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J. Biol. Chem., Vol. 279, Issue 20, 20636-20642, May 14, 2004

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Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice

ROLE OF O-LINKED N-ACETYLGLUCOSAMINE^*

Glendon Parker, Rodrick Taylor, Deborah Jones, and Donald McClain

From the Veterans Affairs Medical Center and Division of Endocrinology, University of Utah School of Medicine, Salt Lake City, Utah 84132

Glycogen synthase is post-translationally modified by both phosphate and O-linked N-acetylglucosamine (O-GlcNAc). In 3T3-L1 adipocytes exposed to high concentrations of glucose, O-GlcNAc contributes to insulin resistance of glycogen synthase. We sought to determine whether O-GlcNAc also regulates glycogen synthase in vivo. Glycogen synthase activity in fat pad extracts was inhibited in streptozotocin (STZ)-treated diabetic mice. The half-maximal activation concentration for glucose 6-phosphate (A_0.5) was increased to 830 ± 120 µM compared with 240 ± 20 µM in control mice (C, p < 0.01), while the basal glycogen synthase activity (%I-form) was decreased to 2.4 ± 1.4% compared with 10.1 ± 1.8% in controls (p < 0.01). Glycogen synthase activity remained inhibited after compensatory insulin treatment. After insulin treatment kinetic parameters of glycogen synthase were more closely correlated with blood glucose (A_0.5, r² = 0.70; %I-form, r² = 0.59) than insulin levels (A_0.5, r² = 0.04; %I-form, r² = 0.09). Hyperglycemia also resulted in an increase in the level of O-GlcNAc on glycogen synthase (16.1 ± 1.8 compared with 7.0 ± 0.9 arbitrary intensity units for controls, p < 0.01), even though the level of phosphorylation was identical in diabetic and control mice either with (STZ: 2.9 ± 1.0 and C: 3.2 ± 0.8) or without (STZ: 12.2 ± 2.8 and C: 13.8 ± 3.0 arbitrary intensity units) insulin treatment. In all mice the percent activation of glycogen synthase that could be achieved in vitro by recombinant protein phosphatase 1 (230 ± 30%) was significantly greater in the presence of -D-N-acetylglucosaminidase (410 ± 60%, p < 0.01). This synergistic stimulation of glycogen synthase due to codigestion by protein phosphatase 1 and -D-N-acetylglucosaminidase was more pronounced in STZ-diabetic mice (310 ± 70%) compared with control mice (100 ± 10%, p < 0.05). The findings demonstrate that O-GlcNAc has a role in the regulation of glycogen synthase both in normoglycemia and diabetes.

Received for publication, November 5, 2003 , and in revised form, February 6, 2004.

^* This work was supported by the research service of the Veterans Administration, National Institutes of Health Grant R01 DK43526, 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. This 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{at}hsc.utah.edu.

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