The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes
Open accessAbstract
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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Expression of CACNA1D is reduced in islets from donors with T2DM, and polymorphism rs312480 influences GIIS, with the at-risk C-allele associated with lower GIIS and insulin content than the T-allele.
“Expression of CACNA1D is reduced in islets from donors with T2DM, and a polymorphism (rs312480) in the gene influences GIIS, the ‘at-risk’ C-allele being associated with lower GIIS and insulin content than the T-allele (539).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [539]
The CACNA1C and CACNA1D expression in islets and beta cells section reports reduced CACNA1D expression in islets from donors with type 2 diabetes. The Effect of genetic variants section reports lower glucose-stimulated insulin release for rs312480 CC than CT islets, but provides no TT comparison or evidence that C is a type 2 diabetes risk allele. It reports insulin release, not lower insulin content. (LLM, conf=0.88)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · cited 3× · see citing works
“To evaluate this idea, we analysed data from genome-wide association studies (GWAS) for type 2 diabetes and quantitative traits [18, 19] in which we detected associations of single nucleotide polymorphisms (SNPs) in CACNA1D with type 2 diabetes.”
BackgroundMethodSelf-citationBraun, M., Ramracheya, R., Bengtsson, M., Zhang, Q., Karanauskaite, J., Partridge, C., Johnson, P. R., & Rorsman, P. (2008) · Diabetes · doi:10.2337/db07-0991 · Cited by 417 · cited 5× · see citing works
“After 48 h, cells were used for electrophysiological capacity measurements as previously described [15].”
BackgroundMethodResultInfluentialBarg, S., Eliasson, L., Renström, E., & Rorsman, P. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s74 · Cited by 227 · cited 2× · see citing works
“The Journal of biological chemistry 275: 39193-39199 [5] Barg S, Eliasson L, Renstrom E, Rorsman P (2002) A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells.”
BackgroundElectrophysiology of Islet Cells
Drews, G., Krippeit-Drews, P., & Düfer, M. (2010) · Advances in Experimental Medicine and Biology · doi:10.1007/978-90-481-3271-3_7 · Cited by 152 · cited 2× · see citing works
“3) is most important appears to be species dependent and to differ between rodents and humans [3].”
BackgroundCharacterization of voltage‐dependent sodium and calcium channels in mouse pancreatic A‐ and B‐cells
Vignali, S., Leiss, V., Karl, R., Hofmann, F., & Welling, A. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2005.102368 · Cited by 96 · cited 3× · see citing works
“2 [6, 7, 39, 40], with a diminished first phase after ablation of the channel [7].”
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Convergent genetic and expression data implicate immunity in Alzheimer's disease
International Genomics of Alzheimer's Disease Consortium (IGAP), Jones, L., Lambert, J., Wang, L., Choi, S., Harold, D., Vedernikov, A., Escott‐Price, V., Stone, T., Richards, A., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1757 · Cited by 199 · see citing works
- Authors
- Reinbothe, T. M., Alkayyali, S., Ahlqvist, E., Tuomi, T., Isomaa, B., Lyssenko, V., & Renström, E.
- Affiliations
- Lund University (SE)
- Corresponding author
- Reinbothe, T. M.
- Venue
- Diabetologia
- Published
- 2012-11-15
- Volume
- 56
- Issue
- 2
- Pages
- 340-349
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2101642808
- Cited by
- 84
- References
- 5
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 1 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 10 · 2013: 2
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- Cav1.3, CACNA1D, L-type calcium channels, type 2 diabetes, insulin secretion, pancreatic beta cells, CACNA1C, Cav1.2, single nucleotide polymorphisms, genetic association, glucose-stimulated insulin secretion, exocytosis, human islets
- MeSH terms
- Adult, Cells, Cultured, Diabetes Mellitus, Type 2, Female, Flow Cytometry, Humans, Insulin, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Calcium Channels, L-Type, Insulin-Secreting Cells
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