Increased activity of the hexosamine synthesis pathway in muscles
of insulin resistant ob/ob mice.
Buse, Maria G., Katherine A. Robinson, Thomas W. Gettys, Ellen G.
McMahon, and Eric A. Gulve.
Departments of Medicine (Division of Endocrinology, Diabetes and
Medical Genetics and Division of Gastroenterology and Hepatology) and
Biochemistry/Molecular biology, Medical University of South Carolina,
Charleston, S.C. 29425 and Cardiovascular Diseases Research, G.D.
Searle and Company, St. Louis, MO, 63167
APStracts 4:0044E, 1997.
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, glutamine: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 GLUT4 concentration was mildly increased in
muscles from ob/ob mice. UDP-HexNAc concentrations in hindlimb
muscles decreased between 8-17 weeks, 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.
Received 7 October 1996; accepted in final form 4 February 1997.
APS Manuscript Number E496-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 20 February 1997