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Aims: In the current study we aimed to evaluat T cell phenotypes and metabolic profiles in high-risk individuals who progressed to type 1 diabetes compared to those remaining disease free., Methods: A Fluorspot assay was used to examine T cell responses to a panel of islet autoantigen peptides in samples obtained 6- and 30-months preceding disease onset and at the same timepoints in non-progressors., Results: We noted a significant increase in the magnitude of the proinflammatory interferon-γ response to proinsulin and insulin peptides in individuals who progressed to type 1 diabetes. In contrast, in the non-progressors, we observed an increase in the regulatory IL-10 response to proinsulin peptides. Furthermore, the T cell responses to the islet peptide panel predisposed towards a proinflammatory interferon-γ bias in the progressors., Conclusions: Collectively, these data suggest that a proinflammatory T cell response is prevalent in high-risk individuals who progress to type 1 diabetes and can be detected up to 6 months prior to onset of disease. This observation, albeit in a small cohort, can potentially be harnessed in disease staging, particularly in identifying autoantibody-positive individuals transitioning from stage 2 (dysglycemia present and pre-symptomatic) to stage 3 (dysglycemia present and symptomatic). The detection of these different T cell phenotypes in progressors and non-progressors suggests the presence of disease endotypes., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.) more...

Aims: To evaluate the feasibility of using self-collected capillary blood samples for islet autoantibody testing to identify risk in relatives of people with Type 1 diabetes., Methods: Participants were recruited via the observational TrialNet Pathway to Prevention study, which screens and monitors relatives of people with Type 1 diabetes for islet autoantibodies. Relatives were sent kits for capillary blood collection, with written instructions, an online instructional video link and a questionnaire. Sera from capillary blood samples were tested for autoantibodies to glutamic acid decarboxylase, islet antigen-2, insulin and zinc transporter 8. 'Successful' sample collection was defined as obtaining sufficient volume and quality to provide definitive autoantibody results, including confirmation of positive results by repeat assay., Results: In 240 relatives who returned samples, the median (range) age was 15.5 (1-49) years and 51% were male. Of these samples, 98% were sufficient for glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 autoantibody testing and 84% for insulin autoantibody testing and complete autoantibody screen. The upper 90% confidence bound for unsuccessful collection was 4.4% for glutamic acid decarboxylase, islet antigen-2 and/or zinc transporter 8 autoantibody assays, and 19.3% for insulin autoantibodies. Despite 43% of 220 questionnaire respondents finding capillary blood collection uncomfortable or painful, 82% preferred home self-collection of capillary blood samples compared with outpatient venepuncture (90% of those aged <8 years, 83% of those aged 9-18 years and 73% of those aged >18 years). The perceived difficulty of collecting capillary blood samples did not affect success rate., Conclusions: Self-collected capillary blood sampling offers a feasible alternative to venous sampling, with the potential to facilitate autoantibody screening for Type 1 diabetes risk., (© 2017 Diabetes UK.) more...

Aim: To examine the hypothesis that the quality, magnitude and breadth of helper T-lymphocyte responses to β cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood., Methods: We studied helper T-lymphocyte reactivity against β-cell autoantigens by measuring production of the pro-inflammatory cytokine interferon-γ and the anti-inflammatory cytokine interleukin-10, using enzyme-linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401), of whom 33 were children/adolescents, and a further 91 were unaffected siblings., Results: Interferon-γ responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children (P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon-γ response was also greater, with 70% of children having an interferon-γ response to three or more peptides compared with 14% of adults (P < 0.0001). Islet β-cell antigen-specific interleukin-10 responses were similar in children and adults in terms of frequency, breadth and magnitude, with the exception of responses to glutamic acid decarboxylase 65, which were significantly less frequent in adults., Conclusions: At diagnosis of Type 1 diabetes, pro-inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age-related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune-based therapies., (© 2016 Diabetes UK.) more...

Aims: A subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives., Methods: GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands., Results: Of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer (P < 0.001), diagnosed at a younger age (P = 0.011) and progressed to insulin faster (P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects (P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative., Conclusion: Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic beta-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility. more...

