OBJECTIVESpecific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes.RESEARCH DESIGN AND METHODSWe consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).RESULTSOf 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).CONCLUSIONSAdult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D–discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D–associated methylation variable positions (T1D–MVPs). We confirmed these T1D–MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D–discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D–MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D–MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D–MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.

Twin studies have helped to define the importance of genetic and environmental factors in the aetiology of disease [1±9]. By measuring concordance rates (both twins affected) in identical (monozygotic) and nonidentical (dizygotic) twins, estimates of genetic influence can be obtained. In primarily genetic disorders, concordance rates should be higher in monozygotic than in dizygotic twins. Differences between monozygotic twins must be due to factors not coded in the germ line, i. e. non-germ-line genetic (e. g. somatic) or environmental factors. Monozygotic twins also show differences in genes that undergo random rearrangement such as immunoglobulin and T-cell receptor genes.Comprehensive population-based studies of twins have only recently been initiated, so most of the information available on diabetic twins is from clinic- AbstractAims. To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. Methods. Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). Results. The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01±57) at 40 years of discordance estimated a 39 % probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50 %. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4 %. Twins of probands diagnosed at 24 years of age or younger had a 38 % probability of diabetes by 30 years of discordance, compared with 6 % for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). Conclusion/interpretation. Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25 % of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age. [Diabetologia (2001) 44: 354±362]

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

OBJECTIVE -The purpose of this study was to estimate whether prevalence of metabolic syndrome in adult European diabetic patients is associated with type of diabetes.RESEARCH DESIGN AND METHODS -A consecutive series of patients attending hospital-based diabetes clinics were assessed for the frequency of metabolic syndrome and compared with population-based control subjects as part of the Action LADA study. In total, 2,011 subjects (aged 30 -70 years) were studied, including 1,247 patients with recent-onset type 2 diabetes without glutamic acid decarboxylase autoantibodies (GADAs), 117 non-insulinrequiring patients with GADAs who had not received insulin therapy for at least 6 months after diagnosis (designated latent autoimmune diabetes of adults [LADA]), 288 type 1 diabetic patients, and 359 normal subjects.RESULTS -Frequency of metabolic syndrome was significantly different in patients with type 1 diabetes (31.9%) and LADA (41.9%) (P ϭ 0.015) and in both conditions was less frequent than in type 2 diabetic patients (88.8%) (P Ͻ 0.0001 for each). Eliminating glucose as a variable, the prevalence of metabolic syndrome was similar in patients with autoimmune diabetes (type 1 diabetes and/or LADA) (17.3%) and control subjects (23.7%) but remained more common in type 2 diabetic patients (47.8%) (P ϭ 0.001 for all groups). In both type 1 diabetic patients and those with LADA, individual components of metabolic syndrome were similar but less common than in type 2 diabetic patients (P Ͻ 0.0001 for each).CONCLUSIONS -The prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes. Excluding glucose as a variable, metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects. Metabolic syndrome is not a characteristic of autoimmune diabetes.