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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period. Methods: All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. Results: Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. Conclusions/interpretation: The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted. [ABSTRACT FROM AUTHOR]

Autoantibodies to islet cell proteins currently provide the only reliable indication that the process leading to type 1 diabetes has started. The period from the first detection of islet autoantibodies to clinical onset of diabetes can last months or years. Longitudinal birth cohort family studies give crucial information concerning the natural history of islet autoimmunity and have already shown that islet autoantibodies, which precede diabetes development, often appear in early infancy. In this issue of Diabetologia, Ziegler et al (DOI:) and Parikka et al (DOI:) report findings from their birth cohort studies after numerous children have entered adolescence, allowing a more complete picture of islet autoimmunity in childhood to be revealed. Both groups are in accord that, between 6 months and 3 years of age, there is an explosion of islet autoimmunity in susceptible children and that the great majority (approximately 80%) of genetically at-risk children who present with diabetes before adolescence develop islet autoimmunity at this young age. These findings emphasise the importance of early life events in disease pathogenesis and have major implications for efforts aimed at preventing type 1 diabetes. [ABSTRACT FROM AUTHOR]

Summary Development of high-risk combinations of multiple islet autoantibodies and type 1 diabetes is associated with high-affinity insulin autoantibodies (IAA), but IAA affinity measurements require large serum volumes. We therefore investigated whether a simplified method of IAA affinity measurement using a low concentration of unlabelled insulin (ULI) competitor discriminated between moderate-high- and low-affinity IAA and identified individuals at highest risk of disease. Samples were assayed by radiobinding microassay using high (4·0 × 10−5 mol/l) and low (7 × 10−9 mol/l) ULI concentrations for competitive displacement in three cohorts of IAA-positive individuals; (1) 68 patients with newly-diagnosed type 1 diabetes; (2) 40 healthy schoolchildren; and (3) 114 relatives of patients with type 1 diabetes followed prospectively for disease development (median follow-up 13 years). IAA results obtained with low ULI were expressed as a percentage of those obtained with high ULI and this was used to classify samples as low or moderate-high affinity (0-50% and >50%, respectively). Sixty-eight patient samples were positive with high and 67 (99%) with low ULI. Forty schoolchildren were IAA-positive with high and 22 (55%) with low ULI ( P < 0·001). Of the relatives, 113 were positive with high and 83 (73%) with low ULI ( P < 0·001). In relatives, moderate-high affinity IAA were associated with multiple islet antibodies ( P < 0·001) and greater diabetes risk than low affinity IAA ( P < 0·001). A single low concentration of ULI competitor can act as a surrogate for complex IAA affinity measurements and identifies those IAA-positive relatives at highest risk of disease progression. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly. Methods: KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results: Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years ( p = 0.003, corrected p [ p] = 0.012) and ( p = 0.001, p = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls ( p = 1.9 × 10). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation: Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group. [ABSTRACT FROM AUTHOR]

Introduction/background Type 1 diabetes is a chronic autoimmune condition characterized by destruction of insulin-producing β cells within the pancreatic islets. It is associated with considerable morbidity and mortality. Incidence levels are rising worldwide. Sources of data Pubmed search (Nov 2010) using keywords: Type 1 diabetes, prevention, trials, immunotherapy. Areas of agreement The causes of disease are multifactorial with genetic and environmental factors playing a part. There is a long pre-clinical period before the onset of overt symptoms, which may be amenable to therapeutic intervention to prevent disease. Areas of controversy The exact nature of causative environmental factors is unknown and much debated. Immunotherapeutic intervention may therefore represent the best option for disease prevention. Growing points Enhancement of ‘regulatory’ immune mechanisms currently shows the most promise as an approach to disease prevention. Areas timely for developing research Clinical trials of early immunotherapeutic intervention may be the answer to disease prevention. [ABSTRACT FROM PUBLISHER]

