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

Abstract

OBJECTIVESeveral 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 METHODSInsulin 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.RESULTSFor 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.CONCLUSIONSFor 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.

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

“…Therefore, carriage of the susceptibility WFS1 variant is related to impaired glucoseinduced insulin response resulting from β-cell dysfunction. These results are in accordance with findings in other populations reporting the relationship between the carriage of various diseaseassociated variants of WFS1 and altered insulin secretion in response to glucose stimulation [10,[19][20][21] and lower pancreatic β-cell function [22]. SNP rs734312 is a missense mutation that is situated in the last exon (exon 8) of WFS1, and leads to an amino acid (aa) substitution of histidine to arginine in codon 611 (H611R).…”

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

“…CDKN2A/B was not associated with proinsulin conversion to insulin [210] or the effect of ambient glycaemia on insulin secretion [211]. Although CDKN2A/B significantly impacted risk of diabetes in a Han Chinese population, this was not related to reduced HOMA-B, although other loci ( CDKAL1 , IGF2BP2 and SLC30A8 ) did impact beta cell function in this population [212].…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…WFS1 gene was also associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicated the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt T2DM [40].…”