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Regulation of Insulin-Stimulated Muscle Glucose Uptake in the Conscious Mouse: Role of Glucose Transport Is Dependent on Glucose Phosphorylation Capacity

Department of Molecular Physiology and Biophysics (P.T.F., H.S.H., D.P.B., R.R.P., K.A.P., D.H.W.) and Mouse Metabolic Phenotyping Center (D.P.B., D.H.W.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Biochemistry (M.J.C.), Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Patrick T. Fueger, Duke University Medical Center, Department of Pharmacology and Cancer Biology, 4321 Medical Park Drive, Suite 200, Durham, North Carolina 27704. E-mail: patrick.fueger{at}duke.edu.

Previous work suggests that normal GLUT4 content is sufficient for increases in muscle glucose uptake (MGU) during hyperinsulinemia, because glucose phosphorylation is the more formidable barrier to insulin-stimulated MGU. It was hypothesized that a partial ablation of GLUT4 would not impair insulin-stimulated MGU when glucose phosphorylation capacity is normal but would do so when glucose phosphorylation capacity is increased. Thus, chow-fed C57BL/6J mice with a GLUT4 partial knockout (GLUT4^+/–), hexokinase II overexpression (HK^Tg), or both (HK^Tg + GLUT4^+/–) and wild-type littermates were studied. Carotid artery and jugular vein catheters were implanted for sampling and infusions at 4 months of age. After a 5-d recovery, 5-h fasted mice (n = 8–11/group) underwent a 120-min saline infusion or insulin clamp (4 mU/kg·min insulin with glucose maintained at 165 mg/dl) and received a 2-deoxy[³H]glucose bolus to provide an index of MGU (R_g) for the soleus, gastrocnemius, and superficial vastus lateralis. Basal R_g from all muscles studied from saline-infused mice were not changed by any of the genetic modifications. HK^Tg mice had augmented insulin-stimulated R_g in all muscles studied compared with remaining genotypes. Insulin-stimulated R_g was not impaired in any of the muscles studied from GLUT4^+/– mice. However, the enhanced insulin-stimulated R_g created by HK overexpression was ablated in HK^Tg + GLUT4^+/– mice. Thus, a 50% reduction of normal GLUT4 content in the presence of normal HK activity does not impair insulin-stimulated MGU. However, when the glucose phosphorylation barrier is lowered by HK overexpression, GLUT4 availability becomes a limitation to insulin-stimulated MGU.

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