Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism
Gooding, J. R., Jensen, M. V., Dai, X., Wenner, B. R., Lu, D., Arumugam, R., ... Newgard, C. B. (2015). Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. Cell Reports, 13(1), 157-167. DOI: 10.1016/j.celrep.2015.08.072
Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet beta 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 beta 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 beta cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing b cell dysfunction in T2D.