The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake.
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 ( approximately 53%), glucose uptake ( approximately 43%), and glycogen synthesis ( approximately 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 approximately 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.
Hawkins
M
M
Division of Endocrinology and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Angelov
I
I
Liu
R
R
Barzilai
N
N
Rossetti
L
L
D000818:Animals; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D014537:Uridine Diphosphate N-Acetylglucosamine; D005947:Glucose