Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Hydrogen sulfide (H2S) has been traditionally known for its toxic effects on living organisms. The role of H2S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H2S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H2S production and insulin release were also assayed. It was found that H2S was generated in rat pancreas islets, catalyzed predominantly by cystathionine gamma-lyase (CSE). Pancreatic CSE expression and H2S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H2S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (P < 0.05). Although in ZF rats it also reduced pancreatic H2S production and serum H2S level, PPG treatment did not alter serum insulin and glucose level. Finally, H2S significantly increased K-ATP channel activity in freshly isolated rat pancreatic beta-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H2S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H2S production from pancreas.