Abstract
Voltage-gated Ca2+ channels (Ca-v) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The beta(3) subunit of Ca-v (Ca-v beta(3)) has been suggested to regulate cytosolic Ca2+ ([Ca2+](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 beta(3) overexpression, altered [Ca2+](i) dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Ca-v beta(3)-deficient (Ca-v beta(-/-)(3)) mice showed improved islet function and enhanced glucose tolerance. Normalization of Ca-v beta(3) expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca2+](i) dynamics and impaired insulin secretion. Importantly, transplantation of Ca-v beta(-/-)(3) islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Ca-v beta(3) overexpression in human islets also impaired insulin secretion. We thus suggest that Ca-v beta(3) may serve as a druggable target for diabetes treatment.
