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@article{Mehta:2016:10.1152/ajpendo.00074.2016,
author = {Mehta, ZB and FIne, N and Pullen, TJ and Cane, MC and Hu, M and Chabosseau, P and Meur, G and Velayos-Baeza, A and Monaco, AP and Marselli, L and Marchetti, P and Rutter, GA},
doi = {10.1152/ajpendo.00074.2016},
journal = {American Journal of Physiology-Endocrinology and Metabolism},
pages = {E488--E507},
title = {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},
url = {http://dx.doi.org/10.1152/ajpendo.00074.2016},
volume = {311},
year = {2016}
}

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TY  - JOUR
AB  - 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.
AU  - Mehta,ZB
AU  - FIne,N
AU  - Pullen,TJ
AU  - Cane,MC
AU  - Hu,M
AU  - Chabosseau,P
AU  - Meur,G
AU  - Velayos-Baeza,A
AU  - Monaco,AP
AU  - Marselli,L
AU  - Marchetti,P
AU  - Rutter,GA
DO  - 10.1152/ajpendo.00074.2016
EP  - 507
PY  - 2016///
SN  - 1522-1555
SP  - 488
TI  - 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
T2  - American Journal of Physiology-Endocrinology and Metabolism
UR  - http://dx.doi.org/10.1152/ajpendo.00074.2016
UR  - http://hdl.handle.net/10044/1/39880
VL  - 311
ER  -

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