Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism
Jessica R. Gooding,
Mette V. Jensen,
Xiaoqing Dai,
Brett R. Wenner,
Danhong Lu,
Ramamani Arumugam,
Mourad Ferdaoussi,
Patrick E. MacDonald,
Christopher B. Newgard
Affiliations
Jessica R. Gooding
Sarah 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, USA
Mette V. Jensen
Sarah 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, USA
Xiaoqing Dai
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada
Brett R. Wenner
Sarah 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, USA
Danhong Lu
Sarah 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, USA
Ramamani Arumugam
Sarah 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, USA
Mourad Ferdaoussi
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada
Patrick E. MacDonald
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada
Christopher B. Newgard
Sarah 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, USA
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.
