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Am J Physiol Endocrinol Metab 272: E1080-E1088, 1997;
0193-1849/97 $5.00
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AJP - Endocrinology and Metabolism, Vol 272, Issue 6 E1080-E1088, Copyright © 1997 by American Physiological Society

ARTICLES

Increased activity of the hexosamine synthesis pathway in muscles of insulin-resistant ob/ob mice

M. G. Buse, K. A. Robinson, T. W. Gettys, E. G. McMahon and E. A. Gulve
Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.

Enhanced glucose flux via the hexosamine biosynthetic pathway has been implicated in insulin resistance. We measured products of this pathway, UDP-N-acetyl hexosamines (UDP-HexNAc), and activity of the rate-limiting enzyme L-glutamine:D-fructose-6-phosphate amidotransferase (GFAT) in tissues of ob/ob mice and lean controls. Ob/ob mice were obese, hyperglycemic, and hyperinsulinemic. Resistance to the effect of insulin on glucose transport was demonstrated in isolated soleus muscles, although total GLUT-4 concentration was mildly increased in muscles from ob/ob mice. UDP-HexNAc concentrations in hindlimb muscles decreased between 8 and 17 wk but were always higher in ob/ob vs. controls (P < 0.001, mean increase 67%). Concentrations of UDP-hexoses and GDP-mannose were similar in ob/ob and control muscles. Muscle GFAT activity declined with age but was increased in ob/ob vs. controls at each age examined (P < 0.001, mean increase 108%). UDP-HexNAc concentrations and GFAT activity were similar in livers of ob/ob and controls. These data suggest that glucose flux via the hexosamine pathway is selectively increased in muscle but not liver of ob/ob mice and may contribute to muscle insulin resistance in this model of non-insulin-dependent diabetes mellitus.


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