UDP-N-acetylglucosamine transferase and glutamine: Fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues

H. Yki-Järvinen, C. Vogt, P. Iozzo, R. Pipek, M. C. Daniels, A. Virkamäki, S. Mäkimattila, L. Mandarino, R. A. DeFronzo, D. McClain, W. K. Gottschalk

    Research output: Contribution to journalArticle

    35 Scopus citations

    Abstract

    Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc β-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residues on intracellular proteins. Increased activity of the hexosamine pathway is a putative mediator of glucose-induced insulin resistance but the mechanisms are unclear. We determined whether O-GlcNAc transferase is found in insulin-sensitive tissues and compared its activity to that of GFA in rat tissues. We also determined whether non-insulin-dependent diabetes mellitus (NIDDM) or acute hyperinsulinaemia alters O-GlcNAc transferase activity in human skeletal muscle. O-GlcNAc transferase was measured using 3H-UDP-GlcNAc and a synthetic cationic peptide substrate containing serine and threonine residues, and GFA was determined by measuring a fluorescent derivative of GlcN6P by HPLC. O-GlcNAc transferase activities were 2-4 fold higher in skeletal muscles and the heart than in the liver, which had the lowest activity, while GFA activity was 14-36-fold higher in submandibular gland and 5-18 fold higher in the liver than in skeletal muscles or the heart. In patients with NIDDM (n = 11), basal O-GlcNAc transferase in skeletal muscle averaged 3.8 ± 0.3 nmol/mg · min, which was not different from that in normal subjects (3.3 ± 0.4 nmol/mg · min). A 180-min intravenous insulin infusion (40 mU/m2 · min) did not change muscle O-GlcNAc transferase activity in either group. We conclude that O-GlcNAc transferase is widely distributed in insulin-sensitive tissues in the rat and is also found in human skeletal muscle. These findings suggest the possibility that O-linked glycosylation of intracellular proteins is involved in mediating glucose toxicity. O-GlcNAc transferase does not, however, appear to be regulated by either NIDDM or acute hyperinsulinaemia, suggesting that mass action effects determine the extent of O-linked glycosylation under hyperglycaemic conditions.

    Original languageEnglish (US)
    Pages (from-to)76-81
    Number of pages6
    JournalDiabetologia
    Volume40
    Issue number1
    DOIs
    StatePublished - Jan 28 1997

      Fingerprint

    Keywords

    • diabetes mellitus
    • glucose
    • hexosamines
    • insulin

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Yki-Järvinen, H., Vogt, C., Iozzo, P., Pipek, R., Daniels, M. C., Virkamäki, A., Mäkimattila, S., Mandarino, L., DeFronzo, R. A., McClain, D., & Gottschalk, W. K. (1997). UDP-N-acetylglucosamine transferase and glutamine: Fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues. Diabetologia, 40(1), 76-81. https://doi.org/10.1007/s001250050645