Journal
DIABETOLOGIA
Volume 56, Issue 2, Pages 340-349Publisher
SPRINGER
DOI: 10.1007/s00125-012-2758-z
Keywords
Beta cell; CACNA1D; Calcium; Ca(v)1.3 channel; Diabetes; Exocytosis; Human; Insulin; Islets
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Funding
- Knut and Alice Wallenberg Foundation
- EU research training network Cavnet [MRTN-CT-2006-035367]
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Voltage-gated calcium channels of the L-type have been shown to be essential for rodent pancreatic beta cell function, but data about their presence and regulation in humans are incomplete. We therefore sought to elucidate which L-type channel isoform is functionally important and its association with inherited diabetes-related phenotypes. Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Ca-v)1.2 and Ca(v)1.3 by absolute quantitative PCR in whole human and rat islets, as well as in clonal cells. Single-cell exocytosis was monitored as increases in cell capacitance after treatment with small interfering (si)RNA against CACNA1D (which encodes Ca(v)1.3). Three single nucleotide polymorphisms (SNPs) were genotyped in 8,987 non-diabetic and 2,830 type 2 diabetic individuals from Finland and Sweden and analysed for associations with type 2 diabetes and insulin phenotypes. In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Ca(v)1.2) by approximately 60-fold and was decreased in islets from type 2 diabetes patients. The latter coincided with diminished secretion of insulin in vitro. CACNA1D siRNA reduced glucose-stimulated insulin release in INS-1 832/13 cells and exocytosis in human beta cells. Phenotype/genotype associations of three SNPs in the CACNA1D gene revealed an association between the C allele of the SNP rs312480 and reduced mRNA expression, as well as decreased insulin secretion in vivo, whereas both rs312486/G and rs9841978/G were associated with type 2 diabetes. We conclude that the L-type calcium channel Ca(v)1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes.
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