Autocrine C-peptide protects INS1 β cells against palmitic acid-induced oxidative stress in peroxisomes by inducing catalase

Aims: C-peptide, produced by pancreatic beta cells and co-secreted in the bloodstream with insulin, has antioxidant properties in glucose- and hydrogen peroxide (H2O2)-exposed INS1 beta cells. Palmitic acid, the most physiologically abundant long-chain free fatty acid in humans, is metabolized in peroxisomes of beta cells accumulating H2O2 that can lead to oxidative stress. Here, we tested the hypothesis that C-peptide protects beta cells from palmitic acid-induced stress by lowering peroxisomal H2O2. Materials and methods: We exposed INS1 beta cells to palmitic acid and C-peptide in the setting of increasing glucose concentration and tested for changes in parameters of stress and death. To study the ability of C-peptide to lower peroxisomal H2O2, we engineered an INS1 beta cell line stably expressing the peroxisomal-targeted H2O2 sensor HyPer, whose fluorescence increases with cellular H2O2. An INS1 beta cell line stably expressing a live-cell fluorescent catalase reporter was used to detect changes in catalase gene expression. Results: C-peptide protects INS1 beta cells from the combined effect of palmitic acid and glucose by reducing peroxisomal H2O2 to baseline levels and increasing expression of catalase. Conclusions: In conditions of glucolipotoxicity, C-peptide increases catalase expression and reduces peroxisomal oxidative stress and death of INS1 beta cells. Maintenance of C-peptide secretion is a pro-survival requisite for beta cells in adverse conditions. Loss of C-peptide secretion would render beta cells more vulnerable to stress and death leading to secretory dysfunction and diabetes.