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Metabolism. 2014 Jan;63(1):104-11. doi: 10.1016/j.metabol.2013.09.005. Epub 2013 Oct 14.

Intestinal gluconeogenesis is crucial to maintain a physiological fasting glycemia in the absence of hepatic glucose production in mice.

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Institut National de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; University of Lyon, Lyon 69008, France; University Lyon 1, Villeurbanne 69622, France.



Similar to the liver and kidneys, the intestine has been strongly suggested to be a gluconeogenic organ. However, the precise contribution of the intestine to endogenous glucose production (EGP) remains to be determined. To define the quantitative role of intestinal gluconeogenesis during long-term fasting, we compared changes in blood glucose during prolonged fasting in mice with a liver-deletion of the glucose-6 phosphatase catalytic (G6PC) subunit (LKO) and in mice with a combined deletion of G6PC in both the liver and the intestine (ILKO).


The LKO and ILKO mice were studied after 6h and 40 h of fasting by measuring metabolic and hormonal plasmatic parameters, as well as the expression of gluconeogenic enzymes in the liver, kidneys and intestine.


After a transient hypoglycemic episode (approximately 60 mg/dL) because of their incapacity to mobilize liver glycogen, the LKO mice progressively re-increased their plasma glucose to reach a glycemia comparable to that of wild-type mice (90 mg/dL) from 30 h of fasting. This increase was associated with a rapid induction of renal and intestinal gluconeogenic gene expression, driven by glucagon, glucocorticoids and acidosis. The ILKO mice exhibited a similar induction of renal gluconeogenesis. However, these mice failed to re-increase their glycemia and maintained a plasma glucose level of only 60 mg/dL throughout the 48 h-fasting period.


These data indicate that intestinal glucose production is essential to maintain glucose homeostasis in the absence of hepatic glucose production during fasting. These data provide a definitive quantitative estimate of the capacity of intestinal gluconeogenesis to sustain EGP during long-term fasting.


EGP; Endogenous glucose production; G6PC; G6Pase; Glucose homeostasis; ILKO; Knockout mice; LKO; PEPCK-c; WT; endogenous glucose production; glucose-6 phosphatase; glucose-6 phosphatase catalytic subunit; intestine and liver knockout mice; liver knockout mice; phosphoenolpyruvate carboxykinase cytosolic form; wild-type

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