The role of glucose-6-phosphatase activity in glucose homeostasis and its potential for diabetes therapy

Glucose metabolism and homeostasis are central to human health and survival. In the body, blood glucose regulation is governed, in part, by the liver and the pancreas.Glycemic control is dependent on the activity of hepatic glucose-6-phosphatase catalytic subunit (G6PC)1 and pancreatic beta cell G6PC2 that both catalyze the hydrolysis of G6P to glucose.Mutations or SNPs in G6PC1 or G6PC2 can directly alter glucose regulation dynamics and cause disease phenotypes.G6PC1 is an attractive target for type 1 and type 2 diabetes mellitus therapy by reducing blood glucose. Inhibiting G6PC1 curbs uncontrolled hepatic glucose production seen in these patients. By contrast, inhibiting G6PC2 reduces blood glucose levels, which is predicted to reduce the risk of several diseases including some forms of cancer. Glucose-6-phosphatase catalytic subunit (G6PC)1 and G6PC2 are crucial for glucose metabolism, regulating processes like glycolysis, gluconeogenesis, and glycogenolysis. Despite their structural and functional similarities, G6PC1 and G6PC2 exhibit distinct tissue-specific expression patterns, G6P hydrolysis kinetics, and physiological functions. This review provides a comprehensive overview of their enzymology and distinct roles in glucose homeostasis. We examine how inactivating mutations in G6PC1 lead to glycogen storage disease, and how elevated G6PC1 and G6PC2 expression can affect the incidence of diabetic complications, risk for type 2 diabetes mellitus (T2DM) and various cancers. We also discuss the potential of inhibiting G6PC1 and G6PC2 to protect against complications from elevated blood glucose levels, and highlight drug development efforts targeting G6PC1 and G6PC2, and the therapeutic potential of inhibitors for disease prevention. Glucose-6-phosphatase catalytic subunit (G6PC)1 and G6PC2 are crucial for glucose metabolism, regulating processes like glycolysis, gluconeogenesis, and glycogenolysis. Despite their structural and functional similarities, G6PC1 and G6PC2 exhibit distinct tissue-specific expression patterns, G6P hydrolysis kinetics, and physiological functions. This review provides a comprehensive overview of their enzymology and distinct roles in glucose homeostasis. We examine how inactivating mutations in G6PC1 lead to glycogen storage disease, and how elevated G6PC1 and G6PC2 expression can affect the incidence of diabetic complications, risk for type 2 diabetes mellitus (T2DM) and various cancers. We also discuss the potential of inhib