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

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 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.

Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation

“…The most notable example is brown fat tissue, where physiological depolarization can exceed 30 mV 97 . Another example is pancreatic β cells, where fatty acid metabolism can markedly depolarize the mitochondria 98 . Neurons have been shown to provide their ATP requirements by either mitochondrial respiration or glycolysis, as required 86 , 99 .…”

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

“…This is because β-cells express the fatty acid receptor GPR40 ( Itoh et al, 2003 ), which, as a G-protein-coupled receptor, activates the phospholipase C pathway that triggers release of calcium ions from the endoplasmic reticulum and stimulates exocytosis of insulin from cytoplasmic insulin granules ( Rorsman and Ashcroft, 2018 ; Usui et al, 2019 ). Alternatively, FFA can also promote upregulation of CYPD and increase the mitochondrial proton leak in β-cells, which enhances non-glucose-stimulated insulin secretion ( Taddeo et al, 2020 ).…”

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

“…Non-esterified free fatty acids have been found to cause insulin secretion in pancreatic beta cells due to an increase in mitochondrial proton leak. Ablation of cyclophilin D or suppression of its activity by NIM811 significantly reduced both proton leak and NGSIS induced by NEFA [ 224 ]. However, other studies should be noted, where cyclosporin A did not inhibit insulin secretion in beta cells [ 225 , 226 ].…”