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

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.

The mitochondrial Ca2+uniporter MCU is required for normal glucose-stimulated insulin secretionin vitroandin vivo

“…Glucose was measured in tail vein blood at 0, 5, 15, 30, 60, 90 and 120 min. using an ACCU-CHECK Aviva glucometer (Roche) (19).…”

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

“…Recently, Kycia et al (9) reported that expression of C2CD4B, but not C2CD4A or VPS13C, was affected by risk alleles. However, the direction of effects of risk alleles differed between the reports, with expression lowered, uniquely in females, in the study of Mehta et al (7) but increased in that of Kycia et al (9). However, both of the latter studies involved relatively small sample numbers.…”

“…This finding argues that the latter gene contributes only to a limited extent towards the effect(s) of risk variants in man. Previous expression quantitative trait (eQTL) studies have demonstrated altered expression of VPS13C and C2CD4A (7), as well as C2CD4B (8) in islets from subjects carrying the risk variants. Recently, Kycia et al (9) reported that expression of C2CD4B, but not C2CD4A or VPS13C, was affected by risk alleles.…”

“…Chromosome 15q hosts a risk locus close to the VPS13C, C2CD4A and C2CD4B genes (5) associated with impaired proinsulin processing. Deletion of Vps13c, which encodes a lipid transporter (6), selectively from the pancreatic β cell (7), has little effect on glucose homeostasis in the mouse. This finding argues that the latter gene contributes only to a limited extent towards the effect(s) of risk variants in man.…”

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

“…Several GWAS variants, including rs7903146 in the TCF7L2 gene, are enriched in regions of open chromatin and confer allele-specific activity to an intronic islet enhancer (Gaulton et al, 2010). Similarly, a T2D-associated risk variant, rs7163757, in the VPS13C/C2CD4A/C2CD4B locus on chromosome 15 (Strawbridge et al, 2011) resides in an islet specific enhancer cluster and affects the expression of nearby genes (Mehta et al, 2016 andKycia et al, 2018).…”