Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces a battery of cytoprotective genes after oxidative stress. Nrf2 aids in liver regeneration by altering insulin signaling; however, whether Nrf2 participates in hepatic glucose homeostasis is unknown. Compared with wild-type mice, mice lacking Nrf2 (Nrf2-null) have lower basal serum insulin and prolonged hyperglycemia in response to an intraperitoneal glucose challenge. In the present study, blood glucose, serum insulin, urine flow rate, and hepatic expression of glucose-related genes were quantified in male diabetic wild-type and Nrf2-null mice. Type 1 diabetes was induced with a single intraperitoneal dose (200 mg/kg) of streptozotocin (STZ). Histopathology and serum insulin levels confirmed depleted pancreatic beta-cells in STZ-treated mice of both genotypes. Five days after STZ, Nrf2-null mice had higher blood glucose levels than wild-type mice. Nine days after STZ, polyuria occurred in both genotypes with more urine output from Nrf2-null mice (11-fold) than wild-type mice (7-fold). Moreover, STZ-treated Nrf2-null mice had higher levels of serum beta-hydroxybutyrate, triglycerides, and fatty acids 10 days after STZ compared with wild-type mice. STZ reduced hepatic glycogen in both genotypes, with less observed in Nrf2-null mice. Increased urine output and blood glucose in STZ-treated Nrf2-null mice corresponded with enhanced gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase)- and reduced glycolysis (pyruvate kinase)-related mRNA expression in their livers. Furthermore, the Nrf2 activator oltipraz lowered blood glucose in wild-type but not Nrf2-null mice administered STZ. Collectively, these data indicate that the absence of Nrf2 worsens hyperglycemia in type I diabetic mice and Nrf2 may represent a therapeutic target for reducing circulating glucose levels.
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PMID:Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. 2008 57

Amino acids are considered to be regulators of metabolism in several species, and increasing importance has been accorded to the role of amino acids as signalling molecules regulating protein synthesis through the activation of the TOR transduction pathway. Using rainbow trout hepatocytes, we examined the ability of amino acids to regulate hepatic metabolism-related gene expression either alone or together with insulin, and the possible involvement of TOR. We demonstrated that amino acids alone regulate expression of several genes, including glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, pyruvate kinase, 6-phospho-fructo-1-kinase and serine dehydratase, through an unknown molecular pathway that is independent of TOR activation. When insulin and amino acids were added together, a different pattern of regulation was observed that depended upon activation of the TOR pathway. This pattern included a dramatic up-regulation of lipogenic (fatty acid synthase, ATP-citrate lyase and sterol responsive element binding protein 1) and glycolytic (glucokinase, 6-phospho-fructo-1-kinase and pyruvate kinase) genes in a TOR-dependent manner. Regarding gluconeogenesis genes, only glucose-6-phosphatase was inhibited in a TOR-dependent manner by combination of insulin and amino acids and not by amino acids alone. This study is the first to demonstrate an important role of amino acids in combination with insulin in the molecular regulation of hepatic metabolism.
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PMID:Integration of insulin and amino acid signals that regulate hepatic metabolism-related gene expression in rainbow trout: role of TOR. 2021 41

