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5-Aminoimidazole-4-Carboxamide-1-β-D-Ribofuranoside Reduces Glucose Uptake via the Inhibition of Na⁺/H⁺ Exchanger 1 in Isolated Rat Ventricular Cardiomyocytes

Institut National de la Santé et de la Recherche Médicale (C.S., S.L.L., E.V.O.), Unité (U) 145 and U907, Institut Fédératif de Recherche 50, Faculté de Médecine, Nice F-06107, France; Centre National de la Recherche Scientifique (D.B., L.C.), Unité Mixte de Recherche 6548, Parc Valrose, Nice F-06108, France; and Université de Nice-Sophia Antipolis (C.S., S.L.L., D.B., L.C., E.V.O.), Nice F-06108, France

Address all correspondence and requests for reprints to: Emmanuel Van Obberghen, Faculté de Medecine, Institut National de la Santé et de la Recherche Médicale Unité 907, Avenue de Valombrose, Nice F-06107, France. E-mail: vanobbeg{at}unice.fr.

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by an increased AMP/ATP ratio. AMPK is now well recognized to induce glucose uptake in skeletal muscle and heart. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is phosphorylated to form the AMP analog ZMP, which activates AMPK. Its effects on glucose transport appear to be tissue specific. The purpose of our study was to examine the effect of AICAR on insulin-induced glucose uptake in adult rat ventricular cardiomyocytes. We studied isolated adult rat ventricular cardiomyocytes treated or not with the AMPK activators AICAR and metformin and, subsequently, with insulin or not. Insulin action was investigated by determining deoxyglucose uptake, insulin receptor substrate-1- or -2-associated phosphatidylinositol 3-kinase activity and protein kinase B (PKB) cascade using antibodies to PKB, glycogen synthase kinase-3, and Akt substrate of 160 kDa. Intracellular pH was evaluated using the fluorescent pH-sensitive dye 2',7'-bis (2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and Na⁺/H⁺ exchanger 1 (NHE1) activity was assessed using the NH₄⁺ prepulse method. Our key findings are as follows. AICAR and metformin enhance insulin signaling downstream of PKB. Metformin potentiates insulin-induced glucose uptake, but surprisingly, AICAR inhibits both basal and insulin-induced glucose uptake. Moreover, we found that AICAR decreases intracellular pH, via inhibition of NHE1. In conclusion, AMPK potentiates insulin signaling downstream of PKB in isolated cardiac myocytes, consistent with findings in the heart in vivo. Furthermore, AICAR inhibits basal and insulin-induced glucose uptake in isolated cardiac myocytes via the inhibition of NHE1 and the subsequent reduction of intracellular pH. Importantly, AICAR exerts these effects in a manner independent of AMPK activation.

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