|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 12, 10022-10027, March 21, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Veterans Affairs Medical Center and Division of
Endocrinology, University of Utah School of Medicine,
Salt Lake City, Utah 84132
We have investigated the mechanism by which high
concentrations of glucose inhibit insulin stimulation of glycogen
synthase. In NIH-3T3-L1 adipocytes cultured in low glucose (LG; 2.5 mM), the half-maximal activation concentration
(A0.5) of glucose 6-phosphate was 162 ± 15 µM. Exposure to either high glucose (HG; 20 mM) or glucosamine (GlcN; 10 mM) increased the
A0.5 to 558 ± 61 or 612 ± 34 µM.
Insulin treatment with LG reduced the A0.5 to 96 ± 10 µM, but cells cultured with HG or GlcN were
insulin-resistant (A0.5 = 287 ± 27 or
561 ± 77 µM). Insulin resistance was not explained by increased phosphorylation of synthase. In fact, culture with GlcN
decreased phosphorylation to 61% of the levels seen in cells cultured
in LG. Hexosamine flux and subsequent enzymatic protein O-glycosylation have been postulated to mediate nutrient
sensing and insulin resistance. Glycogen synthase is modified by
O-linked N-acetylglucosamine, and the level of
glycosylation increased in cells treated with HG or GlcN. Treatment of
synthase in vitro with protein phosphatase 1 increased
basal synthase activity from cells cultured in LG to 54% of total
activity but was less effective with synthase from cells cultured in HG
or GlcN, increasing basal activity to only 13 or 16%. After enzymatic
removal of O-GlcNAc, however, subsequent digestion with
phosphatase increased basal activity to over 73% for LG, HG, and GlcN.
We conclude that O-GlcNAc modification of glycogen synthase
results in the retention of the enzyme in a glucose
6-phosphate-dependent state and contributes to the reduced
activation of the enzyme in insulin resistance.
Insulin Resistance of Glycogen Synthase Mediated by
O-Linked N-Acetylglucosamine*
*
This work was supported by the Research Service of the
Veterans Administration, National Institutes of Health Grant R01
DK43526, the American Diabetes Association (mentor-based postdoctoral
award), and the Ben B. and Iris M. Margolis Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Endocrinology, University of Utah, 30 North 2030 East, Salt Lake City, UT 84132. Tel.: 801-581-7755; Fax: 801-585-0956; E-mail:
donald.mcclain@hsc.utah.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Prats, J. W. Helge, P. Nordby, K. Qvortrup, T. Ploug, F. Dela, and J. F. P. Wojtaszewski Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization J. Biol. Chem., June 5, 2009; 284(23): 15692 - 15700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Taylor, T. S. Geisler, J. H. Chambers, and D. A. McClain Up-regulation of O-GlcNAc Transferase with Glucose Deprivation in HepG2 Cells Is Mediated by Decreased Hexosamine Pathway Flux J. Biol. Chem., February 6, 2009; 284(6): 3425 - 3432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Wang, K. Park, F. Comer, L. C. Hsieh-Wilson, C. D. Saudek, and G. W. Hart Site-Specific GlcNAcylation of Human Erythrocyte Proteins: Potential Biomarker(s) for Diabetes Diabetes, February 1, 2009; 58(2): 309 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hu, J. Suarez, E. Fricovsky, H. Wang, B. T. Scott, S. A. Trauger, W. Han, Y. Hu, M. O. Oyeleye, and W. H. Dillmann Increased Enzymatic O-GlcNAcylation of Mitochondrial Proteins Impairs Mitochondrial Function in Cardiac Myocytes Exposed to High Glucose J. Biol. Chem., January 2, 2009; 284(1): 547 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. A. Soesanto, B. Luo, D. Jones, R. Taylor, J. S. Gabrielsen, G. Parker, and D. A. McClain Regulation of Akt signaling by O-GlcNAc in euglycemia Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E974 - E980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Copeland, J. W. Bullen, and