Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Long-term treatment with glucagon-like peptide (GLP)-1 or its analog can improve insulin sensitivity. However, continuous administration is required due to its short half-life. We hypothesized that continuous production of therapeutic levels of GLP-1 in vivo by a gene therapy strategy may remit hyperglycemia and maintain prolonged normoglycemia. We produced a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) under the cytomegalovirus promoter, intravenously injected it into diabetic ob/ob mice, and investigated the effect of this treatment on remission of diabetes, as well as the mechanisms involved. rAd-GLP-1-treated diabetic ob/ob mice became normoglycemic 4 days after treatment, remained normoglycemic over 60 days, and had reduced body weight gain. Glucose tolerance tests found that exogenous glucose was cleared normally. rAd-GLP-1-treated diabetic ob/ob mice showed improved beta-cell function, evidenced by glucose-responsive insulin release, and increased insulin sensitivity, evidenced by improved insulin tolerance and increased insulin-stimulated glucose uptake in adipocytes. rAd-GLP-1 treatment increased basal levels of insulin receptor substrate (IRS)-1 in the liver and activation of IRS-1 and protein kinase C by insulin in liver and muscle; increased Akt activation was only observed in muscle. rAd-GLP-1 treatment reduced hepatic glucose production and hepatic expression of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fatty acid synthase in ob/ob mice. Taken together, these results show that a single administration of rAd-GLP-1 results in the long-term remission of diabetes in ob/ob mice by improving insulin sensitivity through restoration of insulin signaling and reducing hepatic gluconeogenesis.
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PMID:Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. 1736 25

To investigate the possible role of eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) in metabolism and energy homeostasis, high-fat diet-induced obese mice were treated with a 4E-BP2-specific antisense oligonucleotide (ASO) or a control 4E-BP2 ASO at a dose of 25 mg/kg body wt or with saline twice a week for 6 wk. 4E-BP2 ASO treatment reduced 4E-BP2 levels by >75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by approximately 7% and body fat content by approximately 18%. Treatment decreased liver triglyceride (TG) content by >50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed >8.5% increase in metabolic rate, >40% increase in UCP1 levels in BAT, >45% increase in beta(3)-adrenoceptor mRNA, and 40-55% decrease in mitochondrial dicarboxylate carrier, fatty acid synthase, and diacylglycerol acyltransferase 2 mRNA levels in WAT. 4E-BP2 ASO-transfected mouse hepatocytes showed an increased fatty acid oxidation rate and a decreased TG synthesis rate. In addition, 4E-BP2 ASO-treated mice demonstrated approximately 60 and 29% decreases in hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA, respectively, implying decreased hepatic glucose output. Furthermore, increased phosphorylation of Akt(Ser473) in both liver and fat of 4E-BP2 ASO-treated mice and increased GLUT4 levels in plasma membrane in WAT of the ASO-treated mice were observed, indicating enhanced insulin signaling and increased glucose uptake as a consequence of reduced 4E-BP2 expression. These data demonstrate for the first time that peripheral 4E-BP2 plays an important role in metabolism and energy homeostasis.
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PMID:Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression. 1819 53

We investigated the effect of curcumin on insulin resistance and glucose homeostasis in male C57BL/KsJ-db/db mice and their age-matched lean non-diabetic db/+ mice. Both db/+ and db/db mice were fed with or without curcumin (0.02%, wt/wt) for 6 wks. Curcumin significantly lowered blood glucose and HbA 1c levels, and it suppressed body weight loss in db/db mice. Curcumin improved homeostasis model assessment of insulin resistance and glucose tolerance, and elevated the plasma insulin level in db/db mice. Hepatic glucokinase activity was significantly higher in the curcumin-supplemented db/db group than in the db/db group, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly lower. In db/db mice, curcumin significantly lowered the hepatic activities of fatty acid synthase, beta-oxidation, 3-hydroxy-3-methylglutaryl coenzyme reductase, and acyl-CoA: cholesterol acyltransferase. Curcumin significantly lowered plasma free fatty acid, cholesterol, and triglyceride concentrations and increased the hepatic glycogen and skeletal muscle lipoprotein lipase in db/db mice. Curcumin normalized erythrocyte and hepatic antioxidant enzyme activities (superoxide dismutase, catalase, gluthathione peroxidase) in db/db mice that resulted in a significant reduction in lipid peroxidation. However, curcumin showed no effect on the blood glucose, plasma insulin, and glucose regulating enzyme activities in db/+ mice. These results suggest that curcumin seemed to be a potential glucose-lowering agent and antioxidant in type 2 diabetic db/db mice, but had no affect in non-diabetic db/+ mice.
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PMID:Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. 1839 69