Diabet. Med. 28, 1028-1033 (2011) Abstract 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 FROM AUTHOR]

ims/hypothesis: Insulin autoantibodies (IAA) are important in type 1 diabetes risk assessment. However, their determination varies more between laboratories than other diabetes autoantibodies. The Diabetes Antibody Standardization Program (DASP) aims to improve and standardise measurement of autoantibodies associated with type 1 diabetes. We report the results of measurement of IAA from DASP workshops in 2002, 2003 and 2005. Methods: Up to 32 laboratories in 14 countries participated in each workshop. Aliquots of coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls were circulated to participating laboratories. Reported results were analysed using receiver operator characteristic (ROC) curves. We compared concordance of antibody levels by ranking, IAA and insulin antibody (IA) indices and units derived from an IA standard curve. Results: In all three workshops IAA assay performance had improved compared with DASP 2000. The median area under the ROC curve was 0.73 in DASP 2002, 0.78 in 2003 and 0.80 in 2005 ( p = 0.0012), and median laboratory-assigned sensitivity was 26% in 2002, 36% in 2003 and 45% in 2005 ( p < 0.0001). There was, however, marked variation between assays. The range of AUC was 0.36-0.91 and that of laboratory-assigned sensitivity was 22-57%. Concordance of ranking of patient serum samples was related to AUC ( p < 0.001). Using an index related to common IAA and IA-positive or -negative control sera improved the concordance between assays ( p < 0.0001). Conclusions/interpretation: The overall performance of IAA assays has improved but there is still wide variation between laboratories. Concordance between assays would be improved by the use of a common reference reagent. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a chronic autoimmune condition resulting from T cell–mediated destruction of the insulin-producing cells in the islets of Langerhans. Its primary cause remains unknown, but it has been established that the clinical presentation is preceded by a long prodrome. This enables individuals at high risk of disease to be identified and offers the possibility of intervention to prevent clinical disease. Many groups are working in this field, concentrating on manipulation of environmental exposures that are potential triggers of autoimmunity and on immunomodulation strategies that aim to prevent destruction of β-cells. Some interventions have shown promising results in early trials, but effective disease prevention remains elusive. This article reviews current progress in the field. [ABSTRACT FROM AUTHOR]

Aim To define the incidence and characteristics of latent autoimmune diabetes in adults (LADA). Methods We estimated the incidence of LADA by examining the incidence of Type 2 diabetes and calculating the proportion that were antibody positive. The incidence of Type 2 diabetes was calculated by analysis of computer records of 35 out of 36 general practices in Swansea. In addition, thirty-two practices participated in recruiting people with Type 2 diabetes to have glutamic acid decarboxylase (GAD) antibody testing. Results The crude proportion of Type 2 patients testing positive for GAD antibodies (GADA) was 4.0% (28/683). This figure did not change when we analysed only the practices that tested more than 60% of all eligible patients. In these practices, 79% (387/487) of all eligible patients were GADA tested and 14/387 [3.6% (95% confidence interval: 2.1–6.1%)] were classified as having LADA. This gives an incidence of LADA of 9 per 100 000 (95% confidence interval: 4.4–17.8 per 100 000) people per year registered with a general practitioner. Patients testing positive for GADA were more likely to have a lower body mass index, other antibodies, to present with acute symptoms and to have higher glycated haemoglobin. Conclusions This is the first study of the incidence of LADA in primary care. People with LADA make up a significant proportion of people with apparent Type 2 diabetes. Patients with LADA are likely to be symptomatic, have poorer glycaemic control and have other autoimmune antibodies. [ABSTRACT FROM AUTHOR]

