HLA-Associated Cellular Response to GAD in Type 2 Diabetes with Antibodies to GAD

Abstract

Proliferative response of peripheral blood mononuclear cells (PBMC) to glutamic acid decarboxylase (GAD), which has been reported in patients with type 1 diabetes, was measured in type 2 diabetes, especially in patients with antibodies to GAD initially diagnosed as having type 2 diabetes (anti-GAD⁺ type 2 diabetes). We studied 12 patients with type 1 diabetes, 22 with anti-GAD⁺ type 2 diabetes, 31 with type 2 diabetes who were negative for anti-GAD (anti-GAD^- type 2 diabetes), and 30 healthy control subjects for cellular responses in vitro to GAD. The mean stimulation index (SI) in response to GAD was significantly higher in type 1 diabetes than in anti-GAD^- type 2 diabetes or healthy controls (1.47±0.35 vs. 1.11±0.35, P<0.05, and 1.06±0.07, P<0.05, respectively). The mean SI in response to GAD in anti-GAD⁺ type 2 diabetes was significantly higher than in healthy controls (1.36±0.50 vs. 1.06±0.07, P<0.05). In anti-GAD⁺ type 2 diabetes, the mean SI in response to GAD was significantly higher in patients with alleles susceptible to type 1 diabetes (HLA-DRB1 *0405 and 0901) than those without susceptible alleles (1.55±0.60 vs. 1.12±0.16, P<0.05). All but one patient with a positive response to GAD had developed insulin deficiency (P<0.01 vs. nonresponders). In conclusion, we observed a significantly greater proliferative response to GAD in patients with anti-GAD⁺ type 2 diabetes, especially those with alleles susceptible to type 1 diabetes, and those responses may be a useful predictive marker for later development of insulin deficiency in anti-GAD⁺ type 2 diabetes.