Loss of a2d-1 calcium channel subunit function increases the susceptibility for diabetes
Research output: Contribution to journal › Article
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.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Number of pages||11|
|Publication status||Published - 2017 Apr 1|