Glutamine fructose-6-phosphate amidotransferase (GFAT) gene expression and activity in patients with type 2 diabetes: Inter-relationships with hyperglycaemia and oxidative stress

Vedantham, Srinivasan; Sandhya, Narasimhan; Rangasamy, Sampathkumar; Syed, Farooq; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

doi:10.1016/j.clinbiochem.2007.05.002

Cited by 63 publications

(44 citation statements)

References 38 publications

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“…In mice, anthocyanins were detected in the liver but not in muscle or white fat tissue after the consumption of bilberry extract [40]. It has previously been shown that increased GFAT activity is associated with insulin resistance and postprandial hyperglycemia in T2D [41]. In addition, hepatic JNK-1 induces insulin resistance by serine phosphorylation of IRS1 [42].…”

Section: Discussionmentioning

confidence: 91%

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

Brader¹,

Overgaard²,

Christensen³

et al. 2013

Rev Diabet Stud

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■ AbstractBACKGROUND: Bilberries and blackcurrants are nutrient sources rich in bioactive components, including dietary fibers, polyphenols, and anthocyanins, which possess potent cardiovascular protective properties. Few studies investigating the cardio-protective effects of natural components have focused on whole bilberries or blackcurrants. OBJECTIVE: The aim of this trial was to investigate whether a diet enriched with bilberries or blackcurrants has beneficial effects on glucose metabolism, lipid profile, blood pressure, and expression of genes related to glucose and lipid metabolism. METHODS: Male Zucker Diabetic Fatty (ZDF) rats (n = 48) were randomly assigned to either a control, bilberryenriched, blackcurrant-enriched, or fiber-enriched diet for 8 weeks ad libitum. Real-time quantitative PCR analysis was performed on liver, adipose, and muscle tissue. Berry polyphenol content was determined by HPLC and LC-MS analysis. RESULTS: Bilberry enrichment reduced total (-21%, p = 0.0132) and LDL-cholesterol (-60%, p = 0.0229) levels, but increased HDL-cholesterol to a lesser extent than in controls. This may partly be due to the altered hepatic liver X receptor-α expression (-24%, p < 0.001). Neither bilberries nor blackcurrants influenced glucose metabolism or blood pressure. Nevertheless, transcriptional analysis implied a better conservation of hepatic and adipocyte insulin sensitivity by bilberry enrichment. Anthocyanins constituted 91% and 87% of total polyphenol content in bilberries and blackcurrants, respectively. However, total anthocyanin content (3441 mg/100 g) was 4-fold higher in bilberries than in blackcurrants (871 mg/100 g). CONCLUSIONS: Bilberry consumption ameliorated total and LDL-cholesterol levels, but not HDL-cholesterol levels in ZDF rats. Neither bilberry nor blackcurrant enrichment delayed the development of diabetes or hypertension. Thus, in rats, bilberries may be valuable as a dietary preventive agent against hypercholesterolemia, probably by virtue of their high anthocyanin content.

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Section: Discussionmentioning

confidence: 91%

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

Brader¹,

Overgaard²,

Christensen³

et al. 2013

Rev Diabet Stud

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“…Under physiological conditions, 1-3% of intracellular glucose is shunted from the glycolytic pathway to the hexosamine biosynthesis pathway (HBP), and flux through the HBP increases with glucose concentration (5,10,17,45). Glutamine:fructose-6 phosphate amidotransferase (GFAT) is the rate-limiting enzyme of the HBP responsible for the conversion of L-glutamine and D-fructose 6-phosphate to L-glutamate and D-glucosamine 6-phosphate (GlcN-6-P) (reviewed in Ref.…”

Section: The Incidence Of Diabetes Mellitus (Dm) Is Increasingmentioning

confidence: 99%

Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells

Sage¹,

Walter²,

Shi³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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There is increasing evidence that endoplasmic reticulum (ER) stress contributes to the development of atherosclerosis in diabetes mellitus. The purpose of this study was to determine the effects of increased hexosamine biosynthesis pathway (HBP) flux on ER stress levels and the complications of ER stress associated with diabetes and atherosclerosis in hepatic cells. Glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of the HBP, was overexpressed in HepG2 cells by use of an adenoviral expression system. The ER stress response and downstream effects, including activation of lipid and inflammatory pathways, were determined using real-time PCR, immunoblot analysis, and cell staining techniques. GFAT overexpression resulted in increased expression of ER stress markers, including Grp78, Grp94, calreticulin, and GADD153, relative to cells infected with an empty adenoviral vector. In addition, GFAT overexpression promoted lipid, but not cholesterol, accumulation in hepatic cells as well as inflammatory pathway activation. Treatment with 6-diazo-5-oxo-norleucine, a GFAT antagonist, blocked the effects of GFAT overexpression. Consistent with our in vitro data, hyperglycemic mice presented with elevated markers of hepatic ER stress, glucosamine and lipid accumulation. Together, these data suggest that HBP flux-induced ER stress plays a role in the development of hepatic steatosis and atherosclerosis under conditions of hyperglycemia.

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“…Glucosamine-6-phosphate is further metabolized to UDP-GlcNAc that serves as the major substrate for the formation of O-linked glycoproteins (O-GlcNAc) at serine and threonine residues catalyzed by O-glycosyltransferase. The increased GFAT activity and O-GlcNAc levels are implicated in insulin resistance and type II diabetes mellitus (16,37), associated with increased oxidative stress and, reciprocally, with Akt/eNOS phosphorylation in the endothelial cells, resulting in a decreased endothelial NO production (11,13,27).…”

mentioning

confidence: 99%

The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects

Rajapakse¹,

Ming²,

Carvas³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Rajapakse AG, Ming XF, Carvas JM, Yang Z. The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects. Am J Physiol Heart Circ Physiol 296: H815-H822, 2009. First published January 9, 2009 doi:10.1152/ajpheart.00756.2008.-Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-␣ (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-␣. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-␣. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway. adhesion molecules; endothelium; glucose; O-linked acetylglusamine; superoxide DIABETES MELLITUS is highly associated with an increased risk of cardiovascular morbidity and mortality (10, 34). Chronic hyperglycemia causes glucotoxicity to vascular cells, particularly the endothelial cells, resulting in an increased incidence of cardiovascular events (7). Clinical and experimental studies provide compelling evidence showing that hyperglycemia is associated with impaired endothelium-dependent relaxations (7) and increased endothelial expression of adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) (20, 31). The decreased endothelial nitric oxide (NO) synthase (eNOS) function and upregulation of the adhesion molecules enhance the adhesion of inflammatory cells onto the endothelium followed by a transmigration of the cells into the subendothelial space, a key early process in atherogenesis (15). Numerous proi...

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Glutamine fructose-6-phosphate amidotransferase (GFAT) gene expression and activity in patients with type 2 diabetes: Inter-relationships with hyperglycaemia and oxidative stress

Cited by 63 publications

References 38 publications

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells

The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects

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