title: Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal.
abstract: Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (Rd), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 microg x kg(-1) x min(-1)) and insulin (3 and 18 mU mg x kg(-1) x min(-1)) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to approximately 2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80-150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU x kg(-1) x min(-1), plasma insulin approximately 50 microU/ml), GlcN infusion caused comparable decreases in Rd (15.7 +/- 1.0 [5-7 h] vs. 21.7 +/- 2.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.01) and glycogen synthesis (5.4 +/- 0.5 [5-7 h] vs. 10.4 +/- 1.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). Furthermore, GlcN markedly decreased Rd by 7.8 +/- 1.2 mg x kg(-1) x min(-1) (18.7 +/- 0.7 [5-7 h] vs. 26.5 +/- 1.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.001 vs. control) during IGF-1 (5 microg x kg(-1) x min(-1)) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 +/- 45 vs. 386 +/- 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 +/- 0.5 [5-7 h] vs. 13.9 +/- 0.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in Rd) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU x kg(-1) x min(-1)) were infused for 7 h during euglycemic clamps, and IGF-1 (15 microg x kg(-1) x min(-1)) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on Rd (39.4 +/- 3.2 [4-5 h] vs. 49.8 +/- 3.6 [1-2 h] mg x kg(-1) x min(-1); P < 0.05), which the addition of IGF-1 failed to improve (35.9 +/- 2.3 [6-7 h] vs. 39.4 +/- 3.2 [4-5 h] mg x kg(-1) x min(-1); P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.
authors.affiliation: Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hawkins
authors.forename: N
authors.initials: N
authors.lastname: Barzilai
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: I
authors.initials: I
authors.lastname: Angelov
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.forename: P
authors.initials: P
authors.lastname: Cohen
authors.forename: L
authors.initials: L
authors.lastname: Rossetti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D005944:Glucosamine / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000096:biosynthesis; D006006:Glycogen Synthase / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D006595:Hexosamines; D007328:Insulin; D014537:Uridine Diphosphate N-Acetylglucosamine; D007334:Insulin-Like Growth Factor I; D006003:Glycogen; D006006:Glycogen Synthase; D005947:Glucose; D005944:Glucosamine