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Diabetes. 2017 Apr;66(4):897-907. doi: 10.2337/db16-0336. Epub 2017 Jan 23.

Loss of α2δ-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes.

Author information

1
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
2
Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
3
Department of General Pathology, Medical University Innsbruck, Innsbruck, Austria.
4
Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
5
College of Medicine, University of Cincinnati, Cincinnati, OH.
6
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria petronel.tuluc@uibk.ac.at bernhard.e.flucher@i-med.ac.at.

Abstract

Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-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 are multisubunit protein complexes composed of a pore-forming α1 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 α2δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α2δ-1 subunit reduces the Ca2+ currents through all HVCC isoforms expressed in β-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 β-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most α2δ-1-/- female mice. Together, these findings demonstrate that the loss of the Ca2+ channel α2δ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.

PMID:
28115397
DOI:
10.2337/db16-0336
[Indexed for MEDLINE]
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