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(Received for publication, March 21, 1996, and in revised form, June 11, 1996)
From the Transgenic mice that overexpress
GLUT1 or GLUT4 in skeletal muscle were studied;
the former but not the latter develop insulin resistance. Because
increased glucose flux via the hexosamine biosynthesis pathway has been
implicated in glucose-induced insulin resistance, we measured the
activity of glutamine:fructose-6-phosphate amidotransferase (GFAT;
rate-limiting enzyme) and the concentrations of UDP-N-acetyl
hexosamines (major products of the pathway) as well as UDP-hexoses and
GDP-mannose in hind limb muscles and liver in both transgenic models
and controls. GFAT activity was increased 60-70% in muscles of
GLUT1 but not in GLUT4 transgenics. GFAT
mRNA abundance was unchanged. The concentrations of all
nucleotide-linked sugars were increased 2-3-fold in GLUT1
and were unchanged in GLUT4-overexpressing muscles. Similar
results were obtained in fed and fasted mice. GFAT and nucleotide
sugars were unchanged in liver, where the transgene is not expressed.
We concluded that 1) glucose transport appears to be rate limiting for
synthesis of nucleotide sugars; 2) chronically increased glucose flux
increases muscle GFAT activity posttranscriptionally; 3) increased
UDP-glucose likely accounts for the marked glycogen accumulation in
muscles of GLUT1-overexpressing mice; and 4) glucose flux
via the hexosamine biosynthetic pathway is increased in muscles of
GLUT1-overexpressing but not
GLUT4-overexpressing mice; products of the pathway may
contribute to insulin resistance in GLUT1 transgenics.
Volume 271, Number 38,
Issue of September 20, 1996
pp. 23197-23202
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
Departments of Medicine, Division of
Endocrinology, Diabetes and Medical Genetics, and
Biochemistry/Molecular Biology, Medical University of South Carolina,
Charleston, South Carolina 29425 and the ¶ Departments of
Pediatrics and of Cell Biology and Physiology, Washington University
School of Medicine, St. Louis, Missouri 63110
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