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Glucose-6-phosphatase, abbreviated G6Pase, is an endoplasmic reticulum–bound enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate. This reaction is a crucial step in endogenous glucose production, enabling the liver to release glucose into the bloodstream during fasting.

G6Pase activity depends on a two-component system. The catalytic subunit, G6PC (glucose-6-phosphatase catalytic subunit), resides in the ER membrane, while the glucose-6-phosphate transporter, G6PT (encoded by SLC37A4), transports glucose-6-phosphate from the cytosol into the ER lumen where G6Pase acts. The reaction occurs in the ER lumen and requires efficient trafficking of substrates between compartments.

Expression of G6Pase is highest in liver and kidney, with lower levels in other tissues such as the intestine. The enzyme is essential for maintaining blood glucose homeostasis during fasting and operates in coordination with gluconeogenic and glycogenolytic pathways. Its activity is influenced by hormonal signals that regulate glucose metabolism, though the regulatory network is complex and involves multiple factors.

Genetic defects in G6PC cause glycogen storage disease type Ia (GSD Ia), while mutations in SLC37A4 cause type Ib. Affected individuals typically present with severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, and hyperlipidemia. Management focuses on preventing hypoglycemia through frequent carbohydrate intake and slow-release starch (cornstarch) therapy, along with treatment of metabolic complications; liver transplantation and experimental gene therapies have been explored in some cases.

G6Pase is conserved across vertebrates and remains a central focus in studies of glucose homeostasis and related metabolic disorders.