GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

Abstract

OBJECTIVE To evaluate the significance of GAD antibodies (GADAs) and family history for type 1 diabetes (FH_T1) or type 2 diabetes (FH_T2) in nondiabetic subjects. RESEARCH DESIGN AND METHODS GADAs were analyzed in 4,976 nondiabetic relatives of type 2 diabetic patients or control subjects from Finland. Altogether, 289 (5.9%) were GADA⁺—a total of 253 GADA⁺ and 2,511 GADA⁻ subjects participated in repeated oral glucose tolerance tests during a median time of 8.1 years. The risk of progression to diabetes was assessed using Cox regression analysis. RESULTS Subjects within the highest quartile of GADA⁺ (GADA⁺_high) had more often first-degree FH_T1 (29.2 vs. 7.9%, P < 0.00001) and GADA⁺ type 2 diabetic (21.3 vs. 13.7%, P = 0.002) or nondiabetic (26.4 vs. 13.3%, P = 0.010) relatives than GADA⁻ subjects. During the follow-up, the GADA⁺ subjects developed diabetes significantly more often than the GADA⁻ subjects (36/253 [14.2%] vs. 134/2,511 [5.3%], P < 0.00001). GADA⁺_high conferred a 4.9-fold increased risk of diabetes (95% CI 2.8–8.5) compared with GADA⁻—seroconversion to positive during the follow-up was associated with 6.5-fold (2.8–15.2) and first-degree FH_T1 with 2.2-fold (1.2–4.1) risk of diabetes. Only three subjects developed type 1 diabetes, and others had a non–insulin-dependent phenotype 1 year after diagnosis. GADA⁺ and GADA⁻ subjects did not clinically differ at baseline, but they were leaner and less insulin resistant after the diagnosis of diabetes. CONCLUSIONS GADA positivity clusters in families with type 1 diabetes or latent autoimmune diabetes in adults. GADA positivity predicts diabetes independently of family history of diabetes, and this risk was further increased with high GADA concentrations.