Variants in the FFAR1 Gene Are Associated with Beta Cell Function

Martins Kalis,Leif Groop,Per Levéen,Valeriya Lyssenko,Peter Almgren,Corrado M Cilio,Kathrin Maedler

doi:10.1371/journal.pone.0001090

Abstract

BackgroundThe FFAR1 receptor is expressed mainly in pancreatic beta cells and is activated by medium to long chain free fatty acids (FFAs), as well as by thiazolidinediones, resulting in elevated Ca2+ concentrations and promotion of insulin secretion. These properties suggest that FFAR1 could be a mediator of lipotoxicity and a potential candidate gene for Type 2 diabetes (T2D). We therefore investigated whether variations at the FFAR1 locus are associated with T2D and beta cell function.Methodology/Principal FindingsWe re-sequenced the FFAR1 region in 96 subjects (48 healthy and 48 T2D individuals) and found 13 single nucleotide polymorphisms (SNPs) 8 of which were not previously described. Two SNPs located in the upstream region of the FFAR1 gene (rs1978013 and rs1978014) were chosen and genotyped in 1929 patients with T2D and 1405 healthy control subjects. We observed an association of rs1978013 and rs1978014 with insulinogenic index in males (p = 0.024) and females (p = 0.032), respectively. After Bonferroni corrections, no association with T2D was found in the case-control material, however a haplotype consisting of the T-G alleles conferred protection against T2D (p = 0.0010).Conclusions/SignificanceVariation in the FFAR1 gene may contribute to impaired beta cell function in T2D.

Highlights

Deterioration of beta cell function is a hallmark of Type 2 diabetes (T2D) and is considered to contribute to worsening of glucose tolerance with time [1,2,3,4]
We studied whether single nucleotide polymorphisms (SNPs) in the FFAR1 gene influenced insulin secretion and free fatty acids (FFAs) levels measured during oral glucose tolerance test (OGTT) in 1011 non-diabetic individuals participating in the Botnia study (Table 1) [17]
We identified 13 SNPs and two of these polymorphisms where located in the coding region of the gene, including one synonymous (Val) and one non-synonymous (Arg/His, rs2301151) polymorphism

Summary

Introduction

Deterioration of beta cell function is a hallmark of Type 2 diabetes (T2D) and is considered to contribute to worsening of glucose tolerance with time [1,2,3,4]. Mice with overexpression of FFAR1 show impaired beta cell function and develop diabetes, whereas disruption of the gene reduces FFA-stimulated insulin release [15] and, according to Steneberg et al, protects from diabetes [16] These properties make FFAR1 an interesting candidate for mediating lipotoxicity in beta cells its role in this process is not fully unravelled. The FFAR1 receptor is expressed mainly in pancreatic beta cells and is activated by medium to long chain free fatty acids (FFAs), as well as by thiazolidinediones, resulting in elevated Ca2+ concentrations and promotion of insulin secretion. These properties suggest that FFAR1 could be a mediator of lipotoxicity and a potential candidate gene for Type 2 diabetes (T2D). Variation in the FFAR1 gene may contribute to impaired beta cell function in T2D

Methods

Results

Conclusion