Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism
Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced ch...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715009857 |
| _version_ | 1818154666364502016 |
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| author | Jessica R. Gooding Mette V. Jensen Xiaoqing Dai Brett R. Wenner Danhong Lu Ramamani Arumugam Mourad Ferdaoussi Patrick E. MacDonald Christopher B. Newgard |
| author_facet | Jessica R. Gooding Mette V. Jensen Xiaoqing Dai Brett R. Wenner Danhong Lu Ramamani Arumugam Mourad Ferdaoussi Patrick E. MacDonald Christopher B. Newgard |
| author_sort | Jessica R. Gooding |
| collection | DOAJ |
| description | Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP) and an increase in adenylosuccinate (S-AMP), suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS). Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1). S-AMP also overcomes the defect in glucose-induced exocytosis in β cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing β cell dysfunction in T2D. |
| first_indexed | 2024-12-11T14:30:08Z |
| format | Article |
| id | doaj.art-2a2e0f02c2844c8595998d2bdb5b5447 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T14:30:08Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2a2e0f02c2844c8595998d2bdb5b54472022-12-22T01:02:29ZengElsevierCell Reports2211-12472015-10-0113115716710.1016/j.celrep.2015.08.072Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine MetabolismJessica R. Gooding0Mette V. Jensen1Xiaoqing Dai2Brett R. Wenner3Danhong Lu4Ramamani Arumugam5Mourad Ferdaoussi6Patrick E. MacDonald7Christopher B. Newgard8Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USASarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USAAlberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, CanadaSarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USASarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USASarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USAAlberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, CanadaAlberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, CanadaSarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USAPancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP) and an increase in adenylosuccinate (S-AMP), suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS). Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1). S-AMP also overcomes the defect in glucose-induced exocytosis in β cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing β cell dysfunction in T2D.http://www.sciencedirect.com/science/article/pii/S2211124715009857 |
| spellingShingle | Jessica R. Gooding Mette V. Jensen Xiaoqing Dai Brett R. Wenner Danhong Lu Ramamani Arumugam Mourad Ferdaoussi Patrick E. MacDonald Christopher B. Newgard Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism Cell Reports |
| title | Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism |
| title_full | Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism |
| title_fullStr | Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism |
| title_full_unstemmed | Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism |
| title_short | Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism |
| title_sort | adenylosuccinate is an insulin secretagogue derived from glucose induced purine metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715009857 |
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