Mitochondrial Proton Leak Regulated by Cyclophilin D elevates Insulin Secretion in Islets at Non-Stimulatory Glucose Levels

Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the pre-diabetic state. Herein, we have discovered a mechanism specifically regulating non-glucose stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by non-esterified free fatty acids, the major fuel utilized by beta cells during fasting. We show that the mitochondrial permeability transition pore regulator Cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion (GSIS), by increasing mitochondrial proton leak. Islets from pre-diabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared to lean mice. Proton leak-mediated NGSIS is conserved in human islets and is stimulated by exposure to non-esterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel non-esterified free fatty acid-stimulated pathway selectively driving pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.