Loss of a2d-1 calcium channel subunit function increases the susceptibility for diabetes

Vincenzo Mastrolia, Sylvia M. Flucher, Gerald J. Obermair, Mathias Drach, Helene Hofer, Erik Renström, Arnold Schwartz, Jörg Striessnig, Bernhard E. Flucher, Petronel Tuluc

Research output: Contribution to journalArticlepeer-review

Abstract

Reduced pancreatic b-cell function or mass is the critical problem in developing diabetes. Insulin release from b-cells depends on Ca2+ influx through high voltage- gated Ca2+ channels (HVCCs). Ca2+ influx also regulates insulin synthesis and insulin granule priming and contributes to β-cell electrical activity. The HVCCs aremultisubunit protein complexes composed of a pore-forming a1 and auxiliary β and α2δ subunits. α2δ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of α2δ-1, the dominant α 2δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α 2δ-1 subunit reduces the Ca2+ currents through all HVCC isoforms expressed in b-cells equally in male and female mice. The reduced Ca2+ influx alters the kinetics and amplitude of the global Ca2+ response to glucose in pancreatic islets and significantly reduces insulin release in both sexes. The progression of diabetes in males is aggravated by a selective loss of b-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most α2δ -1 2/2 female mice. Together, these findings demonstrate that the loss of the Ca2+ channel α2β-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.

Original languageEnglish
Pages (from-to)897-907
Number of pages11
JournalDiabetes
Volume66
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1

Subject classification (UKÄ)

  • Endocrinology and Diabetes

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