Diabetes, Vol 45, Issue 12 1734-1743, Copyright © 1996 by American Diabetes Association

ARTICLES

Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal

M Hawkins, N Barzilai, W Chen, I Angelov, M Hu, P Cohen and L Rossetti
Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

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.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. C. Love and J. A. Hanover The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code" Sci. Signal., November 29, 2005; 2005(312): re13 - re13. [Abstract] [Full Text] [PDF]

				B. D. Lazarus, M. D. Roos, and J. A. Hanover Mutational Analysis of the Catalytic Domain of O-Linked N-Acetylglucosaminyl Transferase J. Biol. Chem., October 21, 2005; 280(42): 35537 - 35544. [Abstract] [Full Text] [PDF]

				G. Parker, R. Taylor, D. Jones, and D. McClain Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice: ROLE OF O-LINKED N-ACETYLGLUCOSAMINE J. Biol. Chem., May 14, 2004; 279(20): 20636 - 20642. [Abstract] [Full Text] [PDF]

				D. A. Scroggie, A. Albright, and M. D. Harris The Effect of Glucosamine-Chondroitin Supplementation on Glycosylated Hemoglobin Levels in Patients With Type 2 Diabetes Mellitus: A Placebo-Controlled, Double-blinded, Randomized Clinical Trial Arch Intern Med, July 14, 2003; 163(13): 1587 - 1590. [Abstract] [Full Text] [PDF]

				K. Sakai and D. R. Clemmons Glucosamine Induces Resistance to Insulin-Like Growth Factor I (IGF-I) and Insulin in Hep G2 Cell Cultures: Biological Significance of IGF-I/Insulin Hybrid Receptors Endocrinology, June 1, 2003; 144(6): 2388 - 2395. [Abstract] [Full Text] [PDF]

				R. G. Spiro Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds Glycobiology, April 1, 2002; 12(4): 43R - 56R. [Abstract] [Full Text] [PDF]

				T. Pratipanawatr, K. Cusi, P. Ngo, W. Pratipanawatr, L. J. Mandarino, and R. A. DeFronzo Normalization of Plasma Glucose Concentration by Insulin Therapy Improves Insulin-Stimulated Glycogen Synthesis in Type 2 Diabetes Diabetes, February 1, 2002; 51(2): 462 - 468. [Abstract] [Full Text] [PDF]

				J. A. HANOVER Glycan-dependent signaling: O-linked N-acetylglucosamine FASEB J, September 1, 2001; 15(11): 1865 - 1876. [Abstract] [Full Text] [PDF]

				L. Rossetti Perspective: Hexosamines and Nutrient Sensing Endocrinology, June 1, 2000; 141(6): 1922 - 1925. [Full Text] [PDF]

				C.-B. Book and A. Dunaif Selective Insulin Resistance in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3110 - 3116. [Abstract] [Full Text]

				T. P. Ciaraldi, L. Carter, S. Nikoulina, S. Mudaliar, D. A. McClain, and R. R. Henry Glucosamine Regulation of Glucose Metabolism in Cultured Human Skeletal Muscle Cells: Divergent Effects on Glucose Transport/Phosphorylation and Glycogen Synthase in Non-Diabetic and Type 2 Diabetic Subjects Endocrinology, September 1, 1999; 140(9): 3971 - 3980. [Abstract] [Full Text]

				K. M. Kelley, T. R. Johnson, J. Ilan, and R. W. Moskowitz Glucose regulation of the IGF response system in chondrocytes: induction of an IGF-I-resistant state Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1999; 276(4): R1164 - R1171. [Abstract] [Full Text] [PDF]

				M. Hawkins, I. Angelov, R. Liu, N. Barzilai, and L. Rossetti The Tissue Concentration of UDP-N-acetylglucosamine Modulates the Stimulatory Effect of Insulin on Skeletal Muscle Glucose Uptake J. Biol. Chem., February 21, 1997; 272(8): 4889 - 4895. [Abstract] [Full Text] [PDF]