Glucose-6-phosphatase system (endogenous glucose production) — GSD Ia/Ib, G6PC3-SCN4

The glucose-6-phosphatase system is the endoplasmic-reticulum machinery that carries out the terminal, committed step of endogenous glucose production, shared by gluconeogenesis and glycogenolysis: the hydrolysis of glucose-6-phosphate to free glucose for release into the blood. Because the catalytic site of the phosphatase faces the ER lumen while its substrate is generated in the cytosol, the system couples two integral ER-membrane proteins. The glucose-6-phosphate transporter SLC37A4 (G6PT) is a glucose-6-phosphate:phosphate antiporter that imports cytosolic glucose-6-phosphate into the ER lumen (exchanging for inorganic phosphate). There a glucose-6-phosphatase catalytic subunit hydrolyses it to glucose + Pi: the liver/kidney/intestine isoform G6PC1 supplies blood glucose during fasting, while the ubiquitously expressed paralog G6PC3 serves other tissues (and also handles the incidental substrate 1,5-anhydroglucitol-6-phosphate). The liberated glucose then exits the ER and the cell (via GLUT transporters). Inherited defects define a clinically instructive set: G6PC1 deficiency causes glycogen storage disease type Ia (von Gierke, fasting hypoglycemia/hepatomegaly/lactic acidosis); SLC37A4 deficiency causes GSD type Ib (the same metabolic phenotype PLUS neutropenia/neutrophil dysfunction, because the shared transporter also serves the neutrophil G6PC3 system); and G6PC3 deficiency causes severe congenital neutropenia type 4 (with cardiac/urogenital malformations), not a classic hepatic glycogenosis.