To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A). HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7–20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients. IA-2A prevalence was highest in patients carrying at least one HLA-DRB1*04-DQA1*0301 (385 of 450; 86%), DRB1*07-DQA1*(0201 or 0301) (58 of 64; 91%) or DRB1*09-DQA1*0301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes ( p < 0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB1*03-DQB1*02 or DRB1*07-DQB1*02 haplotypes than in those negative for these haplotypes (52%) ( p = 0.002), but showed an independent positive association with IA-2A level ( p < 0.001). HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB1*04, DRB1*07 and DRB1*09 alleles in linkage disequilibrium with DQA1*0301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is increasing among young adult South Asians. The aim of this study was to determine the prevalence and phenotypic characteristics of diabetes subtypes based on GAD65 autoantibody (GADA) status in those with young adult-onset diabetes in Sri Lanka. Clinical, metabolic and GADA data were available for 992 consecutively recruited individuals with diabetes aged ≤45 years (age at diagnosis 16–40 years). Participants were classified according to the following definitions: type 1 diabetes, insulin-dependent <6 months from diagnosis; latent autoimmune diabetes in adults (LADA), GADA-positive, age ≥30 years and insulin-independent ≥6 months from diagnosis; type 2 diabetes, GADA-negative and insulin-independent ≥6 months from diagnosis. The median (interquartile range) age at diagnosis and diabetes duration were 33.0 (29.0–36.1) and 4.0 (1.1–7.1) years, respectively; 42.1% were male. GADA positivity was seen in 5.4% of participants ( n = 54) and GADA levels negatively correlated with age at diagnosis ( p < 0.0001), BMI ( p < 0.0001) and time to insulin requirement ( p = 0.006). Type 1 diabetes, type 2 diabetes and LADA were present in 7.0%, 89.7% and 2.6%, respectively. The remaining 0.7% of the participants were GADA-positive, insulin independent ≥6 months from diagnosis and were diagnosed at age <30 years. The metabolic syndrome and homeostasis model assessment of beta cell function (HOMA %B) were lowest in GADA-positive type 1 diabetes and increased progressively in latent autoimmune diabetes, GADA-negative type 1 diabetes and type 2 diabetes. Among those requiring insulin, 69.2% had fasting C-peptide levels in the lowest quartile, whereas only 19.5% were GADA-positive ( p < 0.0001). The prevalence of GADA-positive autoimmune diabetes is low among individuals with young adult-onset diabetes in Sri Lanka. Young-onset diabetic phenotypes appear as a continuum from autoimmune type 1 diabetes to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Islet autoantibodies are important in diabetes classification and risk assessment, and as endpoints in observational studies. The Diabetes Autoantibody Standardization Program (DASP) aims to improve and standardise measurement of autoantibodies associated with type 1 diabetes. We report results for glutamic acid decarboxylase autoantibodies (GADA) and islet antigen-2 autoantibodies (IA-2A) from three DASP workshops (2002–2005). Up to 60 laboratories in 18 countries participated in each workshop. Participants received coded serum aliquots from 50 patients with newly diagnosed type 1 diabetes (median age 18 years, range 9–35 years) and 100 blood donor controls. Results were analysed using receiver operator characteristic (ROC) curves with sensitivity adjusted to 95% specificity in workshop controls. GADA assays performed well in all three workshops (median area under the ROC curve [AUC] 0.94; interquartile range 0.91–0.95) and performance was similar to DASP 2000. Performance of IA-2A assays improved over the workshop programme. Median AUC was 0.81 (interquartile range 0.79–0.83) in DASP 2002, 0.82 (interquartile range 0.78–0.84) in 2003, and 0.85 (interquartile range 0.82–0.87) in 2005 ( p < 0.0001). Performance of GADA ELISA improved between 2002 and 2005, and, in DASP 2005, achieved higher median AUC and adjusted sensitivity than RIA. IA-2A ELISA improved and, in DASP 2005, achieved AUCs equivalent to in-house RIA. Assays using IA-2ic or full length IA-2 clones were more sensitive than those using IA-2bdc, with higher AUC ( p = 0.004). GADA and IA-2A assays perform well in discriminating health and disease. The workshop format highlights systematic differences related to assay method and allows full evaluation of novel methods. The programme of autoantibody workshops in type 1 diabetes provides a model for other autoimmune diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the prognostic significance of autoantibodies to IA-2β (IA2βA) in a large, well-characterised population of islet cell antibody (ICA)-positive relatives followed for 5 years in the European Nicotinamide Diabetes Intervention Trial. Autoantibodies to insulin (IAA), glutamate decarboxylase (GADA) and IA-2 (IA2A) were measured in 549 participants at study entry, and IA2A-positive samples tested for IA2βA. First-phase insulin response (FPIR) and oral glucose tolerance were determined at baseline. Of 212 ICA/IA2A-positive participants (median age 12.1 years; 57% male), 113 developed diabetes (5 year cumulative risk 56%), and 148 were also GADA-positive and IAA-positive (4Ab-positive). IA2βA were detected in 137 (65%) ICA/IA2A-positive participants and were associated with an increased 5 year diabetes risk (IA2βA-positive 65 vs 39% in IA2βA-negative, p = 0.0002). The effect was most marked in 4Ab-positive relatives (72% vs 52%, p = 0.003). Metabolic testing further refined risk assessment. Among 101 4Ab-positive relatives with IA2βA, the 5 year risk was 94% in those with a low FPIR (vs 50% in those with a normal FPIR, p < 0.0001), and 95% in those with impaired glucose tolerance (IGT) (vs 66% in those with normal glucose tolerance, p < 0.0001). The median time to diagnosis of 4Ab/IA2βA-positive participants with a low FPIR was 1.5 years. Multivariate analysis confirmed IA2βA status, antibody number, young age, FPIR and IGT as independent determinants of risk. IA2βA are associated with a very high risk of diabetes in ICA/IA2A-positive relatives. Testing for IA2A/IA2βA compares favourably with the IVGTT in identifying a subgroup of autoantibody-positive relatives at increased risk. IA2βA determination should be added to screening protocols of future intervention trials. [ABSTRACT FROM AUTHOR]

Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes, with autoantibodies to islet proteins developing in older patients who have no immediate requirement for insulin therapy. Markers of its clinical course are uncharacterised. The aim of this study was to determine whether persistence of, or changes in, GAD65 autoantibodies (GADAs) in the LADA patients who participated in the United Kingdom Prospective Diabetes Study (UKPDS) were associated with disease progression or insulin requirement. GADA levels and their relative epitope reactivities to N-terminal, middle and C-terminal regions of human GAD65 were determined in 242 UKPDS patients who were GADA-positive at diagnosis; samples taken after 0.5, 3 and 6 years of follow-up were tested using a radiobinding assay. Comparisons were made of GADA status with clinical details and disease progression assessed by the requirement for intensified glucose-lowering therapy. GADA levels fluctuated between 0.5 and 6 years but persisted in 225 of 242 patients. No association of GADA levels with disease progression or insulin requirement was observed. Antibody reactivity was directed to C-terminal and middle epitopes of GAD65 in >70% patients, and the N-terminal in <9%. There were no changes in epitope reactivity pattern over the 6 year follow-up period, nor any association between epitope reactivity and insulin requirement. GADAs persist for 6 years after diagnosis of LADA, but levels and reactivity to different GAD65 epitopes are not associated with disease progression. [ABSTRACT FROM AUTHOR]

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate (‘neutral’), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels. [ABSTRACT FROM AUTHOR]

Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. Patients with LADA ( n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects ( n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. As in type 1 diabetes mellitus, DRB1*0301_DQB1*0201 (odds ratio [OR] = 3.08, 95% CI 2.32–4.12, p = 1.2 × 10−16) and DRB1*0401_DQB1*0302 (OR = 2.57, 95% CI 1.80–3.73, p = 4.5 × 10−8) were the main susceptibility haplotypes in LADA, and DRB1*1501_DQB1*0602 was protective (OR = 0.21, 95% CI 0.13–0.34, p = 4.2 × 10−13). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (OR = 1.79, 95% CI 1.35–2.38, p = 2.7 × 10−5) whereas DRB1*0403 was protective (OR = 0.37, 95% CI 0.13–0.97, p = 0.033). The highest-risk genotypes were DRB1*0301/DRB1*0401 and DQB1*0201/DQB1*0302 (OR = 5.14, 95% CI 2.68–10.69, p = 1.3 × 10−8; and OR = 6.88, 95% CI 3.54–14.68, p = 1.2 × 10−11, respectively). These genotypes and those containing DRB1*0401 and DQB1*0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1*1501 and DQB1*0602 associated with an older age at diagnosis. Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes. [ABSTRACT FROM AUTHOR]

