Blocking Ca Channel β Subunit Reverses Diabetes.

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