Diabetes, Vol 48, Issue 2 310-320, Copyright © 1999 by American Diabetes Association

ARTICLES

Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle

YB Kim, JS Zhu, JR Zierath, HQ Shen, AD Baron and BB Kahn
Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. Euglycemic-hyperinsulinemic clamp studies (12 mU x kg(-1) x min(-1) insulin) in awake rats showed that glucosamine infusion resulted in rapid induction of insulin resistance, with a 33% decrease in glucose infusion rate (P < 0.01). Tissues were harvested after saline alone (basal), 1 min after an insulin bolus (10 U/kg), or after 2 h of insulin clamp in saline- and glucosamine-infused rats. After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. No effect of glucosamine was seen on these signaling events when compared with 2 h of insulin clamp without glucosamine. Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Muniyappa, R. J. Karne, G. Hall, S. K. Crandon, J. A. Bronstein, M. R. Ver, G. L. Hortin, and M. J. Quon Oral Glucosamine for 6 Weeks at Standard Doses Does Not Cause or Worsen Insulin Resistance or Endothelial Dysfunction in Lean or Obese Subjects Diabetes, November 1, 2006; 55(11): 3142 - 3150. [Abstract] [Full Text] [PDF]

				L. M. Gronning, R. Tingsabadh, K. Hardy, K. T. Dalen, P. S. Jat, L. Gnudi, and P. R. Shepherd Glucose induces increases in levels of the transcriptional repressor Id2 via the hexosamine pathway Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E599 - E606. [Abstract] [Full Text] [PDF]

				F. Tremblay, A. Gagnon, A. Veilleux, A. Sorisky, and A. Marette Activation of the Mammalian Target of Rapamycin Pathway Acutely Inhibits Insulin Signaling to Akt and Glucose Transport in 3T3-L1 and Human Adipocytes Endocrinology, March 1, 2005; 146(3): 1328 - 1337. [Abstract] [Full Text] [PDF]

				A. R. Gosmanov, G. E. Umpierrez, A. H. Karabell, R. Cuervo, and D. B. Thomason Impaired expression and insulin-stimulated phosphorylation of Akt-2 in muscle of obese patients with atypical diabetes Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E8 - E15. [Abstract] [Full Text] [PDF]

				J. M. Zabolotny, F. G. Haj, Y.-B. Kim, H.-J. Kim, G. I. Shulman, J. K. Kim, B. G. Neel, and B. B. Kahn Transgenic Overexpression of Protein-tyrosine Phosphatase 1B in Muscle Causes Insulin Resistance, but Overexpression with Leukocyte Antigen-related Phosphatase Does Not Additively Impair Insulin Action J. Biol. Chem., June 4, 2004; 279(23): 24844 - 24851. [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]

				E. B. Arias, J. Kim, and G. D. Cartee Prolonged Incubation in PUGNAc Results in Increased Protein O-Linked Glycosylation and Insulin Resistance in Rat Skeletal Muscle Diabetes, April 1, 2004; 53(4): 921 - 930. [Abstract] [Full Text] [PDF]

				J. Giraud, R. Leshan, Y.-H. Lee, and M. F. White Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling J. Biol. Chem., January 30, 2004; 279(5): 3447 - 3454. [Abstract] [Full Text] [PDF]

				T. L. Steiler, D. Galuska, Y. Leng, A. V. Chibalin, M. Gilbert, and J. R. Zierath Effect of Hyperglycemia on Signal Transduction in Skeletal Muscle from Diabetic Goto-Kakizaki Rats Endocrinology, December 1, 2003; 144(12): 5259 - 5267. [Abstract] [Full Text] [PDF]

				D.-H. Han, M. M. Chen, and J. O. Holloszy Glucosamine and glucose induce insulin resistance by different mechanisms in rat skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2003; 285(6): E1267 - E1272. [Abstract] [Full Text] [PDF]

				Y.-B. Kim, K. Kotani, T. P. Ciaraldi, R. R. Henry, and B. B. Kahn Insulin-Stimulated Protein Kinase C {lambda}/{zeta} Activity Is Reduced in Skeletal Muscle of Humans With Obesity and Type 2 Diabetes: Reversal With Weight Reduction Diabetes, August 1, 2003; 52(8): 1935 - 1942. [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]

