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J. Biol. Chem., Vol. 276, Issue 23, 20101-20107, June 8, 2001
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From the Department of Medicine, Washington University School of
Medicine, St. Louis, Missouri 63110
Muscles and fat cells develop insulin resistance
when exposed to high concentrations of glucose and insulin. We used an
isolated muscle preparation incubated with high levels of glucose and
insulin to further evaluate how glucose-induced insulin resistance
(GIIR) is mediated. Incubation with 2 milliunits/ml insulin and 36 mM glucose for 5 h resulted in an ~50%
decrease in insulin-stimulated muscle glucose transport. The decrease
in insulin responsiveness of glucose transport induced by glucose was
not due to impaired insulin signaling, as insulin-stimulated
phosphatidylinositol 3-kinase activity and protein kinase B
phosphorylation were not reduced. It has been hypothesized that entry
of glucose into the hexosamine biosynthetic pathway with accumulation
of UDP-N-acetylhexosamines (UDP-HexNAcs) mediates GIIR.
However, inhibition of the rate-limiting enzyme GFAT
(glutamine:fructose-6-phosphate amidotransferase) did not protect
against GIIR despite a marked reduction of UDP-HexNAcs. The mRNA
synthesis inhibitor actinomycin D and the protein synthesis inhibitor
cycloheximide both completely protected against GIIR despite the
massive increases in UDP-HexNAcs and glycogen that resulted from
increased glucose entry. Activation of AMP-activated protein kinase
also protected against GIIR. These results provide evidence that GIIR
can occur in muscle without increased accumulation of hexosamine
pathway end products, that neither high glycogen concentration nor
impaired insulin signaling is responsible for GIIR, and that synthesis
of a protein with a short half-life mediates GIIR. They also suggest
that dephosphorylation of a transcription factor may be involved in the
induction of GIIR.
Development of Glucose-induced Insulin Resistance in Muscle
Requires Protein Synthesis*
,
*
This work was supported National Institutes of Health Grant
DK18986 and Diabetes Research and Training Center Grant DK20579.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported initially by a Nakatomi Health Science Foundation
(Tokyo) postdoctoral fellowship and subsequently by an American Diabetes Association mentor-based postdoctoral fellowship.
§
To whom correspondence should be addressed: Washington University
School of Medicine, Div. of Geriatrics and Gerontology, 4566 Scott
Ave., Campus Box 8113, St. Louis, MO 63110. Tel.: 314-362-3506; Fax:
314-362-7657; E-mail: jhollosz@im.wustl.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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