title: Intestinal gluconeogenesis is crucial to maintain a physiological fasting glycemia in the absence of hepatic glucose production in mice.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Armelle
authors.initials: A
authors.lastname: Penhoat
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fayard
authors.forename: Anne
authors.initials: A
authors.lastname: Stefanutti
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rajas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005215:Fasting / Q000097:blood*; D005943:Gluconeogenesis; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D001786:Blood Glucose; D008112:Liver Glycogen; D005952:Glucose-6-Phosphatase
keywords: 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