Clinical, Autoimmune, and Genetic Characteristics of Adult-Onset Diabetic Patients With GAD Autoantibodies in Japan (Ehime Study)

Abstract

OBJECTIVE—To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies.

RESEARCH DESIGN AND METHODS—GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab⁺) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load.

RESULTS—GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non–insulin deficient, and 19 (10.1%) were unclassified. The GADab⁺ insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA_1c. The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab⁺ insulin-deficient patients were significantly higher than those in the GADab⁺ non–insulin-deficient patients (P < 0.05). GADab⁺ patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab⁺ non–insulin-deficient patients. Of note is the fact that the GADab⁺ non–insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab⁺ patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies.

CONCLUSIONS—We conclude that GADab⁺ non–insulin-deficient patients differ from GADab⁺ patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.