Protein malnutrition in utero that induces permanent changes in metabolism has been investigated intensively in various animals in recent years, but to the best of our knowledge, not yet in the mink, a strict carnivore. In the present study, minks were fed either a low-protein (LP) diet, i.e., with a protein:fat:carbohydrate ratio of 14:51:35% of metabolisable energy (ME), or an adequate-protein diet (AP), i.e. 29:56:15% of ME, from when implantation was completed until parturition (17.9 +/- 3.6 days). Respiration and balance experiments were performed during both gestation and lactation. Plasma concentrations of leptin, IGF-1, and insulin were determined by radioimmunoassay; the relative abundances of glucose-6-phosphatase (G-6-Pase), fructose-1,6-bisphosphatase (Fru-1,6-P2ase), phosphoenol-pyruvate carboxykinase (PEPCK), and pyruvate kinase (PKM2) were determined in liver, and abundances of adiponectin and leptin in adipose tissue were determined by real-time quantitative PCR (q PCR). The protein supply only affected quantitative metabolism traits during the period of differentiated feeding. The dietary composition was reflected in the nitrogen metabolism and substrate oxidation, but no effects remained during lactation. The LP dams tended to have a smaller liver mass in relation to body weight than did AP dams (2.5% vs. 2.9%; p = 0.09), significantly less leptin mRNA (p < 0.05), and 30.6% fewer kits per mated female (p = 0.03). Furthermore, F1-generation kits exposed to protein restriction during foetal life (FLP1; 10.3 g) had a lower birth weight (p = 0.004) than did F1-generation kits exposed to adequate protein (FAP1; 11.3 g). Differences remained significant until 21 days of age (120.4 g vs. 127.6 g; p = 0.005). The FLP1 foetuses displayed a lower abundance of Fru-1,6-P2ase mRNA (p = 0.007) and of PKM2 mRNA (p = 0.002) than did FAP1 foetuses. Whether these changes during foetal life cause permanent changes in the glucose homeostasis of the offspring and result in the transmission of epigenetic phenotypic changes, as seen in the rat, needs further investigation.
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PMID:Effect of late gestation low protein supply to mink (Mustela vison) dams on reproductive performance and metabolism of dam and offspring. 2049 62

Using rainbow trout hepatocytes stimulated with l-leucine, l-methionine, or l-lysine in the presence or absence of bovine insulin, we investigated the ability of these amino acids to mimic the effects of a pool of amino acids on protein kinase B (Akt)/target of rapamycin (TOR) signaling pathways and expression of 6 genes known to be subjected to insulin and/or amino acid regulation [glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GK), pyruvate kinase (PK), fatty acid synthase (FAS), and serine dehydratase (SDH)]. Emphasis was placed on leucine, known to be a signaling molecule in mammals, and methionine and lysine that are essential amino acids limiting in plant-based diets for fish. In the presence of insulin, leucine (but not methionine or lysine) phosphorylated Akt and ribosomal protein S6 as previously observed with a pool of amino acids, suggesting that leucine might participate in the activation of the TOR pathway by amino acids in fish, as in mammals. G6Pase, PEPCK, GK, and SDH gene expression were higher in leucine-treated cells compared with control cells. Leucine combined with insulin reduced G6Pase gene expression by 90% and increased FAS gene expression > 4-fold compared with the control treatment. Methionine weakly decreased G6Pase, GK, and SDH gene expression and lysine weakly but significantly decreased the mRNA level of PEPCK. Thus, leucine regulated gluconeogenesis and lipogenesis, but not glycolysis, in the same way as a pool of amino acids. Methionine appeared to be involved in the regulation of specific genes, whereas lysine only had limited effects. These findings are particularly relevant regarding the involvement of amino acids in the regulation of metabolism-related gene expression.
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PMID:L-leucine, L-methionine, and L-lysine are involved in the regulation of intermediary metabolism-related gene expression in rainbow trout hepatocytes. 2110 25

