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

Author:
  • Vincenzo Mastrolia
  • Sylvia M. Flucher
  • Gerald J. Obermair
  • Mathias Drach
  • Helene Hofer
  • Erik Renström
  • Arnold Schwartz
  • Jörg Striessnig
  • Bernhard E. Flucher
  • Petronel Tuluc
Publishing year: 2017-04-01
Language: English
Pages: 897-907
Publication/Series: Diabetes
Volume: 66
Issue: 4
Document type: Journal article
Publisher: American Diabetes Association

Abstract english

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 -12/2 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.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Islet patophysiology
  • ISSN: 0012-1797
Erik Renström
E-mail: erik.renstrom [at] med.lu.se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00