Blocking Ca2+ Channel β3 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.