G. W. Hart Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E17 - E28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Luo, Y. Soesanto, and D. A. McClain Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 651 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Taylor, G. J. Parker, M. W. Hazel, Y. Soesanto, W. Fuller, M. J. Yazzie, and D. A. McClain Glucose Deprivation Stimulates O-GlcNAc Modification of Proteins through Up-regulation of O-Linked N-Acetylglucosaminyltransferase J. Biol. Chem., March 7, 2008; 283(10): 6050 - 6057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Mott, K. Stone, M. C. Gessel, J. C. Bunt, and C. Bogardus Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E444 - E450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rengifo, C. J. Gibson, E. Winkler, T. Collin, and B. E. Ehrlich Regulation of the Inositol 1,4,5-Trisphosphate Receptor Type I by O-GlcNAc Glycosylation J. Neurosci., December 12, 2007; 27(50): 13813 - 13821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Noach, Y. Segev, I. Levi, S. Segal, and E. Priel Modification of Topoisomerase I Activity by Glucose and by O-Glcnacylation of the Enzyme Protein Glycobiology, December 1, 2007; 17(12): 1357 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Luo, G. J. Parker, R. C. Cooksey, Y. Soesanto, M. Evans, D. Jones, and D. A. McClain Chronic Hexosamine Flux Stimulates Fatty Acid Oxidation by Activating AMP-activated Protein Kinase in Adipocytes J. Biol. Chem., March 9, 2007; 282(10): 7172 - 7180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fulop, R. B. Marchase, and J. C. Chatham Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system Cardiovasc Res, January 15, 2007; 73(2): 288 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Tannock, E. A. Kirk, V. L. King, R. LeBoeuf, T. N. Wight, and A. Chait Glucosamine Supplementation Accelerates Early but Not Late Atherosclerosis in LDL Receptor-Deficient Mice J. Nutr., November 1, 2006; 136(11): 2856 - 2861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Marz, J. Stetefeld, K. Bendfeldt, C. Nitsch, J. Reinstein, R. L. Shoeman, B. Dimitriades-Schmutz, M. Schwager, D. Leiser, S. Ozcan, et al. Ataxin-10 Interacts with O-Linked beta-N-Acetylglucosamine Transferase in the Brain J. Biol. Chem., July 21, 2006; 281(29): 20263 - 20270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Cooksey, S. Pusuluri, M. Hazel, and D. A. McClain Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in {beta}-cells Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E334 - E340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A J Taylor, J-M Ye, and C Schmitz-Peiffer Inhibition of glycogen synthesis by increased lipid availability is associated with subcellular redistribution of glycogen synthase J. Endocrinol., January 1, 2006; 188(1): 11 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Buse Hexosamines, insulin resistance, and the complications of diabetes: current status Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E1 - E8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Werstuck, M. I. Khan, G. Femia, A. J. Kim, V. Tedesco, B. Trigatti, and Y. Shi Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model Diabetes, January 1, 2006; 55(1): 93 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hanover, M. E. Forsythe, P. T. Hennessey, T. M. Brodigan, D. C. Love, G. Ashwell, and M. Krause A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout PNAS, August 9, 2005; 102(32): 11266 - 11271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. McClain, M. Hazel, G. Parker, and R. C. Cooksey Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E973 - E979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Kneass and R. B. Marchase Protein O-GlcNAc Modulates Motility-associated Signaling Intermediates in Neutrophils J. Biol. Chem., April 15, 2005; 280(15): 14579 - 14585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Lehman, D.