Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in skeletal muscle proteins in vivo

Yki‐Järvinen, Hannele; Virkamäki, Antti; Daniels, Marc C.; McClain, Donald A.; Gottschalk, William K.

doi:10.1016/s0026-0495(98)90058-0

Cited by 107 publications

(76 citation statements)

References 21 publications

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“…We first found that treatment of mesangial cells with 2 mmol/l glucosamine increased steady-state PAI-1 mRNA levels. As expected from previous reports (19,25,43,44), we have observed in preliminary experiments that UDP-N-acetylhexosamine (UDPHexNAc) levels (measured by high-performance liquid chromatography) were increased 13-fold in mesangial cells after a 3-day incubation with 2 mmol/l glucosamine (data not shown). In transient transfection experiments, incubating mesangial cells with 2 mmol/l glucosamine strongly activated the PAI-1 promoter after 4 days.…”

Section: Discussionsupporting

confidence: 86%

“…High glucose has been previously demonstrated to upregulate PAI-1 promoter activity in vascular smooth muscle cells through 2 Sp1 elements encompassing the promoter segments -76 to -71 and -44 to -39 (36). The ability of glucosamine to increase the cellular levels of UDP-GlcNAc is well established (19,25,43,44), and the transcription factor Sp1 is subject to glucosamine-induced O-linked glycosylation (45,46). In addition, Sp1 was suggested, but not documented, to bind to the portion of the TGF-␣ promoter influenced by glucosamine in vascular smooth muscle cells (23).…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of cells with glucosamine or infusion of glucosamine in vivo increases cellular levels of UDP-GlcNAc, a substrate for both N-and O-linked protein glycosylation (19,25,43,44,66). However, glucosamine appears to block the N-glycosylation of at least some proteins (67,68).…”

Section: Discussionmentioning

confidence: 99%

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Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

2000

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Increased flux through the hexosamine biosynthetic pathway is associated with altered gene expression. To investigate the underlying mechanisms, we treated glomerular mesangial cells with glucosamine and studied the regulation of the plasminogen activator inhibitor (PAI)-1 gene. Incubating mesangial cells with 2 mmol/l glucosamine for 4 days resulted in a 3.1 ± 0.4-fold increase in PAI-1 mRNA levels (P < 0.01) and a 33 ± 9-fold increase in the activity of a transiently transfected PAI-1 promoter-luciferase reporter gene (P < 0.01). Cotransfection of an expression vector for a dominant-negative type II TGF-␤ receptor with the PAI-1 promoter-reporter gene did not interfere with this effect of glucosamine. However, mutation of 2 putative Sp1 sites in the PAI-1 promoter, at -76 to -71 and -44 to -39, markedly reduced induction of PAI-1 luciferase activity by glucosamine, from 8.9 ± 1.9-fold to 1.7 ± 0.5-fold (P < 0.01). An electrophoretic mobility shift assay demonstrated that glucosamine increased Sp1 DNA binding by 31 ± 11% (P < 0.05), implying that the effects of glucosamine were explained, in part, by changes in Sp1 DNA binding. High glucose (20 mmol/l) also activated the transiently transfected PAI-1 promoter (2.5 ± 0.4-fold). This effect was diminished by mutation of both the PAI-1 promoter Sp1 sites (1.2 ± 0.3-fold, P < 0.05). In addition, 6-diazo-5-oxo-L-norleucine, a glutamine:fructose-6-phosphateamidotransferase inhibitor, blocked the induction by high glucose (4.7 ± 0.8-to 0.9 ± 0.1-fold, P < 0.01). These results indicate that stimulation of the PAI-1 promoter by both high glucose and glucosamine involves Sp1 and that the hexosamine pathway may be involved in the regulation of gene expression by high glucose in glomerular mesangial cells. Diabetes 49:863-871, 2000

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

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Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

2000

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“…O-GlcNAc transferase, the enzyme catalyzing the addition of O-GlcNAc, responds to the physiological range of UDP-GlcNAc concentrations occurring in cells (18)(19)(20)(21). An increased level of UDP-GlcNAc, caused by insulin and glucosamine infusion, renders mice insulin-resistant and skeletal muscle proteins exhibit elevated O-GlcNAc levels (22).…”

mentioning

confidence: 99%

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

Vosseller

Wells

Lane

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

437

393

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“…Several recent studies reported evidence that increased intracellular O-GlcNAc modification of proteins has been associated with elevated levels of extracellular glucose and glucosamine [5][6][7]. One study demonstrated that activation of the hexosamine pathway by glucosamine infusion induces insulin resistance by inhibition of early postreceptor insulin signaling via O-GlcNAc modification of insulin receptor substrates IRS-1 and IRS-2 [8].…”

Section: Introductionmentioning

confidence: 99%

Analysis of MGEA5 on 10q24.1–q24.3 encoding the β-O-linked N-acetylglucosaminidase as a candidate gene for type 2 diabetes mellitus in Pima Indians

Farook

Bogardus

Procházka

2002

Molecular Genetics and Metabolism

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Several diseases including type 2 diabetes mellitus (T2DM) are associated with abnormal O-glycosylation of proteins. b-O-linked N-acetylglucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10g24.1-q24.3 removes N-acetylglucosamine (O-GlcNAc), and we investigated this locus in Pima Indians who have the world's highest prevalence of T2DM. We detected two variants but there was no association with parameters of insulin resistance or diabetes in 1300 Pimas. We conclude that mutations in MGEA5 are unlikely to contribute to T2DM in this population. Ó

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Insulin and glucosamine infusions increase O-linked N-acetyl-glucosamine in skeletal muscle proteins in vivo

Cited by 107 publications

References 21 publications

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes

Analysis of MGEA5 on 10q24.1–q24.3 encoding the β-O-linked N-acetylglucosaminidase as a candidate gene for type 2 diabetes mellitus in Pima Indians

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