Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.

Hebert, Leon F.; Daniels, Marc C.; Zhou, Jianxin; Crook, Errol D.; Turner, Ramona L.; Simmons, Shakisha T.; Neidigh, John L.; Zhu, Jin Su; Baron, Alain; McClain, Donald A.

doi:10.1172/jci118876

Cited by 304 publications

(243 citation statements)

References 36 publications

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“…In fact, transgenic mice overexpressing OGT in adipose tissue and striated muscle show decreased insulin-stimulated wholebody glucose disposal, and hyperinsulinemia and hyperleptinemia 40) , which are consistent with the phenotypes observed in GFAT transgenic mice 32,35,36) . Furthermore, insulin stimulation recruits OGT from the nucleus to the plasma membrane, wherein OGT catalyzes O-GlcNAcylation on some insulin signaling proteins and attenuates its signal transduction by altering their phosphorylation status, and hepatic overexpression of OGT impairs the transcription of insulin-responsive genes and causes the perturbation of insulin-induced inhibition of gluconeotransfer of a single GlcNAc from UDP-GlcNAc to serine/threonine residues of substrate proteins 25,26) ; whereas OGA catalyzes the removal of the GlcNAc from such residues 27,28) .…”

Section: O-glcnacylationsupporting

confidence: 76%

“…Actually, irreversible inactivation of glutamine-requiring enzymes, including GFAT, by treatment with glutamine analogues improves hyperglycemia-induced desensitization of insulin-stimulated glucose uptake in rat primary adipocytes 33) , but not in isolated rat skeletal muscle 34) . In addition, the overexpression of GFAT in the skeletal muscle and adipose tissue of transgenic mice leads to insulin resistant phenotypes, characterized by reductions in the whole body glucose disposal rate, glucose uptake in skeletal muscle, and GLUT4 translocation in response to insulin stimulation 35,36) . However, insulin-stimulated glucose uptake in isolated skeletal muscle microexplant cultures of transgenic mice is similar to that of wild-type mice, although transgenic mice overexpressing GFAT, specifically in adipose tissue, display decreased insulin-stimulated glucose uptake in skeletal muscle and reduced serum adiponectin GnT-IV Fig.…”

Section: O-glcnacylationmentioning

confidence: 99%

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Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

Shirato

Kizaki

Ohno

et al. 2012

JPFSM

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Minor amounts of glucose incorporated into the cells is metabolized via the hexosamine biosynthetic pathway, resulting in the production of uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is utilized as a donor substrate for the N-and O-linked glycosylation of extracellular and membrane proteins in the Golgi apparatus, or for the O-linked GlcNAc modification (O-GlcNAcylation) of intracellular proteins in the cytosol. In particular, O-GlcNAcylation, the addition of GlcNAc to serine/threonine residues, is reversibly regulated by the enzymatic activities of O-GlcNAc transferase (OGT) and O-GlcNAcase. Since OGT activity is sensitive to the intracellular UDP-GlcNAc level, flux via the hexosamine pathway influences O-GlcNAcylation. Actually, excess flux via the hexosamine pathway and resultant increased O-GlcNAcylation are associated with several pathophysiological conditions, including insulin resistance. To date, there are several studies addressing the effects of exercise on the hexosamine pathway and O-GlcNAcylation. Thus, this short review focuses on the relationships among exercise, the hexosamine pathway, O-GlcNAcylation, and insulin resistance.

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Section: O-glcnacylationsupporting

confidence: 76%

Section: O-glcnacylationmentioning

confidence: 99%

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

Shirato

Kizaki

Ohno

et al. 2012

JPFSM

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“…Enhanced flux through the hexosamine biosynthesis pathway has been implicated as a contributor to the pathogenesis of insulin resistance (17)(18)(19)(20)(21)56) and, more recently, to the pathogenesis of diabetic nephropathy (25). These effects on cell function may involve alterations in gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Although high glucose-induced insulin resistance was blocked by inhibition of GFA, this did not occur in the case of glucosamine, which promotes flux through the hexosamine pathway distal to this enzyme (17). Similarly, infusion of glucosamine into rats or overexpression of GFA in cultured cells or in trans-genic mice was found to result in insulin resistance (18)(19)(20)(21). Of interest, infusion of glucose, free fatty acids, uridine, or glucosamine into rats, each of which elevated levels of UDP-GlcNAc, increased leptin gene expression in muscle (22).…”

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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“…Further studies revealed that insulin resistance could also be induced by glucosamine [4], which increases flux through the hexosamine biosynthesis pathway by bypassing the rate-limiting step catalysed by glutamine fructose-6-phosphate amidotransferase (GFAT). Overexpression of this enzyme in skeletal muscle and adipose tissue of transgenic mice has also been found to cause insulin resistance [5].…”

Section: Introductionmentioning

confidence: 99%

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

et al. 2005

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Aims/hypothesis: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. Materials and methods: Glucosamine (6.48 mg kg −1 min −1 for 3 h) was infused with or without insulin (10 mU kg −1 min −1 ) into anaesthetised rats under euglycaemic conditions. Results: Glucosamine infusion alone increased blood glucosamine (1.9±0.1 mmol/l) and glucose (5.4±0.2 to 7.7± 0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hindleg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. Conclusion/interpretation: Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.

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Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.

Cited by 304 publications

References 36 publications

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

Effects of exercise on the hexosamine biosynthetic pathway and glycosylation

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

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

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