Article ; Online: Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.
2021 Volume 37, Issue 8, Page(s) 110037
Abstract: Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of ... ...
Abstract | Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential. |
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MeSH term(s) | Adult ; Animals ; Antioxidants/physiology ; Female ; Glucose/metabolism ; Glutathione/biosynthesis ; Glutathione/metabolism ; Humans ; Insulin/metabolism ; Islets of Langerhans/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress/physiology ; Primary Cell Culture ; Pyruvate Carboxylase/metabolism |
Chemical Substances | Antioxidants ; Insulin ; Pyruvate Carboxylase (EC 6.4.1.1) ; Glutathione (GAN16C9B8O) ; Glucose (IY9XDZ35W2) |
Language | English |
Publishing date | 2021-11-24 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2649101-1 |
ISSN | 2211-1247 ; 2211-1247 |
ISSN (online) | 2211-1247 |
ISSN | 2211-1247 |
DOI | 10.1016/j.celrep.2021.110037 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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