then maximize the opportunity to maintain low-risk status in the long-term.
Abstract.
Musich S, Faruzzi SD, Lu C, McDonald T, Hirschland D, Edington DW (2003). Pattern of Medical Charges after Quitting Smoking among those with and without Arthritis, Allergies, or Back Pain.
American Journal of Health Promotion,
18(2), 133-142.
Abstract:
Pattern of Medical Charges after Quitting Smoking among those with and without Arthritis, Allergies, or Back Pain
Purpose. To examine the time frame of changes in medical charges after smoking cessation among (I) those with arthritis, allergies, or back pain and (2) those with none of these chronic conditions. Design. Cross-sectional study using smoking status determined in 1996 and 4-year average medical charges measured from 1996 to 1999. Setting. Nationwide manufacturing corporation (General Motors Corporation). Subjects. A total of 20,332 employees and spouses who completed a health risk appraisal in 1996 were younger than 64 years, were enrolled in indemnity or preferred provider organization health insurance plans during 1996 to 1999, and self-reported no preexisting primary diseases. Measures. Participants were categorized according to 1996 self-reported smoking status into six subgroups: current smokers, former smokers by years since cessation (0-4, 5-9, 10-14, and ≥15 years), and never smokers. Average annual medical charges (1996-1999) among those with chronic conditions (arthritis, allergies, or back pain; N = 11, 921) or without chronic conditions (N = 8411) were examined independently. Never smokers in each group were compared to respective smoker and former smoker subgroups. Results. Current smokers and former smokers without chronic conditions who quit fewer than 5 years earlier had higher medical charges compared with never smokers ($2613 and $3356 vs. $2203, respectively). Among those with chronic conditions, current smokers, former smokers who quit 0 to 4 years ago, and former smokers who quit 5 to 9 years ago had higher medical charges than never smokers ($4208, $4027, and $4050 vs. $3108, respectively). Conclusions. It took approximately 5 years for former smokers without chronic conditions and nearly 10 years for former smokers with chronic conditions to reduce their medical charges to levels close to their respective never smokers. Health promotion practitioners and other decision makers should consider the impact of chronic conditions on the course of medical savings when implementing smoking cessation programs at the worksite.
Abstract.
Wang F, Schultz AB, Musich S, McDonald T, Hirschland D, Edington DW (2003). The relationship between National Heart, Lung, and Blood Institute weight guidelines and concurrent medical costs in a manufacturing population.
American Journal of Health Promotion,
17(3), 183-189.
Abstract:
The relationship between National Heart, Lung, and Blood Institute weight guidelines and concurrent medical costs in a manufacturing population
Purpose. To explore the relationship between the 1998 National Heart, Lung, and Blood Institute (NHLBI) zoeight guidelines and concurrent medical costs. Design. Cross-sectional study. Setting. In a nationwide manufacturing corporation (General Motors Corporation). Subjects. A total of 177,971 employees, retirees, and their adult dependents who were enrolled in Indemnity/PPO health insurance plan during the years 1996 and 1997 and completed one health risk appraisal (HRA) in the same period. Measures. The participants were categorized into six weight groups according to the NHLBI 1998 guidelines (body mass index [BMI]
Abstract.
2002
Musich S, McDonald T, Hirschland D, Edington DW (2002). Excess healthcare costs associated with excess health risks in diseased and non-diseased Health Risk Appraisal participants.
Disease Management and Health Outcomes,
10(4), 251-258.
Abstract:
Excess healthcare costs associated with excess health risks in diseased and non-diseased Health Risk Appraisal participants
Background: Concerns regarding the effectiveness and impact of disease management are largely based on disease compliance measures. Although disease management programs have measured improvements in compliance and quality of life and cost savings from reductions in hospitalizations and emergency room visits, few programs have focused on changing behavioral health risks not directly related to the specific disease. The basic relationship between behavioral health risks and healthcare costs shows that those individuals with more high-risk behaviors are associated with higher healthcare costs compared with those with low-risk behaviors. The concept of excess costs associated with excess risks is a calculation of theoretical maximum percent savings for an entire group assuming everyone reduces to low risk, and changes in healthcare costs follow the changes in risks. Objective: to establish the magnitude of excess healthcare costs associated with excess health risks, given a diagnosed chronic disease. Methods: 135 251 current and retired employees of General Motors Corporation who had completed a Health Risk Appraisal (I-IRA) were evaluated. Participants were continuously enrolled in traditional or Preferred Provider Organization (PPO) medical plans from 1996 to 1999 and had completed at least one HRA between 1996 and 1998. Results: Those with and without self-reported disease averaged 19.2 and 9.1% excess healthcare costs associated with excess health risks, respectively. However, the magnitude of the impact differed across age groups and diseases. Individuals less than 45 years of age with self-reported disease were most affected by the presence of additional health risks (44% excess costs) while those aged ≥65 years without disease were least affected (8.2% excess costs). Among those with diseases, those with diabetes mellitus and bronchitis/emphysema were most affected (19.2 and 21.0%, respectively). Conclusions: Disease management programs should ideally provide a systematic approach to assist patients with interventions that improve overall health, as well as focusing on disease compliance measures. The implications for disease management programs are that, even given the presence of disease, promoting and/or maintaining low-risk status can result in potential cost savings.
