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)

Adiponectin plays important roles in regulating insulin sensitivity and atherogenesis. Adiponectin has been shown to suppress hepatic glucose production in rodents. It has not been reported whether ectopically expressed adiponectin could regulate glucose metabolism in cultured hepatocyte-like cells. In the current study, the effect of adiponectin on glucose production was analyzed by ectopically expressing the protein in hepatoma H4IIE cells using an adenovirus delivery system to generate both human full-length and the globular domain of the protein. Expression of adiponectin in hepatoma H4IIE cells, in the absence of insulin, suppressed expression of the genes encoding glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, rate-limiting enzymes in the gluconeogenic pathway. Furthermore, expression of adiponectin in H4IIE cells suppressed glucose production from lactate and pyruvate. Purified recombinant human adiponectin also reduced glucose production in H4IIE cells and in rat primary hepatocytes in the absence of insulin. These data suggest that adiponectin protein could exert its function independent of the presence of insulin in these culture systems.
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PMID:Adiponectin represses gluconeogenesis independent of insulin in hepatocytes. 1623 52

The orphan receptor small heterodimer partner (SHP; NROB2) is a transcriptional repressor that inhibits nuclear receptor signaling in diverse metabolic pathways. Here, we report that SHP(-/-) mice exhibited hypoinsulinemia with age, which was associated with increased peripheral insulin sensitivity and increased response of isolated islets to glucose stimulation, yet maintain normal levels of blood glucose. Deficiency in SHP function resulted in up-regulation of glucose transporter 4 mRNA and glucose uptake in muscles, and overexpression of SHP in C2C12 cells inhibited both basal and peroxisomal proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha-stimulated glucose transporter 4 expression and glucose uptake. SHP(-/-) hepatocytes showed markedly decreased basal glucose production in cultures, and SHP(-/-) livers had increased glycogen stores and were more sensitive to insulin inhibition of glucose output, which were concomitant with decreased expression for PPARgamma1, fatty acid translocase, glucose-6-phosphatase, and phosphoenol/pyruvate carboxykinase, and increased mRNAs for glucokinase and pyruvate kinase. In white fat, SHP deficiency resulted in up-regulation of genes involved in insulin sensitizing, including PPARgamma2 and adiponectin. We show that, at the transcriptional level, SHP directly represses adiponectin promoter activity by PPARgamma/liver receptor homolog-1. The results suggest that the increases in insulin sensitivity through multiple signaling pathways in muscle, liver, and fat, with an increase in islet secretory function, represent the complex mechanism whereby SHP deficiency leads to improvement in insulin sensitivity, secretion, and diabetes.
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PMID:Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis. 1875 80

LKB1 is a 50 kDa serine/threonine kinase that phosphorylates and activates the catalytic subunit of AMPK at its T-loop residue Thr 172. We prepared adenoviruses expressing the constitutive active (wild-type) form (CA) or dominant negative (kinase inactive, D194A mutant) form (DN) of LKB1 and overexpressed these proteins in cultured myotubes (C2C12 cells) and rat hepatoma cells (FAO cells). When analyzed by immunoblotting with the antibody against Thr172-phosphorylated AMPK, the phosphorylation of AMPK was increased (2.5-fold) and decreased (0.4-fold) in cells expressing CA and DN LKB1, respectively, as compared with Lac-Z expressing control cells. Immunoprecipitation experiments, using isoform-specific antibody, revealed these alterations of AMPK phosphorylation to be attributable to altered phosphorylation of AMPK alpha2, but not alpha1 catalytic subunits, strongly suggesting the alpha2 catalytic subunit to be the major substrate for LKB1 in mammalian cells. In addition, adiponectin or AICAR-stimulated AMPK phosphorylation was inhibited by overexpression of DN LKB1, while phenformin-stimulated phosphorylation was unaffected. These results may explain the difference in AMPK activation mechanisms between AMP and phenformin, and also indicate that AMPK phosphorylation by LKB1 is involved in AMP-stimulated AMPK activation. As a downstream target for AMPK, AICAR-induced glucose uptake and ACCbeta phosphorylation were found to be significantly reduced in DN LKB1 expressing C2C12 cells. The expression of key enzymes for gluconeogenesis, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was also dependent on LKB1 activities in FAO cells. These results demonstrate that LKB1 is a crucial regulator of AMPK activation in muscle and liver cells and, therefore, that LKB1 activity is potentially of importance to our understanding of glucose and lipid metabolism.
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PMID:LKB1, an upstream AMPK kinase, regulates glucose and lipid metabolism in cultured liver and muscle cells. 1708 19

