Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health
The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as me...
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| Published in | Cell metabolism Vol. 32; no. 5; pp. 751 - 766.e11 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
03.11.2020
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| Subjects | |
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| Abstract | The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2−/− mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.
[Display omitted]
•Pyruvate kinase activators (PKa) amplify insulin release in preclinical T2DM models•PKa amplify insulin release via the phosphoenolpyruvate cycle in vivo•PKa acutely short-circuit gluconeogenesis and accelerate red blood cell glycolysis•PKa improve insulin sensitivity, steatosis, and dyslipidemia in obese rats
Abulizi et al. show that small molecule activation of mitochondrial PEPCK (pck2)-dependent phosphoenolpyruvate (PEP) cycling amplifies glucose-stimulated insulin secretion without evidence of islet injury and improves insulin sensitivity in vivo. These are accompanied by decreased gluconeogenesis, increased red blood cell glycolysis, and reduced hepatic steatosis in preclinical rodent models of diabetes. |
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| AbstractList | The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2-/- mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2-/- mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity. The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2 mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity. The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2 −/− mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity. Abulizi et al. show that small molecule activation of mitochondrial PEPCK ( pck2 )-dependent phosphoenolpyruvate (PEP) cycling amplifies glucose-stimulated insulin secretion without evidence of islet injury and improves insulin sensitivity in vivo. These are accompanied by decreased gluconeogenesis, increased red blood cell glycolysis, and reduced hepatic steatosis in preclinical rodent models of diabetes. The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrial PEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycle to improve islet function, as well as metabolic homeostasis, in preclinical rodent models of diabetes. In contrast, treatment with a PK activator did not improve insulin secretion in pck2−/− mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretion but also had higher insulin content and markers of differentiation. In addition to improving insulin secretion, acute PK activation short-circuited gluconeogenesis to reduce endogenous glucose production while accelerating red blood cell glucose turnover. Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheral insulin sensitivity in HFD-fed rats. These data provide a preclinical rationale for PK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity. [Display omitted] •Pyruvate kinase activators (PKa) amplify insulin release in preclinical T2DM models•PKa amplify insulin release via the phosphoenolpyruvate cycle in vivo•PKa acutely short-circuit gluconeogenesis and accelerate red blood cell glycolysis•PKa improve insulin sensitivity, steatosis, and dyslipidemia in obese rats Abulizi et al. show that small molecule activation of mitochondrial PEPCK (pck2)-dependent phosphoenolpyruvate (PEP) cycling amplifies glucose-stimulated insulin secretion without evidence of islet injury and improves insulin sensitivity in vivo. These are accompanied by decreased gluconeogenesis, increased red blood cell glycolysis, and reduced hepatic steatosis in preclinical rodent models of diabetes. |
| Author | Hillion, Joelle Merrins, Matthew J. Abulizi, Abudukadier Mason, Graeme F. Alves, Tiago C. Thomas, Craig Kibbey, Richard G. Ma, Lingjun Wang, Bei Siebel, Stephan Lewandowski, Sophie L. Zhao, Xiaojian Stark, Romana Cardone, Rebecca L. Rinehart, Jesse Sehgal, Raghav Kung, Charles Andrews, Zane B. |
| AuthorAffiliation | 7 Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA 3 Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Biomolecular Chemistry, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA 8 Lead Contact 2 Department of Physiology, Monash University, Melbourne, VIC 3800, Australia 5 Agios Pharmaceuticals, Cambridge, MA 02139, USA 6 Department of Diagnostic Radiology and Psychiatry, Yale University, New Haven, CT 06520, USA 1 Department of Internal Medicine, Yale University, New Haven, CT 06520, USA 4 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, and Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA |
