Glycogen storage disease type 1a (GSD1a) is a rare metabolic disorder due to an absence of glucose‐6 phosphatase (G6Pase) activity. G6Pase is the key enzyme of endogenous glucose production (EGP) and catalyzes the last step before the glucose release into the bloodstream. This function to produce glucose is restricted to the liver, the kidneys and the intestine. GSD1a is characterized by chronic hypoglycemia, hepatomegaly associated with hepatic steatosis and nephromegaly. The longterm complications of G6Pase deficiency include hepatocellular adenomas. The available animal model of GSD1a rarely survive over three months of age and the study of mechanisms of hepatocellular adenomas development cannot be investigated. So, we generated an original mouse model of GSD1a with a liver‐specific invalidation of catalytic subunit of G6Pase gene by an inducible CRE‐LOX strategy (L‐G6pc‐/‐ mice). In this work, we demonstrated that L‐G6pc‐/‐ were viable and totally reproduced the liver pathology of GSD1a, including the late development of hepatocellular adenomas. Then, we have begun liver gene therapy treatment using lentiviral and AAV vectors to correct the hepatic pathology. Finally, concerning glucose homeostasis, we have demonstrated that L‐G6pc‐/‐ were able to regulate blood glucose, during prolonged fast, even in the absence of hepatic glucose production. Rapidly, L‐G6pc‐/‐ mice were able to induce renal and intestinal gluconeogenesis thanks to a key role of glucagon and the development of a metabolic acidosis. These results provide evidence that the major role of the liver for EGP during fasting requires re‐examination