The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17beta-estradiol (E(2)) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E(2), given daily (50 microg/kg s.c.) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E(2) treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression levels of transcription factors such as liver X receptor alpha and SREBP1c were not changed by E(2) treatment, but the expression of the key lipogenic gene SCD1 was reduced. This was accompanied by decreased hepatic triglyceride content. Importantly, E(2) decreased the hepatic expression of glucose-6-phosphatase (G-6-Pase). We conclude that E(2) treatment exerts antidiabetic and antiobesity effects in HFD mice and suggest that this is related to decreased expression of lipogenic genes in WAT and liver and suppression of hepatic expression of G-6-Pase. Decreased plasma levels of resistin probably also play an important role in this context.
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PMID:Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. 1869 13

Normal rats were given catechin-rich green tea as drinking fluid and the effects on hepatic gene expression were examined. The results of DNA microarray analysis and quantitative real-time reverse transcription-polymerase chain reaction indicated the down-regulated expression of genes for glucose-6-phosphatase (G6Pase) and fatty acid synthase, and the up-regulated expression of peroxisome proliferator activated receptor alpha in the rats given green tea for 4 weeks as compared with the water-given animals. One may expect anti-diabetic activity by catechin-rich green tea through its chronic down-regulatory effect on G6Pase expression.
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PMID:Effects of chronic ingestion of catechin-rich green tea on hepatic gene expression of gluconeogenic enzymes in rats. 1926 60

Carnivorous fish are poor users of dietary carbohydrates and are considered to be glucose intolerant. In this context, we have tested, for the first time in rainbow trout, metformin, a common anti-diabetic drug, known to modify muscle and liver metabolism and to control hyperglycemia in mammals. In the present study, juvenile trout were fed with very high levels of carbohydrates (30% of the diet) for this species during 10 days followed by feeding with pellets supplemented with metformin (0.25% of the diet) for three additional days. Dietary metformin led to a significant reduction in postprandial glycemia in trout, demonstrating unambiguously the hypoglycemic effect of this drug. No effect of metformin was detected on mRNA levels for glucose transporter type 4 (GLUT4), or enzymes involved in glycolysis, mitochondrial energy metabolism, or on glycogen level in the white muscle. Expected inhibition of hepatic gluconeogenic (glucose-6-phosphatase, fructose-1,6-bisphosphatase, and phosphoenolpyruvate carboxykinase) mRNA levels was not found, showing instead paradoxically higher mRNA levels for these genes after drug treatment. Finally, metformin treatment was associated with higher mRNA levels and activities for lipogenic enzymes (fatty acid synthase and glucose-6-phosphate dehydrogenase). Overall, this study strongly supports that the induction of hepatic lipogenesis by dietary glucose may permit a more efficient control of postprandial glycemia in carnivorous fish fed with high carbohydrate diets.
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PMID:Metformin improves postprandial glucose homeostasis in rainbow trout fed dietary carbohydrates: a link with the induction of hepatic lipogenic capacities? 1955 3

The aim of the present study was to analyse the effects of partial or total replacement of fish meal (FM) and fish oil (FO) by a mixture of plant protein (PP) and a mixture of vegetable oils (VO) on the hepatic insulin-nutrient-signalling pathway and intermediary metabolism-related gene expression in rainbow trout (Oncorhynchus mykiss). Triplicate groups of fish were fed four practical diets containing graded levels of replacement of FM and FO by PP and VO for 12 weeks: diet 0/0 (100 % FM, 100 % FO); diet 50/50 (50 % FM and 50 % PP, 50 % FO and 50 % VO); diet 50/100 (50 % FM and 50 % PP, 100 % VO); diet 100/100 (100 % PP, 100 % VO). Samplings were performed on trout starved for 5 d then refed with their allocated diet. In contrast to partial substitution (diet 50/50), total substitution of FM and FO (diet 100/100) led to significantly lower growth compared with diet 0/0. The insulin-nutrient-signalling pathway (protein kinase B (Akt), target of rapamycin (TOR), S6 protein kinase 1 (S6K1) and S6) was characterised in trout liver and found to be activated by refeeding. However, changes in diet compositions did not differentially affect the Akt-TOR-signalling pathway. Moreover, expression of genes encoding fructose-1,6-biphosphatase, mitochondrial phosphoenolpyruvate carboxykinase, glucokinase, pyruvate kinase and carnitine palmitoyl transferase 1 were not affected by refeeding or by dietary changes. Refeeding down- and up-regulated the expression of gluconeogenic glucose-6-phosphatase isoform 1 and lipogenic fatty acid synthase genes, respectively. Expression of both genes was also increased with partial replacement of FM and total replacement of FO (diet 50/100). These findings indicate that plant-based diets barely affect glucose and lipid metabolism in trout.
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PMID:Hepatic protein kinase B (Akt)-target of rapamycin (TOR)-signalling pathways and intermediary metabolism in rainbow trout (Oncorhynchus mykiss) are not significantly affected by feeding plant-based diets. 1966 14