Combinations of autoantibody characteristics, including antibody number, titre, subclass and epitope have been shown to stratify type 1 diabetes risk in islet autoantibody-positive relatives. The aim of this study was to determine whether autoantibody characteristics change over time, the nature of such changes, and their implications for the development of diabetes. Five-hundred and thirteen follow-up samples from 141 islet autoantibody-positive first-degree relatives were tested for islet autoantibody titre, IgG subclass, and GAD and IA-2 antibody epitope. All samples were categorised according to four risk stratification models. Relatives had a median follow-up of 6.8 years and 48 developed diabetes during follow-up. Survival analysis was used to determine the probability of change in risk category and of progression to diabetes. For each stratification model, the majority of relatives (71–81%) remained in the same risk category throughout follow-up. In the remainder, changes occurred both from lower to higher and from higher to lower risk categories. For all four models, relatives aged < 15 years were more likely to change risk category than those aged >15 years (0.001 < p < 0.03). Relatives whose autoantibody status changed from low- to high-risk categories had a higher risk of diabetes than relatives who remained in low-risk categories, and inclusion of autoantibody status during follow-up improved diabetes risk stratification in Cox proportional hazards models ( p < 0.001). Changes in islet autoantibodies are relevant to pathogenesis, and are likely to signal alterations in the disease process. Detection of changes through follow-up measurement will improve diabetes risk stratification, particularly in young individuals. [ABSTRACT FROM AUTHOR]

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 β-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: To examine the role of additional immune, genetic and metabolic risk markers in determining risk of diabetes in islet cell antibody (ICA)-positive individuals with a family history of type 1 diabetes recruited into the European Nicotinamide Diabetes Intervention Trial. Methods: Five hundred and fortynine first-degree relatives with confirmed ICA levels ≥20 Juvenile Diabetes Foundation units (mean age 15.9 years; interquartile range 10.4–33.7 years) were recruited from 20 countries. OGTTs and IVGTTs were performed at baseline, antibodies to glutamate decarboxylase (GADA), protein tyrosine phosphatase (IA-2A) and insulin (IAA) were determined by RIA, and HLA class II genotyping was performed by PCR of sequence-specific oligonucleotides. Results: One hundred and fifty-nine participants developed diabetes within 5 years. Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population. Children aged ≤10 years had a 59% risk of diabetes within 5 years, compared with 11% in those ≥25 years (p<0.0001). Using multivariate analysis, independent determinants were age, first-phase insulin response, baseline glucose tolerance and number of additional antibody markers, but not antibody type or genotype. Individuals <25 years with two or more additional antibodies at baseline had a 62% risk of diabetes within 5 years and these combined criteria identified 81% of the cases in the whole cohort. Conclusions/interpretation: We suggest that screening and recruitment for future intervention trials should be limited to family members aged <25 years, and should be based on islet autoantibodies alone. [ABSTRACT FROM AUTHOR]

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.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.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).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.Diabet. Med.22, 634–640 (2005) [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. Diabet. Med. (2004) [ABSTRACT FROM AUTHOR]

