Diagnosis and treatment of anti-insulin antibody-mediated labile glycaemia in insulin-treated diabetes.

AIMS: Anti-insulin antibodies in insulin-treated diabetes can derange glycaemia, but are under-recognised. Detection of significant antibodies is complicated by antigenically distinct insulin analogues. We evaluated a pragmatic biochemical approach to identifying actionable antibodies, and assessed its utility in therapeutic decision making. METHODS: Forty people with insulin-treated diabetes and combinations of insulin resistance, nocturnal/matutinal hypoglycaemia, and unexplained ketoacidosis were studied using broad-specificity insulin immunoassays, polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC) with or without ex vivo insulin preincubation. RESULTS: Twenty-seven people had insulin immunoreactivity (IIR) below 3000 pmol/L that fell less than 50% after PEG precipitation. Insulin binding by antibodies in this group was low and judged insignificant. In 8 people IIR was above 3000 pmol/L and fell by more than 50% after PEG precipitation. GFC demonstrated substantial high molecular weight (HMW) IIR in 7 of these 8. In this group antibodies were judged likely significant. In 2 people immunosuppression was introduced, with a good clinical result in one but only a biochemical response in another. In 6 people adjustment of insulin delivery was subsequently informed by knowledge of underlying antibody. In a final group of 5 participants IIR was below 3000 pmol/L but fell by more than 50% after PEG precipitation. In 4 of these GFC demonstrated low levels of HMW IIR and antibody significance was judged indeterminate. CONCLUSIONS: Anti-insulin antibodies should be considered in insulin-treated diabetes with unexplained glycaemic lability. Combining immunoassays with PEG precipitation can stratify their significance. Antibody depletion may be beneficial, but conservative measures often suffice.

Improving diabetes and endocrinology specialty training with modest resources: the Health Education West Midlands model.

INTRODUCTION: In the current pandemic, there is a significant disruption for medical training. It is essential that clinicians can access high-quality, targeted educational content to support their clinical working and training development. This content must be delivered on a background of increasing clinical pressures and budgetary restrictions. METHODS: Educational innovations and supplementary educational content (such as digitisation, simulation, curriculum mapping, trainee representative role definition, research and innovation training) were implemented. We measured the impact of these interventions on cost reductions and changes in trainees' self-reported confidence levels to manage various clinical scenarios post-interventions. RESULTS: Using digital technologies reduced both costs and administrative burdens. Simulation-based learning helped improve trainees' self-reported confidence levels. CONCLUSION: Collaborative working across training programme directors, specialist training committee members, educational supervisors, trainee representatives and trainees themselves can develop high-quality educational programmes that support clinical exposure. We propose that elements of the model described here can be replicated across regions and different specialties to support the highest quality of education for UK trainees.

Prevalence of undiagnosed type 2 diabetes in patients admitted with acute coronary syndrome: the utility of easily reproducible screening methods.

BACKGROUND: Despite the recognition of the importance of diagnosing dysglycaemia in patients with acute coronary syndrome (ACS) there remains a lack of consensus on the best screening modality. Our primary aims were to determine the prevalence of undiagnosed dysglycaemia and to compare the OGTT and HbA1c criteria for diagnosis of T2DM in patients admitted to hospital with ACS at baseline and at 3-months. We also aimed to investigate the role of a screening algorithm and a predictor score to define glucose tolerance in this population. METHODS: A prospective study in which patients admitted with ACS to two UK teaching hospitals were assessed at baseline and 3 months follow-up. RESULTS: The prevalence of diabetes at baseline was 20% and 16% based on OGTT and HbA1c criteria respectively. Forty three (43) % of the patients with T2DM based on OGTT would have been missed by the HbA1c criteria at baseline. Our screening algorithm identified 87% of patients with T2DM diagnosed with OGTT. Diabetes Predictor score had better sensitivity (>80%) and negative predictive value (>90%) compared to HbA1c criteria. Two thirds of participants with IGS and a third with T2DM changed their glycaemic status at 3 months. CONCLUSIONS: Only 48% of the patients admitted with ACS had normo-glycaemia based on OGTT. OGTT and HbA1c identified two different populations of patients with dysglycaemia with the HbA1c criteria missing almost half the patients with T2DM based on OGTT. Compared to HbA1c criteria our diabetes algorithm and diabetes predictor score had a better correlation with OGTT criteria.

Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts.

BACKGROUND: The thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves' disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1. METHODOLOGY AND PRINCIPAL FINDINGS: We aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P = 1.2×10(-2)-6.2×10(-15), OR = 1.38-1.45) and rs12101255 (P = 1.0×10(-4)-3.68×10(-21), OR = 1.47-1.87) exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics. CONCLUSIONS: We have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.