Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels

• Published in: Diabetes (New York, N.Y.) Vol. 69; no. 2; pp. 131 - 145
• Main Authors: Taddeo, Evan P., Alsabeeh, Nour, Baghdasarian, Siyouneh, Wikstrom, Jakob D., Ritou, Eleni, Sereda, Samuel, Erion, Karel, Li, Jin, Stiles, Linsey, Abdulla, Muhamad, Swanson, Zachary, Wilhelm, Joshua J., Bellin, Melena D., Kibbey, Richard G., Liesa, Marc, Shirihai, Orian S.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.02.2020
• Subjects: Animals; Beta cells; Blood Glucose; Cyclophilins - genetics; Cyclophilins - metabolism; Diabetes; Diabetes mellitus (non-insulin dependent); Diet, High-Fat; Fasting; Fatty acids; Fatty Acids, Nonesterified - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glucose; Humans; Hyperinsulinemia; Insulin; Insulin resistance; Insulin secretion; Insulin Secretion - drug effects; Islets of Langerhans - metabolism; Membrane permeability; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Mitochondrial permeability transition pore; Oleic Acid - chemistry; Oleic Acid - pharmacology; Oxygen Consumption; Palmitic Acid - chemistry; Palmitic Acid - pharmacology; Pancreas; Peptidyl-Prolyl Isomerase F - metabolism; Protons; Secretion
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db19-0379

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 prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified 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 nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.