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

Abstract

Aims: C-peptide, produced by pancreatic β cells and co-secreted in the bloodstream with insulin, has antioxidant properties in glucose- and hydrogen peroxide (H₂O₂)-exposed INS1 β cells. Palmitic acid, the most physiologically abundant long-chain free fatty acid in humans, is metabolized in peroxisomes of β cells accumulating H₂O₂ that can lead to oxidative stress. Here, we tested the hypothesis that C-peptide protects β cells from palmitic acid-induced stress by lowering peroxisomal H₂O₂.

Materials and methods: We exposed INS1 β 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 β cell line stably expressing the peroxisomal-targeted H₂O₂ sensor HyPer, whose fluorescence increases with cellular H₂O₂. An INS1 β cell line stably expressing a live-cell fluorescent catalase reporter was used to detect changes in catalase gene expression.

Results: C-peptide protects INS1 β 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 β cells. Maintenance of C-peptide secretion is a pro-survival requisite for β cells in adverse conditions. Loss of C-peptide secretion would render β cells more vulnerable to stress and death leading to secretory dysfunction and diabetes.

Keywords: C‐peptide; apoptosis; autocrine; diabetes; oxidative stress; palmitic acid; reactive oxygen species (ROS); β cells.