C3aR1 on β cells enhances β cell function and survival

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