Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

Abstract

Aim/hypothesis Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucosetolerant people and in individuals with abnormal glucose regulation. Methods The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes patients. ResultsThe WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decrease in insulinogenic index (p=0.025) and decreased 30-min serum insulin levels (p=0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p=0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p=0.026). To study the complex interaction of WFS1 rs734312 on insulin release Diabetologia (2008) and insulin resistance we introduced Hotelling's T 2 test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p=0.0017). Conclusions/interpretation Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation.

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

“…A very recent GWA study confirmed with WFS1 a type 2 diabetes susceptibility gene region [13], which had been identified earlier by candidate-gene approaches [14][15][16]. Similarly to the other novel gene variants that are associated with type 2 diabetes, two previous studies suggested that WFS1 risk alleles for type 2 diabetes might be associated with impaired pancreatic beta cell function as assessed by OGTT-derived indices of insulin secretion [17,18]. However, it is unclear whether common genetic variants in WFS1 affect insulin secretion directly or secondarily via alteration of insulin sensitivity.…”

“…Although previous studies suggest that progressive loss of insulin secretion might be an important component of the phenotype which predisposes carriers of the WFS1 variant to develop type 2 diabetes [17,18], the pathogenic mechanism of impaired insulin secretion due to genetic variation in the WSF1 locus is not completely established. The highly developed endoplasmic reticulum structure of beta cells is an important factor in beta cell function, comprising production and regulated secretion of insulin to control blood glucose levels [24].…”

“…A recent study showed that GLP-1 receptor-mediated signalling directly modulates the endoplasmic reticulum stress response leading to promotion of beta cell adaptation and survival [26,27]. Given the well-established association of genetic variation in the WFS1 locus with risk of type 2 diabetes, which might result from an impairment of beta cell function [17,18], the aim of the present study was to investigate the influence of a common WFS1 singlenucleotide polymorphism (SNP) on insulin secretion kinetics to i.v. administered glucose during an IVGTT and a hyperglycaemic clamp.…”

Stress hypERactivation in the β-cell

“…[93][94][95] Studies have also suggested that the WFS1 risk allele may be associated with impaired b-cell function and the progressive loss of insulin secretion may predispose carriers of the WFS1 variant to develop type 2 diabetes. 96,97 Recently, the WFS1 risk variant, rs10010131, has been shown to specifically impair GLP-1-induced first phase and second phase insulin secretion. 98 It has been suggested that this impaired response to GLP-1 decreases post-prandial insulin secretion and may influence b-cell growth and differentiation.…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…Rare mutations in WFS1 cause Wolfram syndrome, variation in WFS1 also predisposes to common T2DM. It has been reported that WFS1 gene variants were associated with reduced insulin response to oral but not intravenous glucose [35][36][37][38][39]. WFS1 gene was associated with estimates of a decreased pancreatic -cell function among middle-aged individuals with abnormal glucose regulation [37].…”