Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: Diabetes
Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca(2+) influx through high voltage-gated Ca(2+) channels (HVCC). Ca(2+) influx also regulate insulin synthesis, insulin granule priming and contribute to β-cell electrical activity. The HVCC are multi-subunit 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 Ca(2+) currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca(2+) influx alters the kinetics and amplitude of the global Ca(2+) 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 Ca(2+) channel α2δ-1 subunit function increases the susceptibility for developing diabetes in a sex dependent manner.