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First published online on December 2, 2004.
 Copyright © 2004 by The Physiological Society
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Received September 27, 2004
Revised October 25, 2004
Accepted after revision November 30, 2004

Control of Muscle Glucose Uptake: Test of the Rate-Limiting Step Paradigm in Conscious, Unrestrained Mice

Patrick T Fueger1*, Jane Shearer1, Deanna P Bracy1, Kelly A Posey1, R Richard Pencek1, Owen P McGuinness1, and David H Wasserman1

1 Vanderbilt University

* To whom correspondence should be addressed. E-mail: patrick.fueger{at}duke.edu.

The aim was to test whether in fact glucose transport is rate-limiting in control of muscle glucose uptake (MGU) under physiological hyperinsulinemic conditions in the conscious, unrestrained mouse. C57Bl/6J mice overexpressing GLUT4 (GLUT4Tg), hexokinase II (HKTg), or both (GLUT4Tg + HKTg) were compared to wild type (WT) littermates. Catheters were implanted into a carotid artery and jugular vein for sampling and infusions at 4 mo of age. After a ≥5 d recovery, 5 h fasted conscious mice underwent one of two protocols (n=8-14/group). Saline or insulin (4 mU/kg/min) was infused for 120 min. All mice received a bolus of 2 deoxy[3H]glucose (2DG) at 95 min. Glucose was clamped at ~165 mg/dl during insulin infusion and insulin levels reached ~80 µU/ml. 2DG rate of disappearance from the blood provided an index of whole body glucose clearance. Gastrocnemius, superficial vastus lateralis, and soleus were excised at 120 min to determine 2DG-6-phosphate and calculate an index of MGU (Rg). Results show that whole body and tissue specific indices of glucose utilization were 1) augmented by GLUT4 overexpression, but not HKII overexpression, in the basal state; 2) enhanced by HKII overexpression in the presence of physiological hyperinsulinemia; and 3) largely unaffected by GLUT4 overexpression during insulin clamps whether alone or combined with HKII overexpression. Therefore, while glucose transport is the primary barrier to MGU under basal conditions, glucose phosphorylation becomes a more important barrier during physiological hyperinsulinemia in all muscles. The control of MGU is distributed rather than confined to a single rate-limiting step such as glucose transport since glucose transport and phosphorylation can both become barriers to skeletal muscle glucose influx.


Key words: Glucose transport • Metabolic regulation • Phosphorylation




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