Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR

RR Russell III, R Bergeron… - American Journal of …, 1999 - journals.physiology.org
RR Russell III, R Bergeron, GI Shulman, LH Young
American Journal of Physiology-Heart and Circulatory Physiology, 1999journals.physiology.org
Insulin increases glucose uptake through the translocation of GLUT-4 via a pathway
mediated by phosphatidylinositol 3-kinase (PI3K). In contrast, myocardial glucose uptake
during ischemia and hypoxia is stimulated by the translocation of GLUT-4 to the surface of
cardiac myocytes through a PI3K-independent pathway that has not been characterized.
AMP-activated protein kinase (AMPK) activity is also increased by myocardial ischemia, and
we examined whether AMPK stimulates glucose uptake and GLUT-4 translocation. In …
Insulin increases glucose uptake through the translocation of GLUT-4 via a pathway mediated by phosphatidylinositol 3-kinase (PI3K). In contrast, myocardial glucose uptake during ischemia and hypoxia is stimulated by the translocation of GLUT-4 to the surface of cardiac myocytes through a PI3K-independent pathway that has not been characterized. AMP-activated protein kinase (AMPK) activity is also increased by myocardial ischemia, and we examined whether AMPK stimulates glucose uptake and GLUT-4 translocation. In isolated rat ventricular papillary muscles, 5-aminoimidazole-4-carboxyamide-1-β-d-ribofuranoside (AICAR), an activator of AMPK, as well as cyanide-induced chemical hypoxia and insulin, increased 2-[3H]deoxyglucose uptake two- to threefold. Wortmannin, a PI3K inhibitor, did not affect either the AICAR- or the cyanide-stimulated increase in deoxyglucose uptake but eliminated the insulin-stimulated increase in deoxyglucose uptake. Immunofluorescence studies demonstrated translocation of GLUT-4 to the myocyte sarcolemma in response to stimulation with AICAR, cyanide, or insulin. Preincubation of papillary muscles with the kinase inhibitor iodotubercidin or adenine 9-β-d-arabinofuranoside (araA), a precursor of araATP (a competitive inhibitor of AMPK), decreased AICAR- and cyanide-stimulated glucose uptake but did not affect basal or insulin-stimulated glucose uptake. In vivo infusion of AICAR caused myocardial AMPK activation and GLUT-4 translocation in the rat. We conclude that AMPK activation increases cardiac muscle glucose uptake through translocation of GLUT-4 via a pathway that is independent of PI3K. These findings suggest that AMPK activation may be important in ischemia-induced translocation of GLUT-4 in the heart.
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