Hexosamines and Insulin Resistance

McClain, Donald A.; Crook, Errol D.

doi:10.2337/diab.45.8.1003

Cited by 276 publications

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“…The metabolic rate of the hexosamine pathway is intimately related to the extracellular glucose concentrations [1].…”

Section: Discussionmentioning

confidence: 99%

“…This pathway converts fructose-6-phosphate to glucosamine-6-phosphate via the rate limiting enzyme glutamine: fructose-6-phosphate amidotransferase (GFAT) and is important in insulin resistance [1,2], a condition closely associated with diabetic nephropathy [3]. The HBP has been implicated in other pathogenic processes such as the induction of growth factors in mesangial cells and of leptin in adipose tissue and skeletal muscle [4].…”

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confidence: 99%

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P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

et al. 2003

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Aims/hypothesis. The hexosamine pathway has been implicated in the induction of TGFβ1 expression and in the pathophysiology of diabetic glomerulopathy. Glucose-induced TGFβ1 expression is mediated by p38 mitogen-activated-protein-kinase (p38-MAPK) and this kinase is activated in the diabetic glomeruli. We examined whether the p38-MAPK is implicated in hexosamine-induced TGFβ1 mRNA expression in human mesangial cells. Methods. The products of the hexosamine biosynthetic pathway were increased by the addition of glucosamine or by the overexpression of the rate-limiting enzyme of the hexosamine pathway, glutamine: fructose-6-phosphate amidotransferase (GFAT).Results. Glucosamine addition resulted in cell death. UDP-N-Acetylglucosamine, one of the major hexosamine end-products, was increased in normal (7 mmol/l) and high (25 mmol/l) glucose conditions in GFAT-transfected cells compared to control transfected cells by twofold and 1.7-fold respectively (p≤0.04) and this was accompanied by a 1.6-and 2.3-fold increase (p≤0.02) in TGFβ1 mRNA expression. Addition of the GFAT inhibitor azaserine (10 µmol/l) prevented the induction of TGFβ1 in GFAT transfected cells. GFAT overexpression induced an increase in p38-MAPK activation after 6 and 12 h incubation in normal glucose, and this was prevented by the GFAT inhibitor azaserine. Furthermore, high glucose enhanced p38-MAPK activation in GFAT tranfected cells (p≤0.04). P38-MAPK inhibition using SB202190 (1 µmol/l) reduced hexosamine-induced TGFβ1 expression in normal and high glucose. The activation of the p38-MAPK was dependent on protein kinase-C. Conclusion/interpretation. Overexpression of GFAT increases hexosamine accumulation which mediates TGFβ1 expression via a protein kinase-C and p38-MAPK dependent mechanism. Increased glucose concentrations magnify these effects. [Diabetologia (2003) 46:531-537]

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“…The metabolic rate of the hexosamine pathway is intimately related to the extracellular glucose concentrations [1].…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

et al. 2003

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“…About 1-3% of glucose is normally diverted through the hexosamine biosynthesis pathway, whereby fructose-6-phosphate is converted by the rate-limiting enzyme, glutamine:fructose-6-phosphate-amidotransferase (GFA), to glucosamine-6-phosphate (16). The end product of this pathway, UDP-N-acetylglucosamine (UDP-GlcNAc), is a substrate for protein glycosylation (16).…”

mentioning

confidence: 99%

“…The end product of this pathway, UDP-N-acetylglucosamine (UDP-GlcNAc), is a substrate for protein glycosylation (16). The potential importance of the hexosamine pathway as a high glucose effector was first suggested by studies of insulin resistance.…”

mentioning

confidence: 99%

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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“…Recent studies have shown that increased activity of the hexosamine biosynthetic pathway might contribute to glucose-induced insulin resistance in skeletal muscle (DeFronzo et al 1985;Garvey et al 1987;Rossetti et al 1990;Marshall et al 1991;Baron et al 1995;Robinson et al 1995;Davidson et al 1994;Virkamaki et al 1997), which is a major organ of insulin resistance in NIDDM patients. Specifically, glutamine:fructose-6-phosphate amidotransferase (GFAT1), a key regulator and rate-limiting enzyme in the formation of hexosamine products (Crook et al 1995;McClain et al 1996;Daniels et al 1996;Chen et al 1997), displays elevated activity in the skeletal muscle of NIDDM patients (Yki-Jarvinen et al 1996) and in ob/ob mice, a rodent model of NIDDM . Transgenic mice overexpressing the GFAT1 gene in skeletal muscle and adipose tissue also exhibit insulin resistance, as determined by the hyperinsulinemic euglycemic glucose clump technique (Herbert et al 1996;Cooksey et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Identification of GFAT1-L, a novel splice variant of human glutamine: fructose-6-phosphate amidotransferase (GFAT1) that is expressed abundantly in skeletal muscle

et al. 2001

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Glutamine:fructose-6-phosphate amidotransferase (GFAT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway, which plays an important role in hyperglycemia-induced insulin resistance. To evaluate the role of GFAT1 expression, we analyzed the expression profiles of GFAT1 mRNA in various human tissues using reverse transcriptase-polymerase chain reaction. We report here the identification and cDNA cloning of a novel GFAT1 splice variant expressed abundantly in skeletal muscle and heart. This subtype, designated GFAT1-L, contains a 54-bp insertion within the GFAT1 coding sequence. Recombinant GFAT1-L protein possessed functional GFAT activities and biochemical characteristics similar to GFAT1. Previously, GFAT1 was considered a simplex enzyme. The identification of a novel GFAT1 subtype possessing functional enzymatic activity and tissue-specific expression should provide additional insight into the mechanism of skeletal muscle insulin resistance and diabetes complications.

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Hexosamines and Insulin Resistance

Cited by 276 publications

References 0 publications

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

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

Identification of GFAT1-L, a novel splice variant of human glutamine: fructose-6-phosphate amidotransferase (GFAT1) that is expressed abundantly in skeletal muscle

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