GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor–stimulated muscle glucose utilization
Rémy Burcelin, … , Peter Vollenweider, Bernard Thorens
Rémy Burcelin, … , Peter Vollenweider, Bernard Thorens
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1555-1562. https://doi.org/10.1172/JCI16888.
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Article Metabolism

GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor–stimulated muscle glucose utilization

Abstract

Recent evidence suggests the existence of a hepatoportal vein glucose sensor, whose activation leads to enhanced glucose use in skeletal muscle, heart, and brown adipose tissue. The mechanism leading to this increase in whole body glucose clearance is not known, but previous data suggest that it is insulin independent. Here, we sought to further determine the portal sensor signaling pathway by selectively evaluating its dependence on muscle GLUT4, insulin receptor, and the evolutionarily conserved sensor of metabolic stress, AMP-activated protein kinase (AMPK). We demonstrate that the increase in muscle glucose use was suppressed in mice lacking the expression of GLUT4 in the organ muscle. In contrast, glucose use was stimulated normally in mice with muscle-specific inactivation of the insulin receptor gene, confirming independence from insulin-signaling pathways. Most importantly, the muscle glucose use in response to activation of the hepatoportal vein glucose sensor was completely dependent on the activity of AMPK, because enhanced hexose disposal was prevented by expression of a dominant negative AMPK in muscle. These data demonstrate that the portal sensor induces glucose use and development of hypoglycemia independently of insulin action, but by a mechanism that requires activation of the AMPK and the presence of GLUT4.

Authors

Rémy Burcelin, Valerie Crivelli, Christophe Perrin, Anabela Da Costa, James Mu, Barbara B. Kahn, Morris J. Birnbaum, C. Ronald Kahn, Peter Vollenweider, Bernard Thorens

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Plasma insulin levels of MGLUT4, MIRKO, and AMPK-DN mice and their respe...
Plasma insulin levels of MGLUT4, MIRKO, and AMPK-DN mice and their respective controls infused with glucose into the portal vein. Glucose was infused through the portal vein in control (white bars) and mutant mice (black bars) for 180 min at a rate of ∼25 mg/kg/min. Plasma insulin levels were determined from the tip of the tail vein before and 10, 30, 50, 120, and 180 min after the beginning of the glucose infusion and are reported as mean ± SE for eight to ten mice per group. The insets depict the corresponding AUC (μU/min/ml) for the different groups of mice. (a) MGLUT4 mice; (b) MIRKO mice; (c) AMPK-DN mice. *Statistically different from controls; P < 0.05.