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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 Vps13c(fl/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 Ca(2+) were significantly increased in islets from female KO mice, suggesting impaired Ca(2+) 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.

Original publication

DOI

10.1152/ajpendo.00074.2016

Type

Journal article

Journal

Am J Physiol Endocrinol Metab

Publication Date

01/08/2016

Volume

311

Pages

E488 - E507

Keywords

C2CD4A, GWAS, VPS13C, type 2 diabetes, β-cell, Animals, Blotting, Western, Calcium, Calcium-Binding Proteins, Diabetes Mellitus, Type 2, Female, Glucagon-Secreting Cells, Glucose Intolerance, Insulin, Insulin Resistance, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Nerve Tissue Proteins, Pancreas, Polymorphism, Single Nucleotide, Proteins, Real-Time Polymerase Chain Reaction, Sex Factors