Increased flux through the hexosamine biosynthesis pathway inhibits glucose transport acutely by activation of protein kinase C

Filippis, Anthony; Clark, Stella; Proietto, Joseph

doi:10.1042/bj3240981

Cited by 55 publications

(32 citation statements)

References 34 publications

(26 reference statements)

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“…Furthermore hexosamines promote Sp1 O-linked N-acetylglucosamine glycosylation [33], which stabilizes this transcription factor, increasing its cellular concentrations [34]. Several other studies have proposed a role of the HBP in PKC activation in different cell types [19,35,36,37], and PKC has been shown to mediate glucose-induced p38-MAPK activation [38], confirming our results in control transfected cells.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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

et al. 2003

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“…Transient overexpression of GFAT leads to insulin resistance indicating that this pathway could also be activated in skeletal muscle of glucose infused rats [72]. Of note, recent results showed that activation of this pathway leads to activation of PKC [21] and induces translocation of the PKC isoforms a, e and particularly b, but not z [73] supporting the possibility of an involvement of the hexosamine pathway in the pathogenesis of insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have focussed on the effect of PKC on the insulin signalling cascade showing that activation of PKC inhibits insulin-stimulated glucose transport in rat heart and skeletal muscle and rat adipocytes [21,29,37]. Taken together, in vitro studies indicate that acute increases in glucose induce activation of PKC which, on one hand, induces insulin-independent glucose uptake and, on the other hand, could mediate insulin resistance.…”

mentioning

confidence: 99%

Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle

et al. 2002

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Impairment of the glucose transport in the insulinsensitive tissues contributes to the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus [1,2]. Skeletal muscle represents the most important tissue for the maintenance of a balanced postprandial glucose homeostasis; about 80 % of insulin-stimulated glucose uptake is accounted for by muscle [3±5]. The influx of glucose into muscle is mediated by the glucose transporter proteins GLUT1 and the insulinsensitive GLUT4 [6±11]. Insulin induces the translocation of GLUT4 to the sarcolemma and to special- Abstract Aims/hypothesis. Previous studies on diabetic patients have shown that hyperglycaemia increases glucose uptake in an apparently insulin-independent manner. However, the molecular mechanism has not been clarified. Methods. We studied rats receiving continuous glucose infusion to address this question. In this animal model, rats accommodate systemic glucose oversupply and rapidly develop insulin resistance. Results. Glucose infusion increased both plasma glucose and insulin concentrations to peak after one day. In spite of continuous glucose infusion normoglycaemia was reached after 5 days while insulin concentrations remained higher. Focusing our studies in day 2 (hyperglycaemia/hyperinsulinaemia) and day 5 (normoglycaemia/hyperinsulinaemia) we found, particularly in day 5, that the early steps of the insulin signalling cascade in skeletal muscle of glucose-infused rats were not more activated when compared to control animals as assessed by a comparable phosphorylation of the insulin receptor, IRS-1 and PKB and by an unaltered IRS-1-associated Ptd(Ins) 3' kinase activity. Continuous glucose infusion induced GLUT4 protein expression and translocation to the plasma membrane while neither expression nor translocation of GLUT1 was affected. Translocation of PKC-bI, -bII (> threefold) and -a, -q (to a lesser extent) to the plasma membrane was significantly induced after 2 days but not after 5 days of glucose infusion when normoglycaemia was reached. Conclusions/interpretation. Our data support the hypothesis that continuous glucose infusion induces translocation of GLUT4 while the early steps of the insulin signalling cascade were not increased. These effects could be mediated by activation of PKC. [Diabetologia (2002) 45: 356±368]

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“…As noted above, Sp1 is activated by both conventional and atypical PKC isoforms (63,64) as well as ERK (65), a downstream target of PKC. Filippis et al (79) suggested that glucosamine activates PKC in adipocytes. It has been reported that in mesangial cells, 12 mmol/l glucosamine-a higher concentration than used in the present experiments-caused membrane translocation of several PKC isoforms within hours (80).…”

Section: Discussionmentioning

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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Increased flux through the hexosamine biosynthesis pathway inhibits glucose transport acutely by activation of protein kinase C

Cited by 55 publications

References 34 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

Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle

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

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