Aims/hypothesis. One in four children with Type 1 diabetes in a population-based family study has an affected grandparent. We set out to study the clinical and immune features of diabetes in the grandparents' generation, and to examine sharing of HLA class II susceptibility haplotypes between grandparent and grandchild. Methods. Of 5855 grandparents in the Bart's-Oxford family study, 428 (7.3%) were known to have diabetes. Clinical data and samples were collected from 115 of 213 surviving affected grandparents and from 219 unaffected grandparents within the same families. Samples were tested for ICA and autoantibodies to GAD and IA-2, and typed for HLA-DRB1-DQA1-DQB1. Transmission of HLA class II haplotype from affected and unaffected grandparents to the diabetic proband was compared. Results. Of 115 affected grandparents studied, the median age at diagnosis was 61 years and at analysis was 73 years; 70% were diet or tablet treated and 30% were on insulin. One or more islet autoantibodies were found in 26% and 66% had one or both of the high risk HLA class II susceptibility haplotypes DRB1*03-DQA1*0501-DQB1*0201 or DRB1*04-DQA1*0301-DQB1*0302. In 79 informative families the HLA class II haplotype of the affected grandparent was transmitted to the proband more frequently than expected overall (59%, p=0.02), and in the insulin-treated subgroups (65%, p=0.03). Conclusion/interpretation. A total of 7.3% of grandparents reported a clinical diagnosis of diabetes and 2.2% had features of Type 1 diabetes. Genetic susceptibility was shared between grandparents with diabetes and their affected grandchildren. Diabetes in the grandparents of children with Type 1 diabetes often has an autoimmune basis, even when it presents late in life and does not require insulin treatment. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Although ischaemic heart disease is the predominant cause of mortality in older people with diabetes, age-specific mortality rates have not been published for patients with Type 1 diabetes. The Diabetes UK cohort, essentially one of patients with Type 1 diabetes, now has sufficient follow-up to report all heart disease, and specifically ischaemic heart disease, mortality rates by age. Methods. A cohort of 23,751 patients with insulin-treated diabetes, diagnosed under the age of 30 years and from throughout the United Kingdom, was identified during the period 1972 to 1993 and followed for mortality until December 2000. Age- and sex-specific heart disease mortality rates and standardised mortality ratios were calculated. Results. There were 1437 deaths during the follow-up, 536 from cardiovascular disease, and of those, 369 from ischaemic heart disease. At all ages the ischaemic heart disease mortality rates in the cohort were higher than in the general population. Mortality rates within the cohort were similar for men and women under the age of 40. The standardised mortality ratios were higher in women than men at all ages, and in women were 44.8 (95%CI 20.5–85.0) at ages 20–29 and 41.6 (26.7–61.9) at ages 30–39. Conclusions/interpretation. The risk of mortality from ischaemic heart disease is exceptionally high in young adult women with Type 1 diabetes, with rates similar to those in men with Type 1 diabetes under the age of 40. These observations emphasise the need to identify and treat coronary risk factors in these young patients. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Previous studies have reported an excess of Type II (non-insulin-dependent) diabetes mellitus in parents of children with Type I (insulin-dependent) diabetes mellitus. We set out to characterise the clinical and immunogenetic features of diabetes in parents of affected children, and to test the hypothesis that there is no excess of Type II diabetes within this population. Methods. Clinical details were collected from 3164 parents of 1641 children with Type I diabetes participating in the Bart's-Oxford study of childhood diabetes. Islet cell antibodies, antibodies to GAD and IA-2, and HLA class II genotype were determined in a subset of this group. Individuals were assigned a classification of Type I diabetes on the basis of clinical features and measurement of islet autoantibodies. Results. Of 184 parents with diabetes, 138 (75 %) were on insulin. At least one islet autoantibody was detected in 90 (59 %) of 152 parents tested, and of 116 who were HLA-typed, 23 (20 %) had the highest risk genotype HLA-DRB1*03-DQA1*0501-DQB1*0201 / DRB1*04-DQA1*0301-DQB1*0302. Of 46 non-insulin-treated parents, 12 had islet autoantibodies. Of all parents, 141 (4.5 %) were therefore classified as having Type I diabetes, and 31 (0.98 %) as Type II diabetes; 12 could not be classified because of missing data or samples. Conclusion/interpretation. Autoimmune diabetes can present late and without immediate need for insulin treatment in parents of children with the disease. Previous studies have categorised this as Type II diabetes. Our study suggests that there is no excess of non-autoimmune diabetes in the families of children with Type I diabetes. [Diabetologia (2002) 45: ▪–▪] [ABSTRACT FROM AUTHOR]

Aims/hypothesis: First-degree relatives of patients with Type I (insulin-dependent) diabetes mellitus diagnosed at 20 years of age or under were screened for islet cell antibodies (ICA) in the course of recruitment to an international diabetes prevention trial. Our aim was to evaluate the influence of age, gender, proband characteristics and nationality on the prevalence of ICA and co-existence of autoantibodies to GAD, IA-2 and insulin. Methods: A central laboratory screened samples from 10 326 non-diabetic relatives who were aged less than 40 years, from eight European countries for ICA. Antibodies to GAD and IA-2 were measured in all samples with ICA of 10 JDF units or more. Results: Overall, 8.9 % of relatives had ICA of 10 JDF units or more, 3.8 % with ICA of 20 JDF units or more. Of 921 relatives with ICA of 10 JDF units or more, 29 % had co-existing antibodies to GAD or IA-2 or both. ICA of 10 JDF units or more were more prevalent in males (10.8 %) than females (7.3 %). ICA with GAD or IA-2 antibodies or both were also more common in males (3.4 %) than females (1.9 %) and in relatives under 20 years of age (3.5 % vs 1.5 %). Multiple regression analysis showed nationality to be a determinant of ICA of 10 JDF units or more but not of ICA of 20 JDF units or more or of ICA with co-existing islet antibodies, and confirmed the importance of age and gender as determinants of islet autoimmunity. Conclusions/interpretation: Relatives from different European countries have similar rates of islet autoimmunity despite wide variation in the background incidence of childhood diabetes, and male excess is equally evident in all populations. The male excess of ICA and islet autoimmunity over 10 years of age reflects the higher male incidence of Type I diabetes in this age group, and suggests that boys may be more likely than girls to develop islet autoimmunity during adolescence. [Diabetologia (2002) 45: 217–223] [ABSTRACT FROM AUTHOR]

