LAUSR

Summary Voltage-gated Ca2+ channels (Cav) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The β3 subunit of Cav (Cavβ3) 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 Cavβ3 overexpression, altered [Ca2+]i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Cavβ3-deficient (Cavβ3−/−) mice showed improved islet function and enhanced glucose tolerance. Normalization of Cavβ3 expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca2+]i dynamics and impaired insulin secretion. Importantly, transplantation of Cavβ3−/− islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Cavβ3 overexpression in human islets also impaired insulin secretion. We thus suggest that Cavβ3 may serve as a druggable target for diabetes treatment.