-J. Fu, A. B. Freeman, K. J. Hunt, R. J. Leach, T. Johnson-Pais, J. Hamlington, T. D. Dyer, R. Arya, H. Abboud, et al. A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc-selective N-Acetyl-{beta}-D Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans Diabetes, April 1, 2005; 54(4): 1214 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marshall, O. Nadeau, and K. Yamasaki Glucosamine-induced Activation of Glycogen Biosynthesis in Isolated Adipocytes: EVIDENCE FOR A RAPID ALLOSTERIC CONTROL MECHANISM WITHIN THE HEXOSAMINE BIOSYNTHESIS PATHWAY J. Biol. Chem., March 25, 2005; 280(12): 11018 - 11024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Kneass and R. B. Marchase Neutrophils Exhibit Rapid Agonist-induced Increases in Protein-associated O-GlcNAc J. Biol. Chem., October 29, 2004; 279(44): 45759 - 45765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wells, L. K. Kreppel, F. I. Comer, B. E. Wadzinski, and G. W. Hart O-GlcNAc Transferase Is in a Functional Complex with Protein Phosphatase 1 Catalytic Subunits J. Biol. Chem., September 10, 2004; 279(37): 38466 - 38470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marshall, O. Nadeau, and K. Yamasaki Dynamic Actions of Glucose and Glucosamine on Hexosamine Biosynthesis in Isolated Adipocytes: DIFFERENTIAL EFFECTS ON GLUCOSAMINE 6-PHOSPHATE, UDP-N-ACETYLGLUCOSAMINE, AND ATP LEVELS J. Biol. Chem., August 20, 2004; 279(34): 35313 - 35319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Zachara, N. O'Donnell, W. D. Cheung, J. J. Mercer, J. D. Marth, and G. W. Hart Dynamic O-GlcNAc Modification of Nucleocytoplasmic Proteins in Response to Stress: A SURVIVAL RESPONSE OF MAMMALIAN CELLS J. Biol. Chem., July 16, 2004; 279(29): 30133 - 30142. [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]
|
|
|
|
 |
|
 B. Cheatham Enough Is Enough: Nutrient Sensors and Insulin Resistance Endocrinology, May 1, 2004; 145(5): 2115 - 2117. [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Collier and D. K. Scott Sweet Changes: Glucose Homeostasis Can Be Altered by Manipulating Genes Controlling Hepatic Glucose Metabolism Mol. Endocrinol., May 1, 2004; 18(5): 1051 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hazel, R. C. Cooksey, D. Jones, G. Parker, J. L. Neidigh, B. Witherbee, E. A. Gulve, and D. A. McClain Activation of the Hexosamine Signaling Pathway in Adipose Tissue Results in Decreased Serum Adiponectin and Skeletal Muscle Insulin Resistance Endocrinology, May 1, 2004; 145(5): 2118 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, Y. Jia, J. J. Cooper, T. Hale, Z. Zhang, and S. C. Elbein Common Variants in Glutamine:Fructose-6-Phosphate Amidotransferase 2 (GFPT2) Gene Are Associated with Type 2 Diabetes, Diabetic Nephropathy, and Increased GFPT2 mRNA Levels J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 748 - 755. [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]
|
|
|
|
|
|
S. Obici and L. Rossetti Minireview: Nutrient Sensing and the Regulation of Insulin Action and Energy Balance Endocrinology, December 1, 2003; 144(12): 5172 - 5178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Whelan and G. W. Hart Proteomic Approaches to Analyze the Dynamic Relationships Between Nucleocytoplasmic Protein Glycosylation and Phosphorylation Circ. Res., November 28, 2003; 93(11): 1047 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Clark, P. M. McDonough, E. Swanson, S. U. Trost, M. Suzuki, M. Fukuda, and W. H. Dillmann Diabetes and the Accompanying Hyperglycemia Impairs Cardiomyocyte Calcium Cycling through Increased Nuclear O-GlcNAcylation J. Biol. Chem., November 7, 2003; 278(45): 44230 - 44237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Vocadlo, H. C. Hang, E.-J. Kim, J. A. Hanover, and C. R. Bertozzi A chemical approach for identifying O-GlcNAc-modified proteins in cells PNAS, August 5, 2003; 100(16): 9116 - 9121. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |