Increased risk for endocrine autoimmunity in type 2 diabetic patients with GAD65 autoantibodies

OBJECTIVE: Glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) in type 2 diabetic subjects with secondary failure to sulphonylurea treatment identify the so-called latent autoimmune diabetes of the adult (LADA). The aim of our study was to estimate the risk for endocrine autoimmunity in type 2 diabetic subjects with GAD65Ab. DESIGN AND PATIENTS: We analysed serum samples from 600 adult subjects with a clinical diagnosis of type 2 diabetes mellitus for the presence and levels of GAD65Ab and antibodies directed against the islet autoantigen IA-2/ICA512 (IA-2/ICA512Ab). All the patients had been treated initially with hypoglycaemic agents and/or diet for at least 1 year. GAD65Ab+ subjects were studied for the presence of thyroid peroxidase autoantibodies (TPOAb), 21 hydroxylase autoantibodies (21OHAb) and frequency of HLA class II haplotypes. RESULTS: GAD65Ab were found in 67/600 (11%) and IA-2/ICA512Ab in 12/600 (2%) subjects (P<0.0001). The presence of GAD65Ab, but not that of IA-2/ICA512Ab, was significantly associated with insulin therapy, low BMI (P<0.0001) and low basal C-peptide (P<0.01). Islet-cell antibodies (ICA) were detected in 43/67 (64%) GAD65Ab+ and in 10/12 (83%) IA- 2/ICA512Ab+ subjects. TPOAb occurred more frequently in GAD65Ab+ (16/67, 24%) than in GAD65Ab-subjects (9/174, 5%) (P<0.0001). 21OHAb were detected only in GAD65Ab+ subjects (3/67, 4.5%) (P=0.03 vs. GAD65Ab-subjects). None of the 21OHAb+ subjects had metabolic or clinical signs of adrenal dysfunction. HLA- DRB1*03-DQA1*0501DQB1*0201 (DR3-DQ2) was significantly more frequent in GAD65Ab+ subjects than in healthy controls (OR=5.42, corrected P<0.0026). The presence of TPOAb was significantly associated with DR3-DQ2 (P=0.024). CONCLUSIONS: Our study demonstrates that the presence of GAD65Ab identifies a subgroup of type 2 diabetic patients with high risk for thyroid and adrenal autoimmunity, and that both GAD65Ab and TPOAb are associated with the presence of HLA-DR3-DQ2, in these patients.