Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory 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 prediabetic state. Herei...
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| Published in | Diabetes (New York, N.Y.) Vol. 69; no. 2; pp. 131 - 145 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Diabetes Association
01.02.2020
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| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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 K
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. 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 K ATP 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. 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. 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.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. |
| Author | Bellin, Melena D. Stiles, Linsey Sereda, Samuel Abdulla, Muhamad Wikstrom, Jakob D. Liesa, Marc Baghdasarian, Siyouneh Kibbey, Richard G. Shirihai, Orian S. Swanson, Zachary Wilhelm, Joshua J. Alsabeeh, Nour Erion, Karel Taddeo, Evan P. Li, Jin Ritou, Eleni |
| Author_xml | – sequence: 1 givenname: Evan P. surname: Taddeo fullname: Taddeo, Evan P. organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 2 givenname: Nour surname: Alsabeeh fullname: Alsabeeh, Nour organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait – sequence: 3 givenname: Siyouneh surname: Baghdasarian fullname: Baghdasarian, Siyouneh organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 4 givenname: Jakob D. orcidid: 0000-0002-4287-1774 surname: Wikstrom fullname: Wikstrom, Jakob D. organization: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, and Department of Dermato-Venereology, Karolinska University Hospital, Stockholm, Sweden – sequence: 5 givenname: Eleni surname: Ritou fullname: Ritou, Eleni organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 6 givenname: Samuel surname: Sereda fullname: Sereda, Samuel organization: Endocrinology, Diabetes, Nutrition and Weight Management Section, Department of Medicine, Boston University School of Medicine, Boston, MA – sequence: 7 givenname: Karel surname: Erion fullname: Erion, Karel organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 8 givenname: Jin surname: Li fullname: Li, Jin organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 9 givenname: Linsey surname: Stiles fullname: Stiles, Linsey organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA – sequence: 10 givenname: Muhamad surname: Abdulla fullname: Abdulla, Muhamad organization: Department of Surgery and Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, MN – sequence: 11 givenname: Zachary surname: Swanson fullname: Swanson, Zachary organization: Department of Surgery and Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, MN – sequence: 12 givenname: Joshua J. surname: Wilhelm fullname: Wilhelm, Joshua J. organization: Department of Surgery and Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, MN – sequence: 13 givenname: Melena D. surname: Bellin fullname: Bellin, Melena D. organization: Department of Surgery and Schulze Diabetes Institute, University of Minnesota School of Medicine, Minneapolis, MN, Division of Pediatric Endocrinology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN – sequence: 14 givenname: Richard G. surname: Kibbey fullname: Kibbey, Richard G. organization: Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT – sequence: 15 givenname: Marc orcidid: 0000-0002-5909-8570 surname: Liesa fullname: Liesa, Marc organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA – sequence: 16 givenname: Orian S. orcidid: 0000-0001-8466-3431 surname: Shirihai fullname: Shirihai, Orian S. organization: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA |
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| SubjectTerms | 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 |
| Title | Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels |
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