Mechanism of action of GII (100 mg/kg body weight, po for 15 days) purified from fenugreek (T. foenum-graecum) seeds was studied in the sub-diabetic and moderately diabetic rabbits. In the sub-diabetic rabbits it did not change much the content of total lipids, glycogen and proteins in the liver, muscle and heart (glycogen was not studied in the heart). However, in the moderately diabetic rabbits same treatment decreased total lipids more in the liver (21%) than those in the heart and muscle. Total protein content increased (14%) in the liver but negligible change (5-7%) was observed in heart and muscle. Glycogen increased (17%) in the liver but not in the muscle of the moderately diabetic rabbits (glycogen was not estimated in the heart). Among the enzymes of glycolysis, activity of glucokinase was not affected in the liver of both the sub-diabetic and moderately diabetic rabbits. Phosphofructokinase and pyruvate kinase activity in both sub-diabetic and moderately diabetic rabbits increased (13-50%) indicating stimulation of glycolysis. The activity of gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-diphosphatase of the sub-diabetic rabbits decreased in the liver (15-20%) but not in the kidneys. In the moderately diabetic rabbits after treatment with GII, glucokinase in the liver was not affected much (-9%) but increased well in the muscle (40%). Phosphofructokinase and pyruvate kinase were moderately increased both in the liver and the muscle (18-23%). The gluconeogenic enzyme glucose-6-phosphatase decreased reasonably well in the liver and kidneys (22, 32%). Fructose-1,6-diphosphatase decreased only slightly (10, 9%) in the moderately diabetic rabbits. Thus GII seems to decrease lipid content of liver and stimulate the enzymes of glycolysis (except glucokinase) and inhibit enzymes of gluconeogenesis in the liver of the diabetic especially moderately diabetic rabbits.
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PMID:Mechanism of anti-diabetic action, efficacy and safety profile of GII purified from fenugreek (Trigonella foenum-graceum Linn.) seeds in diabetic animals. 2111 52

The in vivo effect of dehydroepiandrosterone (DHEA) on hepatic glycogen content and on glucose metabolizing enzymes was investigated in male and female Sprague-Dawley rats treated with 0.6% (w/w) DHEA in the diet for 3, 7, 14, 28 and 140 days. The glycolytic enzymes studied (glucokinase, hexokinase, pyruvate kinase) showed a significant persistent decrease in activity in both sexes after 3-7 days of treatment. Gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase) were increased after 3 days, but decreased after 7-14 days. Glycolytic enzymes showed a stronger reduction than gluconeogenic enzymes. Females were slightly more affected than males. Glucose-6-phosphate dehydrogenase was unchanged in females, but increased in males. Glycogen content and the activity of glycogen phosphorylase were reduced after 3 days of treatment. mRNA analysis of glucokinase and phosphorylase indicated that these enzyme alterations were accompanied by reduced transcriptional expression, while glucose-6-phosphate dehydrogenase mRNA levels were unchanged. Withdrawal of DHEA from 4 week-treated rats was associated with an almost complete reversibility of the enzyme alterations after 2 weeks. After long-term treatment (140 days) glucokinase, glucose-6-phosphatase and fructose-1,6-bisphosphatase activities were no longer altered. Since DHEA treatment affects the key enzymes of glucose metabolic pathways in the same sense, it is suggested that DHEA does not regulate individual enzymes but rather common regulatory factors or signalling pathways.
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PMID:Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats. 2154 66

Fisetin (3, 7, 3', 4'-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10mg/kg body weight) to diabetic rats for 30 days established a significant (P<0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (P<0.05) increase in plasma insulin level. In the present study the activities of key enzymes of carbohydrate metabolism were assayed to establish the modulatory actions of fisetin in maintaining the glucose homeostasis. The altered activities of key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (P<0.05) reverted to near normalcy by the administration of fisetin. Thus, fisetin regulates carbohydrate metabolism by modulating the key regulatory enzymes in the hepatic and renal tissues of diabetic rats.
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PMID:Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. 2181 45

