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- Title
Control of muscle glucose uptake: test of the rate-limiting step paradigm in conscious, unrestrained mice.
- Authors
Fueger, Patrick T.; Shearer, Jane; Bracy, Deanna P.; Posey, Kelly A.; Pencek, R. Richard; McGuinness, Owen P.; Wasserman, David H.
- Abstract
The aim of this study was to test whether in fact glucose transport is rate-limiting in control of muscle glucose uptake (MGU) under physiological hyperinsulinaemic conditions in the conscious, unrestrained mouse. C57Bl/6J mice overexpressingGLUT4(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 month of age. After a 5-day recovery period, conscious mice underwent one of two protocols (n= 8–14/group) after a 5-h fast. Saline or insulin (4 mU kg−1 min−1) was infused for 120 min. All mice received a bolus of 2-deoxy[3H]glucose (2-3HDG) at 95 min. Glucose was clamped at∼165 mg dl−1 during insulin infusion and insulin levels reached∼80μU ml−1. The rate of disappearance of 2-3HDG from the blood provided an index of whole body glucose clearance. Gastrocnemius, superficial vastus lateralis and soleus muscles were excised at 120 min to determine 2-3HDG-6-phosphate levels and calculate an index of MGU (Rg). Results show that whole body and tissue-specific indices of glucose utilization were: (1) augmented byGLUT4overexpression, but notHKIIoverexpression, in the basal state; (2) enhanced byHKIIoverexpression in the presence of physiological hyperinsulinaemia; and (3) largely unaffected byGLUT4overexpression during insulin clamps whether alone or combined withHKIIoverexpression. Therefore, while glucose transport is the primary barrier to MGU under basal conditions, glucose phosphorylation becomes a more important barrier during physiological hyperinsulinaemia in all muscles. The control of MGU is distributed rather than confined to a single rate-limiting step such as glucose transport as glucose transport and phosphorylation can both become barriers to skeletal muscle glucose influx.
- Subjects
GLUCOSE; MUSCLES; GLUCOKINASE; INSULIN; PHOSPHORYLATION
- Publication
Journal of Physiology, 2005, Vol 562, Issue 3, p925
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/jphysiol.2004.076158