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Cell Rep. 2015 Oct 6;13(1):157-167. doi: 10.1016/j.celrep.2015.08.072. Epub 2015 Sep 24.

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

Author information

1
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.
2
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
3
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address: pmacdonald@ualberta.ca.
4
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.

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.

PMID:
26411681
PMCID:
PMC4598307
DOI:
10.1016/j.celrep.2015.08.072
[Indexed for MEDLINE]
Free PMC Article

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