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

Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca influx through high voltage-gated Ca channels (HVCCs). Ca 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 α and auxiliary β and αδ subunits. αδ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of αδ-1, the dominant αδ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the αδ-1 subunit reduces the Ca currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca influx alters the kinetics and amplitude of the global Ca 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 αδ-1 female mice. Together, these findings demonstrate that the loss of the Ca channel αδ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.