Hydrogen Sulfide in Diabetic Complications Revisited: The State of the Art, Challenges, and Future Directions

Significance: Diabetes and its related complications are becoming an increasing public health problem that affects hundreds of millions of people globally. Increased disability and mortality rate of diabetic individuals are closely associated with various life-threatening complications, such as atherosclerosis, nephropathy, retinopathy, and cardiomyopathy.Recent Advances: Conventional treatments for diabetes are still limited because of undesirable side effects, including obesity, hypoglycemia, and hepatic and renal toxicity. Studies have shown that hydrogen sulfide (H2S) plays a critical role in the modulation of glycolipid metabolism, pancreatic beta cell functions, and diabetic complications.Critical Issues: Preservation of endogenous H2S systems and supplementation of H2S donors are effective in attenuating diabetes-induced complications, thus representing a new avenue to treat diabetes and its associated complications.Future Directions: This review systematically recapitulates and discusses the most recent updates regarding the therapeutic effects of H2S on diabetes and its various complications, with an emphasis on the molecular mechanisms that underlie H2S-mediated protection against diabetic complications. Furthermore, current clinical trials of H2S in diabetic populations are highlighted, and the challenges and solutions to the clinical transformation of H2S-derived therapies in diabetes are proposed. Finally, future research directions of the pharmacological actions of H2S in diabetes and its related complications are summarized. Antioxid. Redox Signal. 38, 18-44.