Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β-cell are associated with glucose intolerance in humans and mice.

Zenobia B Mehta,Piero Marchetti,Anthony P Monaco,Timothy J Pullen,Lorella Marselli,Pauline Chabosseau,Antonio Velayos-Baeza,Matthew C Cane,Ming Hu,Guy A Rutter,Gargi Meur,Nicholas Fine

doi:10.1152/ajpendo.00074.2016

Abstract

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.

Highlights

THE INCIDENCE OF TYPE 2 DIABETES (T2D) is reaching epidemic proportions across the globe, with deaths from the disease reaching 5.1 million and disease complications costing USD 548 billion in 2013 [30]
Previous studies [17] have revealed that VPS13C expression in human islets is associated with HbA1c levels by massive parallel sequencing (RNA-seq) and microarray analysis at both nominal and permutation P values (P Ͻ 0.05), with lower mRNA levels observed in T2D subjects
We extend these findings here by showing that VPS13C mRNA levels were lower in carriers of risk alleles at rs4502156 and rs7163757 in female, but not male subjects

Summary

Introduction

THE INCIDENCE OF TYPE 2 DIABETES (T2D) is reaching epidemic proportions across the globe, with deaths from the disease reaching 5.1 million and disease complications costing USD 548 billion in 2013 [30]. Genome-wide association studies (GWAS) have identified ϳ90 loci harboring single nucleotide polymorphisms (SNPs) that confer increased disease risk [13, 21, 23, 40, 57, 65, 86]. Such studies have led to the discovery of novel genes involved in T2D, such as T cell factor 7-like 2 (TCF7L2) [21] and SLC30A8 [58, 65]. A role for this protein was demonstrated in prospore formation in S. cerevisiae through the regulation of phosphatidylinositol 4-phosphate [PI[4]P] generation and membrane-bending activity [48, 49]

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