234-OR: Succinate Potentiates Insulin Secretion through SUCNR1

Here, we examined the role of succinate, a metabolite that acts by engaging the succinate receptor 1 (SUCNR1), in regulating insulin secretion by β-cells. We found that glucose increases SUCNR1 expression in β-cells and that activating SUCNR1 with either extracellular succinate or a synthetic agonist boosts glucose-stimulated insulin secretion through the Gq and PKC signaling pathways. Also, we identified that SUCNR1 is essential for preserving insulin secretion in a diet-induced insulin-resistance model. Mice with β-cell-specific SUCNR1 deficiency had impaired glucose tolerance and reduced insulin secretion when fed a high-fat diet, without changes in β-cell mass or insulin sensitivity. To investigate the physiological significance of succinate as a secretagogue in humans, we studied the potential connection between circulating succinate levels and β-cell function in response to oral and intravenous glucose challenges in a cohort of patients with impaired glucose tolerance (IGT). These patients were characterized by presenting hyperinsulinemia during both oral and intravenous glucose tests, compared to normal glucose tolerance (NGT) individuals. Moreover, succinate levels were elevated in IGT patients in response to these challenges compared to NGT patients, whereas circulating GLP-1 levels during the tests were not different between groups. Remarkably, we found that circulating succinate levels are positively correlated with insulin secretion potentiation during intravenous glucose administration, indicating that this system is activated by high glucose levels and partially regulated by the β-cell in an autocrine fashion. These findings suggest that succinate may act as a hormone, potentiating insulin secretion in humans through SUCNR1- a compensatory mechanism particularly relevant in the hyperinsulinemia elicited by insulin resistance. Our work sheds new light on the role of the succinate-SUCNR1 axis as a potential therapeutic target for improving insulin secretion in metabolic disorders.