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.
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 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.
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Zenobia B
authors.initials: ZB
authors.lastname: Mehta
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fine
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pullen
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Pauline
authors.initials: P
authors.lastname: Chabosseau
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom;
authors.forename: Gargi
authors.initials: G
authors.lastname: Meur
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Velayos-Baeza
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; and.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Monaco
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom; g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D050416:Glucagon-Secreting Cells / Q000473:pathology; D018149:Glucose Intolerance / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010179:Pancreas / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012737:Sex Factors; D033921:Vesicular Transport Proteins
chemical_list: D002135:Calcium-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D011506:Proteins; C495324:VPS13C protein, human; D033921:Vesicular Transport Proteins; C497828:Vps13a protein, mouse; D002118:Calcium
keywords: C2CD4A; GWAS; VPS13C; type 2 diabetes; β-cell