Control of Blood Glucose in the Absence of Hepatic Glucose Production During Prolonged Fasting in Mice

Elodie Mutel; Amandine Gautier-Stein; Aya Abdul-Wahed; Marta Amigó-Correig; Carine Zitoun; Anne Stefanutti; Isabelle Houberdon; Jean-André Tourette; Gilles Mithieux; Fabienne Rajas

doi:10.2337/db11-0571

journal article Open Access Nov 13, 2011

Control of Blood Glucose in the Absence of Hepatic Glucose Production During Prolonged Fasting in Mice

Elodie Mutel Amandine Gautier-Stein Aya Abdul-Wahed Marta Amigó-Correig Carine Zitoun Anne Stefanutti Isabelle Houberdon Jean-André Tourette Gilles Mithieux Fabienne Rajas

Diabetes Vol. 60 No. 12 pp. 3121-3131 · American Diabetes Association

View at Publisher Save 10.2337/db11-0571

Abstract

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.

RESEARCH DESIGN AND 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.

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Details

Published: Nov 13, 2011
Vol/Issue: 60(12)
Pages: 3121-3131
License: View

Authors

E

Elodie Mutel