title: The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake.
abstract: 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.
authors.affiliation: Division of Endocrinology and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hawkins
authors.forename: I
authors.initials: I
authors.lastname: Angelov
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Barzilai
authors.forename: L
authors.initials: L
authors.lastname: Rossetti
mesh_terms: 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*
chemical_list: 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