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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 ? 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 ? 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 ? cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing ? cell dysfunction in T2D.

SUBMITTER: Gooding JR

PROVIDER: S-EPMC4598307 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.

Gooding Jessica R JR Jensen Mette V MV Dai Xiaoqing X Wenner Brett R BR Lu Danhong D Arumugam Ramamani R Ferdaoussi Mourad M MacDonald Patrick E PE Newgard Christopher B CB

Cell reports 20150924 1

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 m ...[more]

PMID: 26411681

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Dataset Information

Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.

Publications

Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.

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