Blocking Ca(2+) Channel β(3) Subunit Reverses Diabetes

Voltage-gated Ca(2+) channels (Ca(v)) are essential for pancreatic beta cell function as they mediate Ca(2+) influx, which leads to insulin exocytosis. The β3 subunit of Ca(v) (Ca(v)β(3)) has been suggested to regulate cytosolic Ca(2+) ([Ca(2+)](i)) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Ca(v)β(3) overexpression, altered [Ca(2+)](i) dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Ca(v)β(3)-deficient (Ca(v)β(3)(−/−)) mice showed improved islet function and enhanced glucose tolerance. Normalization of Ca(v)β(3) expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca(2+)](i) dynamics and impaired insulin secretion. Importantly, transplantation of Ca(v)β(3)(−/−) islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Ca(v)β(3) overexpression in human islets also impaired insulin secretion. We thus suggest that Ca(v)β(3) may serve as a druggable target for diabetes treatment.