Polymorphisms in the gene encoding the voltage-dependent Ca2+ channel CaV2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion

Abstract

Aims/hypothesis Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca 2+ channel Ca V 2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. Methods Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n=1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. Results The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p=0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p=0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p= 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p=0.02, disposition index (D I ) p= 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p=0.04) and 60 min (p=0.02) during an IVGTT; and (4) reduced D I over time in the Botnia prospective cohort (p=0.05). Conclusions/interpretation We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.

The αβδ of ion channels in human islet cells

“…10 Subsequently, it was demonstrated that polymorphisms in the gene encoding Ca V 2.3 associate with type 2 diabetes and impaired insulin secretion. 11 In apparent conflict with these findings, we were unable to detect the message for Ca V 2.3 in RNA isolated from human islets (ref. 4 and Amisten S, personal communication).…”

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

“…These findings are somewhat difficult to interpret, since mice of various ages (12-50 weeks) were used without appropriate age-matching or discrimination between male and female animals. The concept is nevertheless intriguing, as several studies have since linked variants in the gene encoding Ca v 2.3 channels to impaired glucose homeostasis in human T2DM patients [66][67][68]. Most notably, the region on chromosome 1q21-25, where the human Ca v 2.3 gene is located, has been linked to young-onset T2DM in Pima Indians [67].…”

Hyperinsulinism and Diabetes: Genetic Dissection of β Cell Metabolism-Excitation Coupling in Mice

“…Ca v 2.3 R-type Ca channel) in β-cells is controversial, and some studies indicate their absence in human islets (Braun et al, 2008; Yang and Berggren, 2005b), but there is evidence for association of Ca v 2.3 polymorphisms with impaired insulin secretion and development of type-2 diabetes (Holmkvist et al, 2007). They appear to play a role in second-phase insulin secretion by mobilizing insulin reserve granules to the readily releasable pool in mice.…”