Abstract

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 K_ATP 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.