				G. J. Parker, K. C. Lund, R. P. Taylor, and D. A. McClain Insulin Resistance of Glycogen Synthase Mediated by O-Linked N-Acetylglucosamine J. Biol. Chem., March 14, 2003; 278(12): 10022 - 10027. [Abstract] [Full Text] [PDF]

				F. Tremblay, C. Lavigne, H. Jacques, and A. Marette Dietary Cod Protein Restores Insulin-Induced Activation of Phosphatidylinositol 3-Kinase/Akt and GLUT4 Translocation to the T-Tubules in Skeletal Muscle of High-Fat-Fed Obese Rats Diabetes, January 1, 2003; 52(1): 29 - 37. [Abstract] [Full Text] [PDF]

				Y.-B. Kim, G. I. Shulman, and B. B. Kahn Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C lambda /zeta but Not on Glycogen Synthase Kinase-3 J. Biol. Chem., August 30, 2002; 277(36): 32915 - 32922. [Abstract] [Full Text] [PDF]

				H. Hori, T. Sasaoka, H. Ishihara, T. Wada, S. Murakami, M. Ishiki, and M. Kobayashi Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice Diabetes, August 1, 2002; 51(8): 2387 - 2394. [Abstract] [Full Text] [PDF]

				C. S. Choi, Y.-B. Kim, F. N. Lee, J. M. Zabolotny, B. B. Kahn, and J. H. Youn Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E233 - E240. [Abstract] [Full Text] [PDF]

				C. Taghibiglou, F. Rashid-Kolvear, S. C. Van Iderstine, H. Le-Tien, I. G. Fantus, G. F. Lewis, and K. Adeli Hepatic Very Low Density Lipoprotein-ApoB Overproduction Is Associated with Attenuated Hepatic Insulin Signaling and Overexpression of Protein-tyrosine Phosphatase 1B in a Fructose-fed Hamster Model of Insulin Resistance J. Biol. Chem., January 4, 2002; 277(1): 793 - 803. [Abstract] [Full Text]

				S. F. Kralik, P. Liu, B. J. Leffler, and J. S. Elmendorf Ceramide and Glucosamine Antagonism of Alternate Signaling Pathways Regulating Insulin- and Osmotic Shock-Induced Glucose Transporter 4 Translocation Endocrinology, January 1, 2002; 143(1): 37 - 46. [Abstract] [Full Text] [PDF]

				Y. T. Kruszynska, D. S. Worrall, J. Ofrecio, J. P. Frias, G. Macaraeg, and J. M. Olefsky Fatty Acid-Induced Insulin Resistance: Decreased Muscle PI3K Activation But Unchanged Akt Phosphorylation J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 226 - 234. [Abstract] [Full Text] [PDF]

				M. Nakamura, A. J. Barber, D. A. Antonetti, K. F. LaNoue, K. A. Robinson, M. G. Buse, and T. W. Gardner Excessive Hexosamines Block the Neuroprotective Effect of Insulin and Induce Apoptosis in Retinal Neurons J. Biol. Chem., November 16, 2001; 276(47): 43748 - 43755. [Abstract] [Full Text] [PDF]

				F. A. Khan, P. B. Goforth, M. Zhang, and L. S. Satin Insulin Activates ATP-Sensitive K+ Channels in Pancreatic {beta}-Cells Through a Phosphatidylinositol 3-Kinase-Dependent Pathway Diabetes, October 1, 2001; 50(10): 2192 - 2198. [Abstract] [Full Text]

				F. Tremblay, C. Lavigne, H. Jacques, and A. Marette Defective Insulin-Induced GLUT4 Translocation in Skeletal Muscle of High Fat-Fed Rats Is Associated With Alterations in Both Akt/Protein Kinase B and Atypical Protein Kinase C ({zeta}/{lambda}) Activities Diabetes, August 1, 2001; 50(8): 1901 - 1910. [Abstract] [Full Text] [PDF]

