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Departments of Medicine of the University of Mississippi Medical Center (D.A.M., R.C.C., L.F.H., P.W.), Jackson, Mississippi 39216 and the Medical University of South Carolina (J.-H.Z., W.T.G.) Charleston, South Carolina 29425; and the Veterans Affairs Medical Centers at Jackson, Mississippi 39216 (D.A.M., R.C.C.) and Charleston, South Carolina 29425 (W.T.G.)
Address all correspondence and requests for reprints to: Donald A. McClain, Division of Endocrinology, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216-4505. E-mail: dam{at}fiona.umsmed.edu
Hexosamines have been hypothesized to mediate aspects of glucose
sensing and toxic effects of hyperglycemia. For example, insulin
resistance results when the rate-limiting enzyme for hexosamine
synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), is
overexpressed in muscle and adipose tissue of transgenic mice. The
glucose infusion rates required to maintain euglycemia at insulin
infusion rates of 0.5, 2, 15, and 20 mU/kg·min were 39–90% lower in
such transgenic mice, compared with their control littermates
(P 
0.01). No differences were observed in
hepatic glucose output, serum insulin levels, or muscle ATP levels.
Uptake of 2-deoxyglucose, measured under conditions of
hyperinsulinemia, was significantly lower in transgenic hindlimb
muscle, compared with controls (85.9 ± 17.8 vs.
166.8 ± 15.1 pmol deoxyglucose/g·min). The decrease in glucose
uptake by transgenic muscle was associated with a disruption in the
translocation of the insulin-stimulated glucose transporter GLUT4.
Fractionation of muscle membranes on a discontinuous sucrose gradient
revealed that insulin stimulation of control muscle led to a 28.8%
increase in GLUT4 content in the 25% fraction and a 61.2% decrease in
the 35% fraction. In transgenic muscle, the insulin-stimulated shifts
in GLUT4 distribution were inhibited by over 70%. Treatment of the
transgenic animals with the thiazolidinedione troglitazone
completely reversed the defect in glucose disposal without changing GFA
activity or the levels of uridine
5'-diphosphate-N-acetylglucosamine. Overexpression of
GFA in skeletal muscle thus leads to defects in glucose transport
similar to those seen in type 2 diabetes. These data support the
hypothesis that excess glucose metabolism through the hexosamine
pathway may be responsible for the diminished insulin sensitivity and
defective glucose uptake that are seen with hyperglycemia.
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