| First Author | Mastrolia V | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 4 | Pages | 897-907 |
| PubMed ID | 28115397 | Mgi Jnum | J:247020 |
| Mgi Id | MGI:5924294 | Doi | 10.2337/db16-0336 |
| Citation | Mastrolia V, et al. (2017) Loss of alpha2delta-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes. Diabetes 66(4):897-907 |
| abstractText | Reduced pancreatic beta-cell function or mass is the critical problem in developing diabetes. Insulin release from beta-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 beta-cell electrical activity. The HVCCs are multisubunit protein complexes composed of a pore-forming alpha1 and auxiliary beta and alpha2delta subunits. alpha2delta is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of alpha2delta-1, the dominant alpha2delta subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the alpha2delta-1 subunit reduces the Ca2+ currents through all HVCC isoforms expressed in beta-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 beta-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most alpha2delta-1-/- female mice. Together, these findings demonstrate that the loss of the Ca2+ channel alpha2delta-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner. |
