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

Abstract

Reduced β-cell mass and increased activities of ATP-sensitive K(+) channels in pancreatic β cells are associated with the pathogenesis of diabetes. Cystathionine γ-lyase (CSE) is a major hydrogen sulfide (H(2)S)-producing enzyme in pancreatic β cells. Herein, we examine the effects of genetic and pharmacologic ablation of CSE on β-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 β-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 β cells from wild-type mice but not in the presence of PPG or in β 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 β-cell functions.

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

“…Similarly, it has also been found that pancreatic CSE expression and H 2 S production are higher in Zucker diabetic fatty (ZDF) rats than in Zucker fatty and Zucker lean rats (101). Enhanced endogenous production of H 2 S in diabetes can induce apoptosis of insulin-secreting beta cells by enhancing endoplasmic reticulum (ER) stress via p38 MAPK activation and also stimulate K ATP channels in insulin-secreting cells (73)(74)(75). These results imply that H 2 S at high concentrations contributes to the pathogenesis of diabetes mellitus.…”

“…The pathogenesis of diabetes is associated with decreased functional beta cell mass and increased activities of K ATP channels in pancreatic beta cells (99,100). It has been reported that in streptozotocin-induced diabetes in mice, pancreatic H 2 S production and CSE activity are significantly upregulated (73,76). Similarly, it has also been found that pancreatic CSE expression and H 2 S production are higher in Zucker diabetic fatty (ZDF) rats than in Zucker fatty and Zucker lean rats (101).…”

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…Additionally, H 2 S is not beneficial in all models of renal injury as its effect can vary with the context (70). Whereas H 2 S ameliorates renin-induced hypertension (71), ischemia-reperfusion injury in the kidney and heart (17,20), obstructive kidney injury (72), preeclampsia (73), and hyperhomocysteinemia-induced chronic kidney disease (74) and protects endothelium against high glucose (75), it assumes a pathologic role as a mediator in cisplatinum-induced kidney cell injury (76), streptozotocin-induced pancreatic ␤ cell injury (77), and colon carcinoma (78). These considerations suggest that a critical evaluation of PDE5 inhibitors and H 2 S donors should be done in long term models of kidney injury in diabetes.…”

Hydrogen Sulfide in Renal Physiology and Disease

“…STZ-induced b cell death is attenuated in mice lacking CSE. Furthermore, NaHS significantly reduces insulin secretion and glucose tolerance but does not increase blood glucose in normoglycemic mice (99). Although intra-islet levels of H2S are increased in mice with type 1 diabetes, plasma levels of H2S are lower in mice with type 1 diabetes than in normoglycemic control mice (17).…”