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

Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc beta-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residues on intracellular proteins. Increased activ...

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Bibliographic Details
Published in:Diabetologia 1997-01, Vol.40 (1), p.76-81
Main Authors: 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
Format: Article
Language:English
Subjects:
Adipose Tissue - enzymology
Animals
Biopsy
Diabetes Mellitus, Type 2 - enzymology
Diabetes Mellitus, Type 2 - pathology
Epididymis - enzymology
Female
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - analysis
Humans
Insulin Resistance - physiology
Liver - enzymology
Male
Muscle, Skeletal - enzymology
Myocardium - enzymology
N-Acetylglucosaminyltransferases - analysis
N-Acetylglucosaminyltransferases - metabolism
Rats
Rats, Sprague-Dawley
Sensitivity and Specificity
Submandibular Gland - enzymology
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Summary:Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc beta-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.
ISSN:0012-186X
1432-0428
DOI:10.1007/s001250050645