Abstract

Objective To evaluate the significance of GAD antibodies (GADA) and family history for type 1 or type 2 diabetes (FH_T1) in non-diabetic subjects.

Research design and methods GADA were analysed in 4976 non-diabetic relatives of type 2 diabetic patients or control subjects from Finland. Altogether 289 (5.9%) were GADA+. 253 GADA+ and 2511 GADA- 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 Those within highest quartile of GADA+ (GADA+_high;) had more often 1^st 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 non-diabetic (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. 134/2511 (5.3%), P<0.00001]. GADA+_high conferred a 4.9-fold increased risk of diabetes (95% CI 2.8 – 8.5) as compared with GADA-. Seroconversion to positive during the follow–up was associated with 6.5-fold (2.8 – 15.2) and 1^st degree FH_T1 with 2.2-fold (1.2-4.1) risk of diabetes. Only three subjects developed type 1 diabetes, others had a non-insulin dependent phenotype one 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 LADA. GADA positivity predicts diabetes independently of family history of diabetes and this risk was further increased with high GADA concentrations.