glucose6fosfatase

Glucose-6-phosphatase is an endoplasmic reticulum–resident enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate, a key step in endogenous glucose production during fasting. It is expressed mainly in liver, kidney, and small intestine, with the catalytic activity occurring in the lumen of the endoplasmic reticulum. The enzyme relies on the glucose-6-phosphate transporter (G6PT, encoded by SLC37A4) to move glucose-6-phosphate into the ER lumen, where it is hydrolyzed by the catalytic subunit.

The catalytic subunit is encoded by G6PC, a gene family that includes G6PC1, G6PC2, and G6PC3. G6PC1 is the principal hepatic isoform, while G6PC2 is enriched in pancreatic islets and G6PC3 has broader expression with distinct clinical associations. The overall pathway enables the release of glucose into the bloodstream during periods of fasting, supporting systemic glucose homeostasis.

Genetic disorders associated with glucose-6-phosphatase deficiency include glycogen storage disease type Ia (GSD Ia) caused by G6PC1 mutations and glycogen storage disease type Ib (GSD Ib) caused by SLC37A4 mutations. Individuals with these conditions typically present with severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, and hyperlipidemia; GSD Ib can also feature neutropenia and increased infection risk.

Management focuses on maintaining euglycemia through frequent carbohydrate intake or uncooked cornstarch, along with monitoring and treating metabolic complications. In GSD Ib, additional care addresses neutropenia and infection risk.