GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

Abstract

OBJECTIVETo evaluate the significance of GAD antibodies (GADAs) and family history for type 1 diabetes (FHT1) or type 2 diabetes (FHT2) in nondiabetic subjects.RESEARCH DESIGN AND METHODSGADAs 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.RESULTSSubjects within the highest quartile of GADA+ (GADA+high) had more often first-degree FHT1 (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 FHT1 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.CONCLUSIONSGADA 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.

Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway

“…several years before diabetes was diagnosed. A recent prospective study reported that GADA positivity in nondiabetic cases markedly increased the risk of future diabetes [19]. We found that those who were antibody-positive both in the prediabetic and diabetic state were phenotypically more similar to individuals with type 1 diabetes compared with those who were positive only after the diagnosis of diabetes.…”

Association of variants in HLA-DQA1-DQB1, PTPN22, INS, and CTLA4 with GAD autoantibodies and insulin secretion in nondiabetic adults of the Botnia Prospective Study

“…It is possible that genes not associated with GADA explain the association between family history of type 1 diabetes and non-insulin-dependent diabetes. This is supported by the fact that the effect of family history of type 1 diabetes on risk of diabetes was independent of GADA and that the genetic background of type 1 diabetes and GADA differs (2,14,15). Alternatively, the association might be due to shared environmental factors.…”

“…In the Botnia Prospective Study, we followed 2764 initially nondiabetic relatives or spouses of type 2 diabetic patients (2,16,17). Information about firstto third-degree family history of type 1 and type 2 diabetes was retrieved from questionnaires or clinical investigation of the relatives.…”

“…Serum C-peptide, triglyceride, total cholesterol, and HDL were measured at fasting and serum insulin as well as plasma glucose at K5, 0, 30, 60, and 120 min during a 75 g oral glucose tolerance test (OGTT). GADA and insulinoma antigen 2 autoantibody (IA-2A) measurements were available for 2764 (100%) and 2298 (83%) subjects respectively (for details, see (2)). At baseline, 236 (8.5%) were GADA positive and 53 became positive during the follow-up (2).…”

“…Both major subtypes have genetic and environmental risk factors. Among the factors shown to increase the risk of developing non-insulin-dependent diabetes, at least in Northern Europe, are glutamic acid decarboxylase autoantibodies (GADA) and family history of type 1 diabetes (1,2). With respect to family history of type 1 diabetes, the association was not restricted to GADA-positive patients developing diabetes, i.e.…”