The Pathogenic Role of Cystathionine γ-Lyase/Hydrogen Sulfide in Streptozotocin-Induced Diabetes in Mice

Reduced beta-cell mass and increased activities of ATP-sensitive K(+) channels in pancreatic beta cells are associated with the pathogenesis of diabetes. Cystathionine gamma-lyase (CSE) is a major hydrogen sulfide (H(2)S)-producing enzyme in pancreatic beta cells. Herein, we examine the effects of genetic and pharmacologic ablation of CSE on beta-cell functions and their correlation with streptozotocin (STZ)-induced diabetes. Compared with wild-type mice, CSE knockout (CSE KO) mice that received STZ injections exhibited a delayed onset of diabetic status. The application of DL-propargylglycine (PPG) to inhibit CSE activity protected wild-type mice from STZ-induced hyperglycemia and hypoinsulinemia. STZ significantly increased pancreatic H(2)S production in wild-type mice but not in CSE KO mice. STZ induced more apoptotic beta-cell death in wild-type mice than in CSE KO mice. STZ exposure decreased the viability of cultured INS-1E cells, which was partly reversed by PPG co-treatment. STZ also significantly stimulated H(2)S production in cultured INS-1E cells. In addition, STZ stimulated ATP-sensitive K(+) currents in pancreatic beta cells from wild-type mice but not in the presence of PPG or in beta cells from CSE KO mice. Sodium hydrosulfide injection instantly increased blood glucose, decreased plasma insulin, and deteriorated glucose tolerance in mice. Take together, these results provide evidence that the CSE/H(2)S system plays a critical role in regulating beta-cell functions. (Am J Pathol 2011, 179:869-879; DOI: 10.1016/j.ajpath.2011.04.028)