Loss of a2d-1 calcium channel subunit function increases the susceptibility for diabetes

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.