Aims: To test the effect of continuing metformin on weight gain and glycaemic control in patients with poorly controlled Type 2 diabetes who need to start insulin., Methods: Patients with Type 2 diabetes on maximum tolerated oral agents referred for insulin conversion were recruited from hospital diabetes clinics into a double-blind randomized placebo-controlled trial. The 183 participants received metformin or placebo, titrated up to 2 g a day or maximum tolerated dose, with insulin started according to local practice. The main outcome measures were weight change over 12 months, HbA1c, insulin dose, frequency of hypoglycaemia, treatment satisfaction, and well-being., Results: Over 12 months, metformin was associated with less weight gain than placebo [mean 6.1 kg vs. 7.6 kg; adjusted difference 1.5 kg (95% confidence interval 0.2-2.9); P=0.02], a greater reduction in HbA1c[1.5% vs. 1.3%; adjusted difference 0.5% (0.1-0.9); P=0.02] and a lower insulin requirement [62 units vs. 86; adjusted difference 25 units (15-34); P<0.001], but also more hypoglycaemia [relative risk of any episode 1.24 (1.02-1.1); P=0.03]. Treatment satisfaction improved more in patients on metformin than on placebo (P<0.001), as did the positive well-being score (P=0.02)., Conclusions: Metformin decreases weight gain, lowers insulin requirement, and improves glycaemic control, and should be continued in patients with Type 2 diabetes who transfer to insulin. more...

Aims: To investigate mortality in South Asian patients with insulin-treated diabetes and compare it with mortality in non South Asian patients and in the general population., Methods: A prospective cohort study was conducted of 828 South Asian and 27 962 non South Asian patients in the UK with insulin-treated diabetes diagnosed at ages under 50 years. The patients were followed for up to 28 years. Ethnicity was determined by analysis of names. Standardized mortality ratios (SMRs) were calculated, comparing mortality in the cohort with expectations from the mortality experience of the general population., Results: SMRs were significantly raised in both groups of patients, particularly the South Asians, and especially in women and subjects with diabetes onset at a young age. The SMRs for South Asian patients diagnosed under age 30 years were 3.9 (95% CI 2.0-6.9) in men and 10.1 (5.6-16.6) in women, and in the corresponding non South Asians were 2.7 (2.6-2.9) and 4.0 (3.6-4.3), respectively. The SMR in women was highly significantly greater in South Asians than non South Asians. The mortality in the young-onset patients was due to several causes, while that in the patients diagnosed at ages 30-49 was largely due to cardiovascular disease, which accounted for 70% of deaths in South Asian males and 73% in females., Conclusions: South Asian patients with insulin-treated diabetes suffer an exceptionally high mortality. Clarification of the full reasons for this mortality are needed, as are measures to reduce levels of known cardiovascular disease risk factors in these patients., (Copyright 2004 Diabetes UK) more...

Aims: To assess mortality in patients with diabetes incident under the age of 30 years., Methods: A cohort of 23 752 diabetic patients diagnosed under the age of 30 years from throughout the United Kingdom was identified during 1972-93 and followed up to February 1997. Following notification of deaths during this period, age- and sex-specific mortality rates, attributable risks and standardized mortality rates were calculated., Results: The 23 752 patients contributed a total of 317 522 person-years of follow-up, an average of 13.4 years per subject. During follow-up 949 deaths occurred in patients between the ages of 1 and 84 years, 566 in males and 383 in females. All-cause mortality rates in the patients with diabetes exceeded those in the general population at all ages and within the cohort were higher for males than females at all ages except between 5 and 15 years. The relative risk of death (standardized mortality ratio, SMR), was higher for females than males at all ages, being 4.0 (95% CI 3.6-4.4) for females and 2.7 (2.5-2.9) for males overall, but reaching a peak of 5.7 (4.7-7.0) in females aged 20-29, and of 4.0 (3.1-5.0) in males aged 40-49. Attributable risks, or the excess deaths in persons with diabetes compared with the general population, increased with age in both sexes., Conclusions: This is the first study from the UK of young patients diagnosed with diabetes that is large enough to calculate detailed age-specific mortality rates. This study provides a baseline for further studies of mortality and change in mortality within the United Kingdom. more...

Aims: To measure cause-specific mortality, by age, in patients with insulin-treated diabetes incident at a young age., Methods: A cohort of 23 752 patients with insulin-treated diabetes diagnosed under the age of 30 years, from throughout the United Kingdom, was identified during 1972-93 and followed to February 1997. Death certificates have been obtained for deaths during the follow-up period and cause-specific mortality rates and standardized mortality ratios by age and sex are reported., Results: During the follow-up period 949 deaths occurred and at all ages mortality rates were considerably higher than in the general population. Acute metabolic complications of diabetes were the greatest single cause of excess death under the age of 30 years. Cardiovascular disease was responsible for the greatest proportion of the deaths from the age of 30 years onwards., Conclusions: Deaths in patients with diabetes diagnosed under the age of 30 have been reported and comparisons drawn with mortality in the general population. To reduce these deaths attention must be paid both to the prevention of acute metabolic deaths and the early detection and treatment of cardiovascular disease and associated risk factors. more...