The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes |
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Authors: | T M Reinbothe S Alkayyali E Ahlqvist T Tuomi B Isomaa V Lyssenko E Renström |
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Institution: | 1. Department of Clinical Sciences, Islet Pathophysiology, Lund University Diabetes Centre, CRC 91-11, Jan Waldenstr?ms gata 35, 20502, Malm?, Sweden 2. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malm?, Sweden 3. Department of Medicine, Helsinki University Central Hospital, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland 4. Folkh?lsan Research Center, Biomedicum Helsinki, Helsinki, Finland 5. City of Jakobstad Department of Social Services and Public Health, Jakobstad, Finland
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Abstract: | Aims/hypothesis 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. Methods Beta cells of human islets from cadaver donors were enriched using FACS to study the expression of the genes encoding voltage-gated calcium channel (Cav)1.2 and Cav1.3 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 Cav1.3). 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. Results In FACS-enriched human beta cells, CACNA1D mRNA expression exceeded that of CACNA1C (which encodes Cav1.2) 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. Conclusion/interpretation We conclude that the L-type calcium channel Cav1.3 is important in human glucose-induced insulin secretion, and common variants in CACNA1D might contribute to type 2 diabetes. |
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