GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization.
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.
Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Rémy
R
Burcelin
Valerie
V
Crivelli
Christophe
C
Perrin
Anabela
A
Da Costa
James
J
Mu
Barbara B
BB
Kahn
Morris J
MJ
Birnbaum
C Ronald
CR
Kahn
Peter
P
Vollenweider
Bernard
B
Thorens
D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003964:Diaphragm / Q000378:metabolism; D005799:Genes, Dominant; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology*; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000378:metabolism
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D003847:Deoxyglucose; D011972:Receptor, Insulin; D000263:Adenylate Kinase; D005947:Glucose