				Y.-B. Kim, S. Uotani, D. D. Pierroz, J. S. Flier, and B. B. Kahn In Vivo Administration of Leptin Activates Signal Transduction Directly in Insulin-Sensitive Tissues: Overlapping but Distinct Pathways from Insulin Endocrinology, July 1, 2000; 141(7): 2328 - 2339. [Abstract] [Full Text] [PDF]

				B. Draznin, P. Miles, Y. Kruszynska, J. Olefsky, J. Friedman, I. Golovchenko, R. Stjernholm, K. Wall, M. Reitman, D. Accili, et al. Effects of Insulin on Prenylation as a Mechanism of Potentially Detrimental Influence of Hyperinsulinemia Endocrinology, April 1, 2000; 141(4): 1310 - 1316. [Abstract] [Full Text] [PDF]

				M. Hawkins, M. Hu, J. Yu, H. Eder, P. Vuguin, L. She, N. Barzilai, M. Leiser, J. M. Backer, and L. Rossetti Discordant Effects of Glucosamine on Insulin-stimulated Glucose Metabolism and Phosphatidylinositol 3-Kinase Activity J. Biol. Chem., October 29, 1999; 274(44): 31312 - 31319. [Abstract] [Full Text] [PDF]

				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]

				S. Vemuri and R. B. Marchase The Inhibition of Capacitative Calcium Entry Due to ATP Depletion but Not Due to Glucosamine Is Reversed by Staurosporine J. Biol. Chem., July 16, 1999; 274(29): 20165 - 20170. [Abstract] [Full Text] [PDF]

				S. A. Qureshi, V. Ding, Z. Li, D. Szalkowski, D. E. Biazzo-Ashnault, D. Xie, R. Saperstein, E. Brady, S. Huskey, X. Shen, et al. Activation of Insulin Signal Transduction Pathway and Anti-diabetic Activity of Small Molecule Insulin Receptor Activators J. Biol. Chem., November 17, 2000; 275(47): 36590 - 36595. [Abstract] [Full Text] [PDF]

				C. Huppertz, B. M. Fischer, Y.-B. Kim, K. Kotani, A. Vidal-Puig, L. J. Slieker, K. W. Sloop, B. B. Lowell, and B. B. Kahn Uncoupling Protein 3 (UCP3) Stimulates Glucose Uptake in Muscle Cells through a Phosphoinositide 3-Kinase-dependent Mechanism J. Biol. Chem., April 13, 2001; 276(16): 12520 - 12529. [Abstract] [Full Text] [PDF]

				F. Tremblay and A. Marette Amino Acid and Insulin Signaling via the mTOR/p70 S6 Kinase Pathway. A NEGATIVE FEEDBACK MECHANISM LEADING TO INSULIN RESISTANCE IN SKELETAL MUSCLE CELLS J. Biol. Chem., October 5, 2001; 276(41): 38052 - 38060. [Abstract] [Full Text] [PDF]

				C. L. Venable, E. U. Frevert, Y.-B. Kim, B. M. Fischer, S. Kamatkar, B. G. Neel, and B. B. Kahn Overexpression of Protein-tyrosine Phosphatase-1B in Adipocytes Inhibits Insulin-stimulated Phosphoinositide 3-Kinase Activity without Altering Glucose Transport or Akt/Protein Kinase B Activation J. Biol. Chem., June 9, 2000; 275(24): 18318 - 18326. [Abstract] [Full Text] [PDF]

				J. M. Zabolotny, Y.-B. Kim, O. D. Peroni, J. K. Kim, M. A. Pani, O. Boss, L. D. Klaman, S. Kamatkar, G. I. Shulman, B. B. Kahn, et al. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance PNAS, April 24, 2001; 98(9): 5187 - 5192. [Abstract] [Full Text] [PDF]

				B. A. Nelson, K. A. Robinson, and M. G. Buse Defective Akt activation is associated with glucose- but not glucosamine-induced insulin resistance Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E497 - E506. [Abstract] [Full Text] [PDF]