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

Publication ,  Journal Article
Gooding, JR; Jensen, MV; Dai, X; Wenner, BR; Lu, D; Arumugam, R; Ferdaoussi, M; MacDonald, PE; Newgard, CB
Published in: Cell Rep
October 6, 2015

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.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

October 6, 2015

Volume

13

Issue

1

Start / End Page

157 / 167

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Primary Cell Culture
  • Patch-Clamp Techniques
  • Mycophenolic Acid
  • Metabolome
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin
 

Citation

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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 Rep, 13(1), 157–167. https://doi.org/10.1016/j.celrep.2015.08.072
Gooding, Jessica R., Mette V. Jensen, Xiaoqing Dai, Brett R. Wenner, Danhong Lu, Ramamani Arumugam, Mourad Ferdaoussi, Patrick E. MacDonald, and Christopher B. Newgard. “Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.Cell Rep 13, no. 1 (October 6, 2015): 157–67. https://doi.org/10.1016/j.celrep.2015.08.072.
Gooding JR, Jensen MV, Dai X, Wenner BR, Lu D, Arumugam R, et al. Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. Cell Rep. 2015 Oct 6;13(1):157–67.
Gooding, Jessica R., et al. “Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism.Cell Rep, vol. 13, no. 1, Oct. 2015, pp. 157–67. Pubmed, doi:10.1016/j.celrep.2015.08.072.
Gooding JR, Jensen MV, Dai X, Wenner BR, Lu D, Arumugam R, Ferdaoussi M, MacDonald PE, Newgard CB. Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. Cell Rep. 2015 Oct 6;13(1):157–167.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

October 6, 2015

Volume

13

Issue

1

Start / End Page

157 / 167

Location

United States

Related Subject Headings

  • Signal Transduction
  • Rats, Sprague-Dawley
  • Rats
  • Primary Cell Culture
  • Patch-Clamp Techniques
  • Mycophenolic Acid
  • Metabolome
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin