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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Vincenzo Mastrolia
  • Sylvia M. Flucher
  • Gerald J. Obermair
  • Mathias Drach
  • Helene Hofer
  • Erik Renström
  • Arnold Schwartz
  • Jörg Striessnig
  • Bernhard E. Flucher
  • Petronel Tuluc
Organisations
External organisations
  • Medical University of Innsbruck
  • University of Cincinnati
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)897-907
Number of pages11
JournalDiabetes
Volume66
Issue number4
Publication statusPublished - 2017 Apr 1
Publication categoryResearch
Peer-reviewedYes