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

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. 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 β cell functions, and diabetic complications. 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. 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.