Increased activity of the hexosamine synthesis pathway in muscles of insulin-resistant ob/ob mice.
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.
Buse
M G
MG
Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.
Robinson
K A
KA
Gettys
T W
TW
McMahon
E G
EG
Gulve
E A
EA
D000375:Aging / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006595:Hexosamines / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D024510:Muscle Development; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism; D014539:Uridine Diphosphate Sugars / Q000378:metabolism
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D006595:Hexosamines; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D014539:Uridine Diphosphate Sugars; D014537:Uridine Diphosphate N-Acetylglucosamine; D005947:Glucose