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(Received for publication, October 7, 1996, and in revised form, November 22, 1996)
From the Division of Endocrinology and the Diabetes Research and
Training Center, Albert Einstein College of Medicine,
Bronx, New York 10461
To delineate the biochemical mechanism by which
increased availability of GlcN impairs insulin action on skeletal
muscle glucose uptake, we replenished the uridine pool during GlcN
administration. Co-infusion of uridine with GlcN prevented the
GlcN-induced fall in skeletal muscle UDP-glucose levels (24.9 ± 5.3 versus 10.1 ± 2.9 nmol/g; p < 0.01) and further increased the skeletal muscle UDP-GlcNAc levels
(198.4 ± 26.3 versus 96.0 ± 8.4 nmol/g;
p < 0.01). Greater reductions in the rates of glucose
infusion (~53%), glucose uptake (~43%), and glycogen synthesis
(~60%) were observed with the addition of uridine. Similarly, the
infusion of uridine alone markedly increased the skeletal muscle levels
of both UDP-glucose (55.2 ± 14.2 versus 17.8 ± 6.1 nmol/g; p < 0.01) and UDP-GlcNAc (86.8 ± 8.8 versus 35.9 ± 8.4 nmol/g; p < 0.05) and induced marked insulin resistance. The decrease in insulin
action on peripheral glucose uptake was highly correlated with the
increase in skeletal muscle UDP-GlcNAc levels. Finally, immunoisolation
of GLUT4-containing vesicles revealed that the rate of labeled GlcN
incorporation was ~100-fold greater following GlcN compared with
saline infusions (p < 0.01). We suggest that the
marked reduction in insulin action induced by GlcN and uridine is
mediated by increased accumulation of muscle
UDP-N-acetylhexosamines, perhaps via altered glycosylation of protein(s) in GLUT4-containing vesicles.
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