SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes

Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of Insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates Insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Mice with β-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and Insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving Insulin secretion in diet-induced Insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of Insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for Insulin secretion relevant to the hyperinsulinemia of prediabetic states.