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

作者：Gooding Jessica R; Jensen Mette V; Dai Xiaoqing; Wenner Brett R; Lu Danhong; Arumugam Ramamani; Ferdaoussi Mourad; MacDonald Patrick E^*; Newgard Christopher B

来源：Cell Reports, 2015, 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.

• 出版日期2015-10-6