Abstract.
Schultz AB, Lu C, Barnett TE, Yen LTC, McDonald T, Hirschland D, Edington DW (2002). Influence of participation in a worksite health-promotion program on disability days.
Journal of Occupational and Environmental Medicine,
44(8), 776-780.
Abstract:
Influence of participation in a worksite health-promotion program on disability days
This study assessed the impact of health-promotion program participation on short-term and long-term disability absence days during a 6-year period in a manufacturing company. Male, hourly, active employees (n = 4189) were analyzed from 1995 to 2000. Disability absences were compared for program participants and nonparticipants from baseline (1995) through 5 years of the program. The percentage of nonparticipants absent on any given day was greater than that of participants. Moreover, the average number of disability absence days incurred by nonparticipants significantly increased from baseline to program year 5 compared with participants. The total amount saved each year in disability absence days for the 2596 program participants was $623,040, which resulted in a savings-to-cost ratio of 2.3 per year. Participation in worksite health-promotion programs may lead to reduced disability days in a manufacturing worksite population.
Abstract.
2001
Yen L, Edington MP, McDonald T, Hirschland D, Edington DW (2001). Changes in health risks among the participants in the United Auto Workers - General Motors lifesteps health promotion program.
American Journal of Health Promotion,
16(1), 7-15.
Abstract:
Changes in health risks among the participants in the United Auto Workers - General Motors lifesteps health promotion program
Purpose. To examine health risk changes among participants of a multicomponent worksite health promotion program. Design. A study using health risk changes among health risk appraisal (HRA) participants linked to program participation records. Baseline risk and participation in multiple programs were examined in relation to risk change in multivariate models. Setting. Worksite health promotion programming sponsored by the United Auto Workers (UAW) and General Motors (GM). Subjects. Active employees (12,984) who voluntarily participated in an HRA in each of two program years. Intervention. The nationwide program was a mailed HRA and a 1-800 nurse line. A pilot program (implemented in two cities) added screening, wellness programs, a materials resource, and, for high risk participants, health coaching and vouchers for medical office visits. Measures. Using 13 selected health risk factors from the HRA, changes in overall health risks were measured as program outcomes in three ways: one-directional, net, and risk status change. Results. A greater decrease in the number of health risks was observed with increased program participation. The decrease was significantly related to the number of baseline risk factors and eligibility for high risk programs. Associated with program participation, the number of people at low risk status increased from 70.1% to 71.3% at year 2 among nationwide participants and from 52.4% to 58.9% among pilot participants. Conclusions. Participation was associated with a significant impact on health risk. Baseline risk of participants and eligibility for high risk programs were necessary factors to control when measuring program effects on health risk changes.
Abstract.
Braunstein A, Li Y, Hirschland D, McDonald T, Edington DW (2001). Internal associations among health-risk factors and risk prevalence.
American Journal of Health Behavior,
25(4), 407-417.
Abstract:
Internal associations among health-risk factors and risk prevalence
Objective: to explore risk associations between health variables and to compare these associations with the prevalence of each risk. Methods: Manufacturing-company employees (N=16,879) completed a self-reported health risk appraisal with on-site biometric screening. Results: Risk prevalence and risk association findings differed by gender, age, and overall risk level. Risks that were most highly associated with other risks were different from risks that were most prevalent. Conclusions: the findings suggest that in addition to risk prevalence, individual characteristics and the level of association between risks are also important to consider when planning health interventions.
Abstract.
Musich S, Ignaczak A, McDonald T, Hirschland D, Edington DW (2001). Self-reported utilization of preventive health services by retired employees age 65 and older.
Journal of the American Geriatrics Society,
49(12), 1665-1672.
Abstract:
Self-reported utilization of preventive health services by retired employees age 65 and older
OBJECTIVES: Increased utilization of preventive services among the aging has been associated with improved health status and decreased medical costs. We sought to examine the use of the Health Risk Appraisal (HRA) in benchmarking compliance and characterizing those retired employees who met preventive service guidelines. DESIGN: a retrospective cohort study of retired employees age 65 and older. SETTING: Nation-wide health promotion program offered by General Motors Corporation. PARTICIPANTS: 59,670 retired General Motors employees age 65 and older who participated in a nationwide mailed HRA health promotion program. MEASUREMENTS: Preventive health services compliance was measured using selected HRA questions. Gender, HRA participation patterns, overall health risk status, medical plan selection and disease status were examined as predictors of increased compliance. Multivariate logistic regression models were developed to test the relative contributions of participant characteristics to increased utilization. RESULTS: the self-reported HRA data indicated that compliance levels were higher than national averages. The Healthy People 2000 goals for the preventive services studied were met and exceeded (with the exception of tetanus immunization). Higher compliance was associated with being male, younger than 70 years, multiple-year HRA participation, overall low risk status and HMO insurance plan selection. CONCLUSION: the results from the HRA indicated that this population participated at a higher level than a comparable national sample exceeding goals set by Healthy People 2000.
Abstract.