Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012;7(3):e32755.
doi: 10.1371/journal.pone.0032755. Epub 2012 Mar 9.

CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3

Maddalena Trombetta  1 , Sara Bonetti, Marialinda Boselli, Fabiola Turrini, Giovanni Malerba, Elisabetta Trabetti, PierFranco Pignatti, Enzo Bonora, Riccardo C Bonadonna
Affiliations

CACNA1E variants affect beta cell function in patients with newly diagnosed type 2 diabetes. the Verona newly diagnosed type 2 diabetes study (VNDS) 3

Maddalena Trombetta et al. PLoS One. 2012.

Abstract

Background: Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca(2+) channel Ca(V)2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes.

Methodology/principal findings: In 595 GAD-negative, drug naïve patients (mean ± SD; age: 58.5 ± 10.2 yrs; BMI: 29.9 ± 5 kg/m(2), HbA1c: 7.0±1.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering ∼93% of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p<0.05-0.01). Both major alleles of rs2184945 and rs3905011 were each (p<0.01 and p<0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p<0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p<0.05).

Conclusions/significance: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongly associated to beta cell function. Genotyping CACNA1E might be of help to infer the beta cell functional phenotype and to select a personalized treatment.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Gene structure, location of polymorphic sites, and pairwise LD among SNPs in CACNA1E.
The upper portion of the figure shows the gene structure and location of the polymorphisms genotyped in the VNDS population. The lower portion of the figure shows a schematic of the pairwise LD, calculated as r 2, among the SNPs in the VNDS patients. The dotted lines connect each SNP name and position with the corresponding cell in the LD matrix. Increasing level of LD is shown by darker grayscale.
Figure 2
Figure 2. Effects of CACNA1E score on the curve relating insulin secretion rate (y axis) to glucose concentration (x axis), i.e. the proportional control of beta cell function, in patients with newly diagnosed type 2 diabetes of the VNDS.
The CACNA1E score was computed by considering two levels for rs2184945 (TT and AA/AT) and 3 levels for rs3905011 (AA, GA and GG) and by scoring them from 0 to 1 or 2 respectively. The CACNA1E score could range from a minimum of 0 (double genotype rs2184945TT–rs3905011AA) to a maximum of 3 (a rs2184945AA/AT–rs3905011GG genotype) (Supporting Information S1 Table S13). The higher was the CACNA1E score, the lower was the beta cell insulin secretory response to glucose (p<0.005 after adjusting for age, gender and BMI). Data are presented as mean±SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Yang SN, Berggren PO. CaV2.3 channel and PKClambda: new players in insulin secretion. J Clin Invest. 2005;115:16–20. - PMC - PubMed
    1. Williams ME, Marubio LM, Deal CR, Hans M, Brust PF, et al. Structure and functional characterization of neuronal alpha 1E calcium channel subtypes. J Biol Chem. 1994;269:22347–22357. - PubMed
    1. Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, et al. CaV2.3 calcium channels control second-phase insulin release. J Clin Invest. 2005;115:146–154. - PMC - PubMed
    1. Pereverzev A, Vajna R, Pfitzer G, Hescheler J, Klockner U, et al. Reduction of insulin secretion in the insulinoma cell line INS-1 by overexpression of a Ca(v)2.3 (alpha1E) calcium channel antisense cassette. Eur J Endocrinol. 2002;146:881–889. - PubMed
    1. Matsuda Y, Saegusa H, Zong S, Noda T, Tanabe T. Mice lacking Ca(v)2.3 (alpha1E) calcium channel exhibit hyperglycemia. Biochem Biophys Res Commun. 2001;289:791–795. - PubMed

Publication types

MeSH terms

  NODES
Association 1
INTERN 1
twitter 2