| First Author | Mehta ZB | Year | 2016 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 311 |
| Issue | 2 | Pages | E488-507 |
| PubMed ID | 27329800 | Mgi Jnum | J:241413 |
| Mgi Id | MGI:5902010 | Doi | 10.1152/ajpendo.00074.2016 |
| Citation | Mehta ZB, et al. (2016) Changes in the expression of the type 2 diabetes-associated gene VPS13C in the beta-cell are associated with glucose intolerance in humans and mice. Am J Physiol Endocrinol Metab 311(2):E488-507 |
| abstractText | 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 beta-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the beta-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 (betaVps13cKO) 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 beta-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and betaVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and beta-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. |
