Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation

Accalia Fu, Juan Carlos Alvarez-Perez, Daina Avizonis, Tatsuya Kin, Scott B. Ficarro, Dong Wook Choi, Esra Karakose, Mehmet G. Badur, Lindsay Evans, Carolina Rosselot, Gaelle Bridon, Gregory H. Bird, Hyuk Soo Seo, Sirano Dhe-Paganon, Jurre J. Kamphorst, Andrew F. Stewart, A. M. James Shapiro, Jarrod A. Marto, Loren D. Walensky, Russell G. JonesAdolfo Garcia-Ocana, Nika N. Danial

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC–urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism.

Original languageEnglish
Pages (from-to)432-446
Number of pages15
JournalNature Metabolism
Issue number5
StatePublished - 1 May 2020


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