title: Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Gooding
authors.affiliation: 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.
authors.forename: Mette V
authors.initials: MV
authors.lastname: Jensen
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dai
authors.affiliation: 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.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Wenner
authors.affiliation: 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.
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Ramamani
authors.initials: R
authors.lastname: Arumugam
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
authors.forename: Mourad
authors.initials: M
authors.lastname: Ferdaoussi
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address: pmacdonald@ualberta.ca.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: 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. Electronic address: chris.newgard@duke.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000264:Adenylosuccinate Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000265:Adenylosuccinate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006147:Guanine / Q000494:pharmacology; D006801:Humans; D007291:Inosine Monophosphate / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055442:Metabolome / Q000235:genetics; D009173:Mycophenolic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D007291:Inosine Monophosphate; C012168:adenylosuccinate; D000249:Adenosine Monophosphate; D006147:Guanine; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; D000264:Adenylosuccinate Lyase; D000265:Adenylosuccinate Synthase; D009173:Mycophenolic Acid; D005947:Glucose