Glucose Metabolism and Pyruvate Carboxylase Enhanceglutathione Synthesis and Restrict Oxidative Stress in Beta-Cells

Glucose metabolism modulates β-cell responses to diabetogenic stress, including inflammation. Here, we probed the specific metabolic mechanisms that relay the protective effect of glucose in beta-cell 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 β-cells 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 pools is essential.