We tested the hypothesis that common genetic variability of β cell mass and/or function genes may influence β cell functional mass in type 2 diabetes (T2DM). We studied 590 drug-naive GAD-negative patients with newly diagnosed T2DM (age: median=60.0 yrs; I.Q. range: 5266; BMI: 29.3 kg/m2; 26.532.9). β cell functional mass was assessed by state-of-art mathematical modeling of glucose/C-peptide curves during a 240 frequently sampled OGTT, to provide the β cell responses to the rate of increase of glucose (derivative control: DC) and to glucose concentration (proportional control, PC). Insulin sensitivity, measured by the insulin clamp technique, acted as an internal control for the number of false positive hits. Forty-five SNPs, selected to cover over 90% of common genetic variability, were genotyped in 8 MODY (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL) and 2 neonatal diabetes mellitus (NDM) (KCNJ11, ABCC8) genes. Allelic variants of 4 SNPs (rs1303722 and rs882019 of GCK, rs7310409 of HNF1A and rs5219 of KCNJ11, the latter being a known type 2 diabetes risk variant) were significantly associated to changes in DC of β cell function (P=0.007−0.03). Allelic variants of 5 other SNPs (rs2869084 and rs6031544 of HNF4A, rs10774580 of HNF1A, rs1801262 of NEUROD1, and rs7129639 of ABCC8) were found to influence significantly PC of β cell function (P=0.001−0.04). Only 1 (rs6721191 of KLF11) out of 45 SNPs was associated to insulin sensitivity (P=0.047). In multivariate regression models, combining GCK, HNF1A and KCNJ11 SNPs accounted for ~2.5% of DC of β-cell function, whereas combining HNF4A, HNF1A, NEUROD1 and ABCC8 SNPs accounted for ~3.6% of PC of β cell function. Thus, common variability of MODY and NDM genes is significantly associated to β cell functional mass in patients with type 2 diabetes, thereby potentially playing a role in the pathophysiology of the disease and in its metabolic prognosis.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
05 - 09 May 2012
European Society of Endocrinology