Chromium has been recognized as an essential trace element that plays an important role in carbohydrate metabolism. However, the molecular mechanisms involved in its action are not clear. This study was undertaken to understand the mechanism of chromium action in experimental diabetes. Streptozotocin-induced diabetic animals were administered chromium as chromium picolinate (CrP) at a daily dose of 1 mg/kg body weight for a period of 4 weeks. It was observed that chromium complexed with picolinate was effective in lowering plasma glucose levels as well as was able to alleviate polyphagia, polydipsia, and weight loss in diabetic animals. Administration of chromium was also found to normalize glycogen content in liver of diabetic animals to near control levels. The reduction in plasma glucose levels by chromium was accompanied by increase in activity of glycolytic enzymes (e.g., glucokinase, phosphofructokinase, and pyruvate kinase) and by suppression in activity of gluconeogenic enzymes (e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) in liver. Hepatic glucose uptake was found to be increased by chromium supplementation as demonstrated by decrease in Km and increase in Vmax values in diabetic animals. Chromium levels were lower in the liver of diabetic rats when compared with that of control rats. A negative correlation was observed between plasma glucose and chromium concentration in patients with diabetes. The data suggests that chromium supplementation as CrP is beneficial in correcting hyperglycemia, implying that the modulation of the glucose metabolism by chromium may be therapeutically beneficial in the treatment of diabetes.
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PMID:Ameliorating effect of chromium administration on hepatic glucose metabolism in streptozotocin-induced experimental diabetes. 2228 84

Growth performance and metabolism were investigated in mink kits (n = 210) exposed to the same dietary treatment as their dams (n = 30), i.e. high (HP; 61% of metabolisable energy, ME), medium (MP; 48% of ME) or low (LP; 30% of ME) protein supply, from birth until 10 weeks of age. The kits were weighed weekly, and were measured by means of balance experiment and indirect calorimetry, in weeks eight and nine post-partum (p.p.). At weaning (seven weeks p.p.) and 10 weeks p.p. one kit per litter was killed and blood, liver and kidneys were collected. Plasma amino acid profiles, and hepatic abundance of mRNA for phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-biphosphatase, pyruvate kinase and glucose-6-phosphatase (G-6-Pase) by q-PCR, were determined. There were no differences in live weights among kits the first four weeks of life when kits solely consumed milk, but male LP kits were the heaviest. After transition to solid feed MP kits weighed most at nine weeks of age (p < 0.05). At eight weeks of age, the kits fed the LP diet retained less (p < 0.05) N than HP and MP kits. Heat production did not differ among kits, although protein oxidation was higher (p < 0.001) in HP kits than in LP kits. Kits fed the LP diet had lower (p < 0.05) plasma concentrations of lysine, methionine and leucine than MP kits. Dietary treatment was not reflected in the relative abundance of any of the studied mRNAs, but kits had significantly lower abundance of all studied mRNA than their dams, ranging from 83% less PEPCK abundance to 40% less for G-6-Pase. The kidney mass was smallest (p < 0.01) in kits fed the LP diet, and liver masses were largest (p < 0.001) in HP kits. The results indicate that the LP diet did not meet the protein requirements for mink kits in the transition period from milk to solid feed. The capacity to regulate the rate of gluconeogenesis was even more limited in young mink kits than in adult dams. However, young mink kits can regulate protein oxidation in response to dietary protein supply, probably by adapting the size of the liver and kidneys to the level of protein supply.
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PMID:Metabolic and growth response of mink (Neovison vison) kits until 10 weeks of age when exposed to different dietary protein provision. 2272 69

Pyridoxamine supplementation caused the alteration of the expression of genes encoding six gluconeogenesis-related proteins. The expression levels of phosphoenolpyruvate carboxykinase, pyruvate kinase, and pyruvate dehydrogenase kinase 4 in the pyridoxamine-supplemented mice were higher than those in the control mice. In contrast, the pyridoxamine supplementation caused lower expression levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, carbohydrate response element-binding protein, glucocorticoid receptor, and glucose-6-phosphatase. The pyridoxamine-supplemented mice showed significantly low glucose clearance in a glucose tolerance test, but they showed no symptoms of diabetes, which was estimated according to the levels of hemoglobin A1c and blood glucose. Pyruvate challenge testing suggested that pyridoxamine supplementation enhanced gluconeogenic activity from pyruvate. The results showed that a high-dose of pyridoxamine may require a careful inquiry concerning its validity.
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PMID:Abnormality in expression levels of gluconeogenesis-related genes by high-dose supplementation with pyridoxamine in mice. 2281 75


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