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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.

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Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
Department of General Pathology, Medical University Innsbruck, Innsbruck, Austria.
Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
College of Medicine, University of Cincinnati, Cincinnati, OH.
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria


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.

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