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© 2001 by the American Diabetes Association, Inc.
Free Fatty Acids Induce Peripheral Insulin Resistance Without Increasing Muscle Hexosamine Pathway Product Levels in Rats
From the Diabetes Research Center, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
Address correspondence and reprint requests to Jang H. Youn, PhD, Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, 1333 San Pablo Ave., MMR 626, Los Angeles, CA 90089-9142. E-mail: youn{at}usc.edu .
To evaluate the role of the hexosamine biosynthesis pathway (HBP) in
fat-induced insulin resistance, we examined whether fat-induced insulin
resistance is additive to that induced by increased HBP flux via glucosamine
infusion and, if so, whether such additive effects correlate with muscle HBP
product levels. Prolonged hyperinsulinemic (
550 pmol/l) euglycemic clamps
were conducted in conscious overnight-fasted rats. After the initial 150 min
to attain steady-state insulin action, rats received an additional infusion of
saline, Intralipid, glucosamine, or Intralipid and glucosamine (n = 8
or 9 for each) for 330 min. At the conclusion of clamps, skeletal muscles
(soleus, extensor digitorum longus, and tibialis anterior) were taken for the
measurement of HBP product levels. Intralipid and glucosamine infusions
decreased insulin-stimulated glucose uptake (Rd) by 38 and
28%, respectively. When the infusions were combined, insulin-stimulated
Rd decreased 47%, significantly more than with Intralipid
or glucosamine alone (P < 0.05). The glucosamine-induced insulin
resistance was associated with four- to fivefold increases in muscle HBP
product levels. In contrast, the Intralipid-induced insulin resistance was
accompanied by absolutely no increase in HBP product levels in all of the
muscles examined. Also, when infused with glucosamine, Intralipid decreased
insulin action below that with glucosamine alone without changing HBP product
levels. In a separate study, short-term (50 and 180 min) Intralipid infusion
also failed to increase muscle HBP product levels. In conclusion, increased
availability of plasma free fatty acids induces peripheral insulin resistance
without increasing HBP product levels in skeletal muscle.
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