Purpose: Oxidative stress is implicated in pancreatic β-cell dysfunction, yet clinical outcomes of antioxidant therapies on diabetes are inconclusive. Since reactive oxygen species (ROS) can function as signaling intermediates for glucose-stimulated insulin secretion (GSIS), we hypothesize that exogenously boosting cellular antioxidant capacity dampens signaling ROS and GSIS.
Methods: To test the hypothesis, we formulated a mathematical model of redox homeostatic control circuit comprising known feedback and feedforward loops and validated model predictions with plant-derived antioxidant sulforaphane (SFN).
Results: SFN acutely (30-min treatment) stimulated basal insulin secretion in INS-1(832/13) cells and cultured mouse islets, which could be attributed to SFN-elicited ROS as N-acetylcysteine or glutathione ethyl ester suppressed SFN-stimulated insulin secretion. The mathematical model predicted an adapted redox state characteristic of strong induction of endogenous antioxidants but marginally increased ROS under prolonged SFN exposure, a state that attenuates rather than facilitates glucose-stimulated ROS and GSIS. We validated the prediction by demonstrating that although 24-h treatment of INS-1(832/13) cells with low, non-cytotoxic concentrations of SFN (2-10 μM) protected the cells from cytotoxicity by oxidative insult, it markedly suppressed insulin secretion stimulated by 20 mM glucose.
Conclusions: Our study indicates that adaptive induction of endogenous antioxidants by exogenous antioxidants, albeit cytoprotective, inhibits GSIS in β-cells.