Objective: To determine the extent of celiac autoimmunity in type 1 diabetic patients and the overlap between islet and celiac autoimmunity in their nondiabetic relatives.Research Design and Methods: IgA antibodies to tissue transglutaminase were determined in serum taken from 433 type 1 diabetic patients and 1,442 nondiabetic first-degree relatives. Samples with transglutaminase antibodies above the 97.5th percentile of 347 schoolchildren were also assayed for IgA anti-endomysial antibodies (EMAs). Markers of islet autoimmunity (islet cell antibodies and autoantibodies to insulin, glutamate decarboxylase. and protein tyrosine phosphatase IA-2) had previously been measured in all relatives.Results: In the absence of known celiac disease, the prevalence of transglutaminase antibody levels above the 97.5th percentile of the schoolchildren was 13.4% in diabetic patients and 7.0% in nondiabetic relatives. ENMAs were found in addition to transglutaminase antibodies in 2.6% of probands and in 1.9% of first-degree relatives, but none of the schoolchildren. Transglutaminase antibodies were found to persist in 10 of 30 patients and in 30 of 59 relatives with follow-up samples taken at least 2 years after the initial sample. Of 186 nondiabetic relatives with islet autoantibodies, only 10 also had transglutaminase antibodies.Conclusions: We found a high prevalence of celiac autoimmunity in patients and first-degree relatives of children with type 1 diabetes, but we found limited overlap between islet and celiac autoimmunity in nondiabetic relatives. The high prevalence of celiac autoimmunity may be explained by shared genetic susceptibility and identifies a population within which screening for the disease may be justified. [ABSTRACT FROM AUTHOR]

Aims/Hypothesis. To examine the prevalence of subclinical islet autoimmunity in children from two countries with a twofold to threefold difference in incidence of childhood Type I (insulin-dependent) diabetes mellitus.¶Methods. Sera were collected from 2860 English and 3053 Lithuanian non-diabetic schoolchildren according to the same protocol. Occult diabetes was excluded by blood glucose measurement. Antibodies to GAD and the protein tyrosine phosphatase IA-2 were measured with standardised radiobinding assays in a single laboratory. Islet cell antibodies and insulin autoantibodies were additionally measured in all samples with GAD and/or IA-2 antibody levels above the 97.5th centile of the English schoolchildren.¶Results. Of Lithuanian schoolchildren 2.7 % had GAD antibodies above the 97.5th centile of the English schoolchildren but only 0.2 % had antibodies to IA-2 above this threshold (p < 0.001). Islet cell and/or insulin autoantibodies above the 97.5th centile were found in 22 Lithuanian and 16 English schoolchildren and the overall prevalence of two or more antibodies on or above the 97.5th centile was similar [0.7 % (0.5–1.1) vs 0.6 % (0.4–1.0)] in the two cohorts.¶Conclusion/interpretation. The prevalence of multiple antibody markers was similar in the cohorts from the two populations, despite the two to three-fold difference in incidence of diabetes. The unexpectedly high prevalence of subclinical islet autoimmunity suggests that the incidence of diabetes in Lithuania is likely to increase in the near future. [Diabetologia (2001) 44: 16–21] [ABSTRACT FROM AUTHOR]