Genetic selection is commonly used in farm animals to manage body fat content. In rainbow trout, divergent selection for low or high muscle fat content leads to differences in utilization of dietary energy sources between the fat muscle line (FL) and the lean muscle line (LL). To establish whether genetic selection on muscle fat content affects the hepatic insulin/nutrient signaling pathway, we analyzed this pathway and the expression of several metabolism-related target genes in the livers of the two divergent lines under fasting and then refeeding conditions. Whereas glycemia returned to basal level 24 h after refeeding in FL trout, it remained elevated in the LL trout. Target of rapamycin (TOR) protein was more abundant in the livers of FL trout than in LL trout, and refeeding activation of the hepatic TOR signaling pathway (TOR, S6K1, and S6) was therefore enhanced. Genes related to glycolysis (glucokinase and pyruvate kinase) and gluconeogenesis (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) were only slightly affected by refeeding and genetic selection. Refeeding stimulated expression of lipogenic genes and the sterol-responsive element binding protein (SREBP1), and expression of fatty acid synthase, glucose-6-phosphate dehydrogenase, and serine dehydratase was predominant in the livers of FL fish compared with LL fish. In agreement with recent findings linking TOR to lipogenesis control, we concluded that genetic selection for muscle fat content resulted in overactivation of the TOR signaling pathway-associated lipogenesis and probably also improved utilization of glucose.
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PMID:Rainbow trout genetically selected for greater muscle fat content display increased activation of liver TOR signaling and lipogenic gene expression. 1971 Mar 90

The effects of ursolic acid on the polyol pathway and glucose homeostasis-related metabolism were examined in the livers of streptozotocin (STZ)-induced diabetic mice fed a high-fat (37% calories from fat) diet for 4 weeks. Male mice were divided into nondiabetic, diabetic control, and diabetic-ursolic acid (0.05% wt/wt) groups. Diabetes was induced by the injection of STZ (200 mg/kg body weight, intraperitoneally). Although an ursolic acid supplement lowered the blood glucose level, it did not affect the plasma leptin and adiponectin levels. The present study shows that the blood glucose levels have a positive correlation with the hepatic sorbitol dehydrogenase activities (r = 0.39, P < .05). Ursolic acid significantly inhibited sorbitol dehydrogenase activity as well as aldose reductase activity in the liver. The supplementation of ursolic acid significantly increased glucokinase activity, while decreasing glucose-6-phosphatase activity in the livers of STZ-induced diabetic mice. Ursolic acid significantly elevated the hepatic glycogen content compared with the diabetic control group. Supplementation with ursolic acid significantly lowered the plasma total cholesterol, free fatty acid, and triglyceride concentrations compared with the diabetic control group, whereas it normalized hepatic triglyceride concentration. A negative correlation was found between the hepatic triglyceride concentration and blood glucose levels (r = -0.50, P < .01) in regard to insulin-dependent diabetic mice. The hepatic fatty acid synthase activity was significantly lower in the ursolic acid group than in the diabetic control group, whereas hepatic fatty acid beta-oxidation and carnitine palmitoyltransferase activities were significantly higher. These results indicate that ursolic acid may be beneficial in preventing diabetic complications by improving the polyol pathway as well as the lipid metabolism and that it can function as a potential modulator of hepatic glucose production, which is partly mediated by up-regulating glucose utilization and glycogen storage and down-regulating glyconeogenesis in the liver.
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PMID:Inhibitory effects of ursolic acid on hepatic polyol pathway and glucose production in streptozotocin-induced diabetic mice. 1984 80

Consumption of a diet high in barley beta-glucan (BG) has been shown to prevent insulin resistance. To investigate the mechanism for the effects of barley BG, three groups of male 7-wk-old C57BL/6J mice were fed high-fat diets containing 0, 2, or 4% of barley BG for 12 wk. The 2% BG and 4% BG groups had significantly lower body weights compared with the 0% BG group. The 4% BG group demonstrated improved glucose tolerance and lower levels of insulin-resistance index and glucose-dependent insulinotropic polypeptide. Consumption of the BG diet decreased hepatic lipid content. Mice on the BG diet also demonstrated decreased fatty acid synthase and increased cholesterol 7alpha-hydroxylase gene expression levels. The BG diet promoted hepatic insulin signaling by decreasing serine phosphorylation of insulin receptor substrate 1 and activating Akt, and it decreased mRNA levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In summary, consumption of BG reduced weight gain, decreased hepatic lipid accumulation, and improved insulin sensitivity in mice fed a high-fat diet. Insulin signaling enhanced due to the expression changes of glucose and lipid metabolism genes by BG consumption. Consumption of barley BG could be an effective strategy for preventing obesity, insulin resistance, and the metabolic syndrome.
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PMID:Consumption of barley beta-glucan ameliorates fatty liver and insulin resistance in mice fed a high-fat diet. 2011 96


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