OBJECTIVE -The aim of the present study was to define heterogeneity of adult-onset autoimmune diabetes based on characterization of GAD antibodies (GADAs). RESEARCH DESIGN AND METHODS-Patients enrolled in a nationwide survey, the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study, have been screened for GADAs and IA-2 antibodies (IA-2As) and further characterized for GADA titer, antibodies to thyroid peroxidase (TPO), and HLA DRB1-DQB1 polymorphisms.RESULTS -Of 4,250 consecutive type 2 diabetic patients, 4.5% had either GADAs and/or IA-2As. Patients with autoimmune diabetes showed a clinical phenotype significantly different from that of type 2 diabetes, including higher fasting glucose and A1C, lower BMI and uric acid, lower prevalence of metabolic syndrome and its components, and higher frequency of TPO antibodies. More interestingly, analysis of GADA titers showed a bimodal distribution that identified two subgroups of patients with high (Ͼ32 GADA arbitrary units) and low (Յ32 GADA arbitrary units) GADA titers. Compared with those with low GADA titers, patients with high GADA titers had more prominent traits of insulin deficiency and a profile of more severe autoimmunity resulting in higher A1C, lower BMI, a lower prevalence of metabolic syndrome and its components (P Ͻ 0.02 for all), a higher prevalence of IA-2As, TPO antibodies (P Ͻ 0.003 for both), and DRB1*03-DQB1*0201 (50 vs. 26.8%, P ϭ 0.001), and a decreasing frequency of DQB1*0602 and DRB1*0403 (from type 2 to low and to high GADA titer autoimmune diabetes; P Ͻ 0.001 for trend for both comparisons).CONCLUSIONS -GADA titers identify two subgroups of patients with adult-onset autoimmune diabetes having distinct clinical, autoimmune, and genetic features. Diabetes Care 30:932-938, 2007

OBJECTIVEZinc transporter 8 (ZnT8) is an islet β-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine the prevalence and role of antibodies to ZnT8 (ZnT8As) in adult-onset diabetes.RESEARCH DESIGN AND METHODSZnT8As were measured by a radioimmunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH2-terminal proteins in 193 patients with adult-onset autoimmune diabetes having antibodies to either GAD (GADAs) or IA-2 (IA-2As) and in 1,056 antibody-negative patients with type 2 diabetes from the Non Insulin Requiring Autoimmune Diabetes (NIRAD) study.RESULTSZnT8As-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8As-NH2 were rare. ZnT8As were associated with younger age and a high GADA titer. The use of GADAs, IA-2As, and ZnT8As in combination allowed a stratification of clinical phenotype, with younger age of onset of diabetes and characteristics of more severe insulin deficiency (higher fasting glucose and A1C, lower BMI, total cholesterol, and triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one, and no antibodies (all Ptrend < 0.001). Autoantibody titers, association with high-risk HLA genotypes, and prevalence of thyroid peroxidase antibodies followed the same trend (all P < 0.001).CONCLUSIONSZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes.

In LADA subjects, high GADA titer was associated with a profile of more severe autoimmunity and, in male gender, specifically predisposed to thyroid autoimmunity. A regular screening for other antibodies is recommended in LADA patients according to GADA titer and gender.

Background-Excess fat is one of the main determinants of insulin resistance, representing the metabolic basis for developing future cardiovascular disease. The aim of the current study was to find an easy-to-detect clinical marker of insulin resistance which can be used to identify young subjects at increased risk of cardiovascular disease. Methods and Results-Four-hundred and seventy-seven overweight/obese children and adolescents (mean age 10.31Ϯ2.80 years) were consecutively enrolled. Standard deviation score body mass index, fasting biochemical parameters, and homeostasis model assessment of insulin resistance were evaluated. Statistical differences were investigated using multiple linear regression analysis. Manual measure of wrist circumference was evaluated in all children and adolescents. Fifty-one subjects, randomly selected, underwent nuclear magnetic resonance imaging of the wrist to evaluate transversal wrist area at the Lister tubercle level. A statistically significant association was found between manual measure of wrist circumference and insulin levels or homeostasis model assessment of insulin resistance (␤ϭ0.34 and 0.35, respectively; PϽ10 Ϫ5 for both comparisons). These associations were more significant than those between SD score body mass index and insulin levels or homeostasis model assessment of insulin resistance (␤ϭ0.12 and 0.10, respectively; PՅ0.02 for both comparisons). Nuclear magnetic resonance imaging acquisition clarified that the association between wrist circumference and insulin levels or homeostasis model assessment of insulin resistance reflected the association with bone tissue-related areas (PՅ0.01 for both) but not with the adipose tissue ones (PϾ0.05), explaining 20% and 17% of the variances of the 2 parameters. Conclusions-Our findings suggest a close relationship among wrist circumference, its bone component, and insulin resistance in overweight/obese children and adolescents, opening new perspectives in the prediction of cardiovascular disease.

Hashimoto's thyroiditis (HT) is an autoimmune disease resulting from a complex interaction between genetic and environmental factors. The genetic loci conferring susceptibility need to be still defined. The aim of the present study was to determine whether Cytotoxic T-Lymphocyte-Associated Antigen-4 (CTLA-4), HLA DRB1, and DQB1 genes were associated to HT in an Italian population. We evaluated the allele distribution of the following loci: CTLA-4 exon 1 A49G dimorphism, which resulted in an amino acidic exchange (Thr/Ala) in the leader peptide, CTLA-4 3' microsatellite, HLA DRB1 and DQB1 in 126 patients with HT and in 301 control subjects from an Italian population (Lazio region). CTLA-4 exon 1 A49G dimorphism was typed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP); CTLA-4 3' microsatellite alleles were defined using a fluorescence-based method. HLA DRB1 and DQB1 alleles were typed using a SSO reverse line blot method and a probeless procedure based on allele group-specific amplification followed by DNA heteroduplex analysis, respectively. Data were initially analyzed by chi2 test or Fisher's exact test. Multiple logistic regression analysis was then applied on factors with significant crude odds ratios and on CTLA-4 exon 1 A49G dimorphism to investigate their independent effects. The two polymorphic sites at CTLA-4 gene did not increase the risk for HT. The distribution of HLA DRB1 and DQB1 alleles did not show any significant difference between patients and controls, however, the DRB1*04-DQB1*0301 haplotype was significantly increased in patients. Other factors that increase the risk of disease were gender and age. Females showed approximately 18 times more risk than males; subjects older than 50 years had an odds ratio of 6.6. These data suggest that these two polymorphic sites at CTLA-4 do not play a major role in the susceptibility of the disease in an Italian population while female gender, age over 50 years, HLA DRB1*04-DQB1*0301 haplotype increase the risk of developing HT.