Hydrogen Sulfide and Glucose Homeostasis: A Tale of Sweet and the Stink

Significance: Among many endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays an important role in the regulation of glucose homeostasis. In this article we discuss different functional roles of H2S in several metabolic organs/tissues required in the maintenance of glucose homeostasis. Recent Advances: New evidence has emerged revealing the insulin sensitizing role of H2S in adipose tissue and skeletal muscle biology. In addition, H2S was demonstrated to be a potent stimulator of gluconeogenesis via the induction and stimulation of various glucose-producing pathways in the liver. Critical Issues: Similar to its other physiological effects, H2S exhibits paradoxical characteristics in the regulation of glucose homeostasis: (1) H2S stimulates glucose production via activation of gluconeogenesis and glycogenolysis in hepatocytes, yet inhibits lipolysis in adipocytes; (2) H2S stimulates glucose uptake into adipocytes and skeletal muscle but inhibits glucose uptake into hepatocytes; (3) H2S inhibits insulin secretion from pancreatic beta cells, yet sensitizes insulin signaling and insulin-triggered response in adipose tissues and skeletal muscle. It is also unclear the impact H2S may have on glucose metabolism and utilization by other vital organs, such as the brain. Future Directions: Recent reports and ongoing studies lay the foundation for a general, although highly incomplete, understanding of the effect of H2S on regulating glucose homeostasis. In this review, we describe the molecular mechanisms and physiological outcomes of the gasotransmitter H2S on organs and tissues required for homeostatic maintenance of blood glucose. Future directions highlighting the H2S-mediated homeostatic control of glucose metabolism under physiological and insulin-resistant conditions are also discussed.