| AuthorAffiliation_xml | – name: 6 Department of Diagnostic Radiology and Psychiatry, Yale University, New Haven, CT 06520, USA – name: 7 Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA – name: 3 Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Biomolecular Chemistry, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA – name: 4 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, and Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA – name: 5 Agios Pharmaceuticals, Cambridge, MA 02139, USA – name: 1 Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – name: 2 Department of Physiology, Monash University, Melbourne, VIC 3800, Australia – name: 8 Lead Contact |
| Author_xml | – sequence: 1 givenname: Abudukadier orcidid: 0000-0003-0828-1604 surname: Abulizi fullname: Abulizi, Abudukadier organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 2 givenname: Rebecca L. surname: Cardone fullname: Cardone, Rebecca L. organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 3 givenname: Romana orcidid: 0000-0002-4264-0060 surname: Stark fullname: Stark, Romana organization: Department of Physiology, Monash University, Melbourne, VIC 3800, Australia – sequence: 4 givenname: Sophie L. orcidid: 0000-0002-2838-7054 surname: Lewandowski fullname: Lewandowski, Sophie L. organization: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Biomolecular Chemistry, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA – sequence: 5 givenname: Xiaojian surname: Zhao fullname: Zhao, Xiaojian organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 6 givenname: Joelle surname: Hillion fullname: Hillion, Joelle organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 7 givenname: Lingjun orcidid: 0000-0003-2223-7626 surname: Ma fullname: Ma, Lingjun organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 8 givenname: Raghav orcidid: 0000-0002-9387-1758 surname: Sehgal fullname: Sehgal, Raghav organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 9 givenname: Tiago C. surname: Alves fullname: Alves, Tiago C. organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 10 givenname: Craig surname: Thomas fullname: Thomas, Craig organization: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, and Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 11 givenname: Charles surname: Kung fullname: Kung, Charles organization: Agios Pharmaceuticals, Cambridge, MA 02139, USA – sequence: 12 givenname: Bei surname: Wang fullname: Wang, Bei organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 13 givenname: Stephan surname: Siebel fullname: Siebel, Stephan organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA – sequence: 14 givenname: Zane B. orcidid: 0000-0002-9097-7944 surname: Andrews fullname: Andrews, Zane B. organization: Department of Physiology, Monash University, Melbourne, VIC 3800, Australia – sequence: 15 givenname: Graeme F. orcidid: 0000-0002-6573-5222 surname: Mason fullname: Mason, Graeme F. organization: Department of Diagnostic Radiology and Psychiatry, Yale University, New Haven, CT 06520, USA – sequence: 16 givenname: Jesse orcidid: 0000-0003-4839-4005 surname: Rinehart fullname: Rinehart, Jesse organization: Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA – sequence: 17 givenname: Matthew J. surname: Merrins fullname: Merrins, Matthew J. organization: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Biomolecular Chemistry, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA – sequence: 18 givenname: Richard G. surname: Kibbey fullname: Kibbey, Richard G. email: richard.kibbey@yale.edu organization: Department of Internal Medicine, Yale University, New Haven, CT 06520, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33147485$$D View this record in MEDLINE/PubMed |
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| Keywords | human islets anaplerosis pyruvate kinase cataplerosis mitochondrial GTP fatty liver insulin secretion mitochondrial PEPCK phosphoenolpyruvate cycle insulin resistance |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS R.G.K. conceived the study and wrote the paper with A.A., R.L.C., and R. Stark. A.A. and R.L.C. performed the main body of experiments with contributions from R. Stark., T.C.A., S.L.L., J.H., and L.M. and assisted by B.W., X.Z., R. Sehgal, and S.S. C.K., C.T., R.S., Z.B.A., G.F.M., and J.R. provided reagents and technical expertise. R.G.K., G.F.M., M.J.M., R.S., and Z.B.A. obtained funding. R.G.K., A.A., R.L.C., R. Stark., S.L.L., M.J.M., C.T., and C.K. interpreted the data and edited the manuscript. |
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| SubjectTerms | anaplerosis Animals cataplerosis fatty liver Homeostasis human islets Insulin - metabolism insulin resistance insulin secretion Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria - metabolism mitochondrial GTP mitochondrial PEPCK Phosphoenolpyruvate - metabolism phosphoenolpyruvate cycle pyruvate kinase Pyruvate Kinase - metabolism Rats Rats, Sprague-Dawley |
| Title | Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health |
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