Loss of α 2 δ-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 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 α2 δ subunits. α2 δ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of α2 δ-1, the dominant α2 δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α2 δ-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 α2 δ-1-/- female mice. Together, these findings demonstrate that the loss of the Ca2+ channel α2 δ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.