Blocking Ca2+ Channel β3 Subunit Reverses Diabetes

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 β3 subunit of Ca_v (Ca_vβ₃) 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_vβ₃ overexpression, altered [Ca²⁺]_i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Ca_vβ₃-deficient (Ca_vβ₃^-/-) mice showed improved islet function and enhanced glucose tolerance. Normalization of Ca_vβ₃ expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca²⁺]_i dynamics and impaired insulin secretion. Importantly, transplantation of Ca_vβ₃^-/- islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Ca_vβ₃ overexpression in human islets also impaired insulin secretion. We thus suggest that Ca_vβ₃ may serve as a druggable target for diabetes treatment.

Keywords: Ca(2+) dynamics; Ca(v)β(3); diabetes; insulin secretion; pancreatic islets.