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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Monophosphate / analogs & derivatives*
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Adenosine Monophosphate / metabolism
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Adenosine Monophosphate / pharmacology
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Adenylosuccinate Lyase / antagonists & inhibitors
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Adenylosuccinate Lyase / genetics
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Adenylosuccinate Lyase / metabolism
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Adenylosuccinate Synthase / antagonists & inhibitors
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Adenylosuccinate Synthase / genetics
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Adenylosuccinate Synthase / metabolism
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Animals
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Cell Line, Tumor
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Cysteine Endopeptidases
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism*
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Diabetes Mellitus, Type 2 / pathology
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Endopeptidases / genetics
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Endopeptidases / metabolism
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Enzyme Inhibitors / pharmacology
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Exocytosis / drug effects
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Gene Expression Regulation
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Glucose / metabolism
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Glucose / pharmacology*
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Guanine / pharmacology
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Humans
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Inosine Monophosphate / metabolism
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Insulin / biosynthesis
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / drug effects*
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Metabolome / genetics
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Mycophenolic Acid / pharmacology
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Patch-Clamp Techniques
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Primary Cell Culture
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Rats
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Rats, Sprague-Dawley
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Signal Transduction
Substances
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Enzyme Inhibitors
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Insulin
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Inosine Monophosphate
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adenylosuccinate
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Adenosine Monophosphate
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Guanine
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Endopeptidases
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SENP1 protein, human
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Cysteine Endopeptidases
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Adenylosuccinate Lyase
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Adenylosuccinate Synthase
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Mycophenolic Acid
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Glucose