Nicotinamide, the amide derivative of nicotinic acid, has over the past forty years been given at high doses for a variety of therapeutic applications. It is currently in trial as a potential means of preventing the onset of Type I (insulin-dependent) diabetes mellitus in high-risk, first-degree relatives. Nicotinamide is for regulatory purposes classed as a food additive rather than a drug and has not therefore required the formal safety evaluation normally expected of a new therapy. Because the safety of treatment with megadoses of vitamins cannot be assumed, a full literature review has been undertaken. The therapeutic index of nicotinamide is wide but at very high doses reversible hepatotoxicity has been reported in animals and humans. Minor abnormalities of liver enzymes can infrequently occur at the doses used for diabetes prevention. There is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; at very high doses it does however potentiate islet tumour formation in rats treated with streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can occur in rats but growth in children is unaffected. Studies of its effects on glucose kinetics and insulin sensitivity are inconsistent but minor degrees of insulin resistance have been reported. The drug is well tolerated, especially in recent studies which have used relatively pure preparations of the vitamin. Experience to date therefore suggests that the ratio of risk to benefit of long-term nicotinamide treatment would be highly favourable, should the drug prove efficacious in diabetes prevention. High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged. [Diabetologia (2000) 43: 1337–1345] [ABSTRACT FROM AUTHOR]

Summary L‐selectin (CD62L) is a cell adhesion molecule which plays a key role in the initiation of leucocyte migration from blood vessels to sites of local inflammation. The aim of this study was to investigate T‐lymphocyte expression of CD62L antigen and serum levels of soluble L‐selectin (sL‐selectin) in subjects with clinical and preclinical type I diabetes to determine whether they could provide surrogate markers for disease activity. CD62L selectin expression on memory T lymphocytes was studied by cytometric analysis in 22 patients with newly diagnosed type I diabetes, 20 first‐degree relatives of patients with type I diabetes, 14 patients with Graves’ disease, and 22 healthy controls. sL‐selectin levels were measured by enzyme‐linked immunosorbent assay (ELISA) in enlarged groups of subjects in these categories, as well as in patients with long‐standing type I diabetes, treated Graves’ disease and type II (non‐insulin dependent) diabetes. L‐selectin levels were also related to islet autoantibodies, human leucocyte antigen (HLA) genotype and L‐selectin T668C gene polymorphisms. L‐selectin expression on memory T lymphocytes was reduced in newly diagnosed diabetes and islet autoantibody positive siblings compared with controls. sL‐selectin levels were significantly raised in newly diagnosed type I diabetes compared with controls, with intermediate levels in family members, both with and without islet autoantibodies, and in long‐standing type I diabetes. Levels were also raised in patients with untreated Graves’ disease. Patients with type II diabetes had sL‐selectin levels which did not differ from controls. sL‐selectin levels correlated with the presence of diabetes‐associated HLA alleles in both family members and controls; levels also fell with increasing age in family members. Multiple regression analysis showed that... [ABSTRACT FROM AUTHOR]

SummaryAims 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. [ABSTRACT FROM AUTHOR]

SummaryAims 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. [ABSTRACT FROM AUTHOR]

Interleukin-2 receptors are released in the circulation in response to antigenic or mytogenic stimulation of T-lymphocytes. Abnormal serum interleukin-2 receptor levels have been found in young children with type 1 diabetes and 'prediabetes.' We measured interleukin-2 receptor levels in 17 patients with newly diagnosed type 1 diabetes, 21 patients with long-standing type 1 diabetes, 19 patients with long-standing type 2 diabetes, 19 islet-cell antibody positive nondiabetic polyendocrine patients, 12 islet-cell antibody-positive first-degree relatives of patients with type 1 diabetes and compared the results to age- and sex-matched normal controls. We found significantly lower interleukin-2 receptor levels in patients with newly diagnosed and long-standing type 1 diabetes compared to normal controls (87 ± 11 and 93 ± 11 vs. 142 ± 25 and 132 ± 40 U/ml, P < 0.001 and P < 0.01). There were no significant differences in interleukin-2 receptor levels between prediabetic groups and normal controls or patients with long-standing type 1 or type 2 diabetes. There was no correlation between glycosylated hemoglobin, blood glucose levels, and interleukin-2 receptor in the groups with long-standing type 1 or type 2 diabetes. We conclude that patients with type 1 diabetes have low interleukin-2 receptor serum levels. This phenomenon is acquired close to disease onset and is unlikely to be an early markers of type 1 diabetes. [ABSTRACT FROM AUTHOR]