The human L-type calcium channel Ca(v)1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes.
(2013) In Diabetologia 56(2). p.340-349- 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 (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... (More)
- 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 (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. RESULTS: 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. CONCLUSION/INTERPRETATION: 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3347337
- author
- Reinbothe, Thomas LU ; Alkayyali, Sami LU ; Ahlqvist, Emma LU ; Tuomi, Tiinamaija LU ; Isomaa, Bo ; Lyssenko, Valeriya LU and Renström, Erik LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Diabetologia
- volume
- 56
- issue
- 2
- pages
- 340 - 349
- publisher
- Springer
- external identifiers
-
- wos:000313075500014
- pmid:23229155
- scopus:84878770912
- pmid:23229155
- ISSN
- 1432-0428
- DOI
- 10.1007/s00125-012-2758-z
- language
- English
- LU publication?
- yes
- id
- 2158f1a0-65b5-446a-9394-ebf90d2c1586 (old id 3347337)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23229155?dopt=Abstract
- date added to LUP
- 2016-04-01 10:45:24
- date last changed
- 2024-04-07 17:36:27
@article{2158f1a0-65b5-446a-9394-ebf90d2c1586, 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 (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. RESULTS: 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. CONCLUSION/INTERPRETATION: 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.}}, author = {{Reinbothe, Thomas and Alkayyali, Sami and Ahlqvist, Emma and Tuomi, Tiinamaija and Isomaa, Bo and Lyssenko, Valeriya and Renström, Erik}}, issn = {{1432-0428}}, language = {{eng}}, number = {{2}}, pages = {{340--349}}, publisher = {{Springer}}, series = {{Diabetologia}}, title = {{The human L-type calcium channel Ca(v)1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes.}}, url = {{https://lup.lub.lu.se/search/files/2109204/4403357.pdf}}, doi = {{10.1007/s00125-012-2758-z}}, volume = {{56}}, year = {{2013}}, }