Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon.
OBJECTIVE
Since the pioneering work of Claude Bernard, the scientific community has considered the liver to be the major source of endogenous glucose production in all postabsorptive situations. Nevertheless, the kidneys and intestine can also produce glucose in blood, particularly during fasting and under protein feeding. The aim of this study was to better define the importance of the three gluconeogenic organs in glucose homeostasis.


METHODS
We investigated blood glucose regulation during fasting in a mouse model of inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc(-/-) mice), encoding a mandatory enzyme for glucose production. Furthermore, we characterized molecular mechanisms underlying expression changes of gluconeogenic genes (G6pc, Pck1, and glutaminase) in both the kidneys and intestine.


RESULTS
We show that the absence of hepatic glucose release had no major effect on the control of fasting plasma glucose concentration. Instead, compensatory induction of gluconeogenesis occurred in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis. Moreover, the extrahepatic action of glucagon took place in wild-type mice.


CONCLUSIONS
Our study provides a definitive quantitative estimate of the capacity of extrahepatic gluconeogenesis to sustain fasting endogenous glucose production under the control of glucagon, regardless of the contribution of the liver. Thus, the current dogma relating to the respective role of the liver and of extrahepatic gluconeogenic organs in glucose homeostasis requires re-examination.
Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France.
Elodie
E
Mutel
Amandine
A
Gautier-Stein
Aya
A
Abdul-Wahed
Marta
M
Amigó-Correig
Carine
C
Zitoun
Anne
A
Stefanutti
Isabelle
I
Houberdon
Jean-André
JA
Tourette
Gilles
G
Mithieux
Fabienne
F
Rajas
D000138:Acidosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon; D005952:Glucose-6-Phosphatase; D005972:Glutaminase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose