Glycemia Determines the Effect of Type 2 Diabetes Risk Genes on Insulin Secretion

OBJECTIVE: Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms. RESEARCH DESIGN AND METHODS: Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT). Participants were genotyped for 10 diabetes risk SNPs associated with β-cell dysfunction: rs5215 (KCNJ11), rs13266634 (SLC30A8), rs7754840 (CDKAL1), rs10811661 (CDKN2A/2B), rs10830963 (MTNR1B), rs7903146 (TCF7L2), rs10010131 (WFS1), rs7923837 (HHEX), rs151290 (KCNQ1), and rs4402960 (IGF2BP2). Furthermore, the impact of the interaction between genetic variation in TCF7L2 and glycemia on changes in insulin secretion was tested in 315 individuals taking part in a lifestyle intervention study. RESULTS: For the SNPs in TCF7L2 and WFS1, we found a significant interaction between glucose control and insulin secretion (all P ≤ 0.0018 for glucose × genotype). When plotting insulin secretion against glucose at 120 min OGTT, the compromising SNP effects on insulin secretion are most apparent under high glucose. In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027). Increased glucose levels at baseline predicted an increase in insulin secretion upon improvement of glycemia by lifestyle intervention only in carriers of the risk alleles. CONCLUSIONS: For the diabetes risk genes TCF7L2 and WFS1, which are associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicates the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt type 2 diabetes.