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Role of Insulin Receptor in the Regulation of Glucose Uptake in Neonatal Hepatocytes

Institute of Biochemistry/Department of Biochemistry and Molecular Biology, Joint Center Consejo Superior de Investigaciones Científicas/Universidad Complutense, School of Pharmacy, 28040 Madrid, Spain

Address all correspondence and requests for reprints to: Manuel Benito or Angela M. Valverde, Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Ciudad Universitaria, 28040 Madrid, Spaín. E-mails: benito{at}farm.ucm.es or valverde{at}farm.ucm.es.

The liver plays a major role in the regulation of glucose homoeostasis. Evidence from liver-specific insulin receptor knockout mice (LIRKO) suggested that insulin’s direct and indirect effects on glucose utilization by the liver both require the presence of hepatic insulin receptors (IR). To address this issue, we have generated immortalized neonatal hepatocytes bearing (HIR LoxP) or not (HIR KO) IR. The lack of IR significantly decreased basal glucose uptake in neonatal hepatocytes from 3- to 14-d-old mice, and the expression of glucose transporter 1 (GLUT1), GLUT2, and glucokinase (GK) remained unchanged throughout development. HIR KO reconstituted hepatocytes with IR_A but not with IR_B isoform and restored basal glucose uptake up to the levels observed in HIR LoxP cells. However, both IR isoforms associated with GLUT1 or GLUT2. Overexpression of IGF-I receptor (IGF-IR) increased basal glucose uptake in neonatal hepatocytes lacking or not IR. This effect was also accompanied by its association with GLUT1 or GLUT2. Exogenous expression of GLUT4 had no effect on basal glucose uptake in neonatal hepatocytes. However, HIR LoxP hepatocytes expressing exogenous GLUT4 increased glucose uptake in the presence of insulin without showing association between GLUT4 and IR. Our data clearly indicate that IR plays a direct role in the regulation of basal glucose uptake/transport by the hepatocytes, and either type A IR or IGF-IR works on glucose uptake as a GLUT1- or GLUT2-associated cotransporter. Thus, IR mediates glucose uptake through its specific association with endogenous, but not with exogenous, glucose transporters in neonatal hepatocytes.

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