Cyclophilin D-Dependent Mitochondrial Proton Leak in ß Cells Promotes Basal Insulin Secretion

Abstract

Prediabetic subjects display hypersecretion of insulin at basal levels of blood glucose, a phenomenon termed basal hypersecretion. The molecular mechanisms underlying basal hypersecretion and how it may lead to beta cell failure are not well understood. Islets isolated from prediabetic animals and humans have an inherently high mitochondrial proton leak. However, the molecular entity responsible for this leak and its role in basal hypersecretion are not known. We hypothesize that basal secretion is regulated by proton leak mediated by the permeability transition pore (PTP) functioning in a low conductance state. Our data indicate that islets from high fat diet animals display basal hypersecretion of insulin, increased mitochondrial proton leak, and increased expression of Cyclophilin D, a PTP regulator. Moreover, acute stimulation of islets with amino acids (leucine/glutamine) and fatty acids (oleate/palmitate) at basal glucose concentrations increases leak. Pharmacological and genetic inhibition of Cyclophilin D reverses nutrient induced islet leak and insulin secretion. Pharmacological stimulation of mitochondrial proton leak is sufficient to induce basal hyper secretion. Inhibition of CypD-mediated proton leak might constitute a novel target to test the role of basal hyperinsulinemia in the development of diabetes and obesity. Disclosure N. Alsabeeh: None. E. Taddeo: None. J.D. Wikström: None. E. Ritou: None. L. Stiles: None. M. Liesa: None. O. Shirihai: None.