Family history of Type 1 diabetes affects insulin secretion in patients with ‘Type 2’ diabetes

Abstract

The aim was to evaluate the impact of family history of diabetes on the phenotype of patients diagnosed with Type 2 diabetes and the frequency of susceptibility genotypes. Patients with Type 2 diabetes with family history for both Type 1 and Type 2 diabetes (FH(MIX, n) = 196) or Type 2 diabetes only (FH(T2), n = 139) matched for age, sex, BMI and age at diagnosis, underwent an oral glucose tolerance test and a combined glucagon test and insulin tolerance test. Glutamic acid decarboxylase (GAD) antibodies and major Type 1 and Type 2 diabetes susceptibility gene variants were analysed. Patients were stratified into groups according to family history or GAD antibody positivity (GADA+, GADA-) or a combination of these (GADA+/FH(MIX), GADA+/FH(T2), GADA-/FH(MIX), GADA-/FH(T2)). Compared with other patients, those with FH(MIX) more often had GAD antibodies (14.3 vs. 4.3%, P = 0.003), and those with both FH(MIX) and GAD antibodies had the highest frequency of insulin deficiency (stimulated serum C-peptide < 0.7 nmol/l, GADA+/FH(MIX) 46.4% vs. GADA-/FH(MIX) 9.5% (P < 0.00001), GADA-/FH(T2) 4.5% (P < 0.00001), GADA+/FH(T2) 0%). Patients with GADA+/FH(MIX) more often had HLA-DQB1 risk genotypes compared with patients with GADA-/FH(MIX) or GADA-/FH(T2D) (47 vs. 23 or 14%, P = 0.05 and P < 0.00001, respectively). In logistic regression analyses, FH(MIX), GAD antibody positivity and HLA risk genotypes were independently associated with insulin deficiency. A family history for both type 1 and type 2 diabetes was associated with higher prevalence of GAD antibodies and HLA-DQB1 risk genotypes than a family history of type 2 diabetes only, and was associated with earlier and more severe development of insulin deficiency, which was only partially explained by GAD antibodies and HLA.