C3aR1 on β cells enhances β cell function and survival

Abstract

Pancreatic {beta} cell dysfunction is critical to the development of type 2 diabetes (T2D). We show that the complement receptor C3aR1 on {beta} cells plays an essential role in maintaining {beta} cell homeostasis, especially under the metabolic duress of obesity and T2D. Mice with {beta} cell specific deletion of C3ar1 have worse glucose tolerance, lower insulin levels, and decreased {beta} cell mass. Islets from {beta} cell specific C3ar1 knockout ({beta}-C3aR1 KO) mice demonstrate impaired insulin secretion. Disruption of C3ar1 on {beta} cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and {beta} cell-derived C3aR1. Markers of {beta} cell identity were decreased while stress markers were increased in {beta}-C3aR1 KO mice. Islets from {beta}-C3aR1 KO also exhibit increased {beta} cell death to lipotoxicity. Finally, we show that C3AR1 is positively correlated with insulin secretion in human islets. These findings indicate that C3aR1 expression on {beta} cells is necessary to maintain optimal {beta} cell function and preserve {beta} cell mass in T2D.