Early obesity and late onset of insulin resistance associated with hormonal imbalances occur in FSH receptor-deficient follitropin receptor knockout female mice. This study tests the hypothesis that chronic high-fat diet aggravates obesogenic changes in a depot-specific manner and explores some molecular links of hormone imbalances with insulin resistance. In SV 129 mice, hormonal imbalances seem obligatory for exacerbation of diet-induced obesity. Visceral adiposity, glucose intolerance, and lipid disturbances in 9-month follitropin receptor knockout females were associated with decrease in adiponectin signaling. High-molecular-weight plasma adiponectin and adipose tissue adiponectin mRNA were decreased. Adiponectin receptors R1 and R2 mRNA was selectively altered in mesenteric fat but not periuterine fat. R2 decreased in the liver and R1 was higher in muscle. Whereas hepatic adenosine monophosphate T-activated protein kinase activity was down-regulated, both phosphoenolpyruvate carboxykinase and glucose-6-phosphatase enzymes were up-regulated. Longitudinally, diminishing sex hormone signaling in adipose tissue was associated with progressive down-regulation of adiponectin activity and gradual impaired glucose tolerance. Chronic high-fat diet in SV129 wild-type mice did not produce overt obesity but induced visceral fat depot changes accompanied by liver lipid accumulation, high cholesterol, and up-regulation of inflammation gene mRNAs. Thus, TNF-alpha, C-C motif chemokine receptor-2, and C-C motif chemokine ligand-2 were selectively elevated in mesenteric fat without altering glucose tolerance and adiponectin signaling. Our study highlights adiponectin signaling and regulation to be involved in hormone imbalance-induced insulin resistance and demonstrates selective visceral adipose depot alterations by chronic high-fat diet and induction of inflammatory genes.
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PMID:Changes in adiponectin and inflammatory genes in response to hormonal imbalances in female mice and exacerbation of depot selective visceral adiposity by high-fat diet: implications for insulin resistance. 1771 50

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

Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) was isolated from Artemisia princeps to investigate the dose-response effects on blood glucose regulation and pancreatic beta-cell function in type 2 diabetic mice. Db/db mice were divided into control (eupatilin-free, AIN-76 standard diet), low-Eupa (0.005g/100g diet) and high-Eupa (0.02g/100g diet) groups. The supplementation of eupatilin for 6 weeks significantly lowered fasting blood glucose concentration while it increased hepatic glycogen content. In particular, high-Eupa reduced hemoglobin A(1c) and plasma glucagon levels along with a simultaneous increase in plasma insulin and adiponectin levels. The supplementation of eupatilin significantly lowered hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, while it increased glucokinase activity in the liver. The pancreatic insulin concentration was higher in the eupatilin-supplemented groups. Also the pancreatic insulin concentration of eupatilin groups was higher than the control group. These results suggest that eupatilin played the role of an antidiabetic functional component in A. princeps by enhancing hepatic and plasma glucose metabolism as well as by increasing insulin secretion in type 2 diabetic mice.
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PMID:Eupatilin, isolated from Artemisia princeps Pampanini, enhances hepatic glucose metabolism and pancreatic beta-cell function in type 2 diabetic mice. 1870 53

The steroid hormone 20-hydroxyecdysone (20HE) is an essential signaling molecule that modulates molting response in insects and may function as a putative anabolic factor in vertebrate animals, although no mammalian 20HE receptor has been identified. Here we show that in H4IIE cell culture, 20HE treatment decreased expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), reduced glucose production, and induced Akt2 phosphorylation sensitive to the phosphoinositide-3 kinase pathway-specific inhibitor LY-294002. Daily oral administration of 20HE (10 mg/kg for 13 wk) ameliorated obesity and insulin resistance in C57BL/6J mice fed a high-fat diet and produced a significant decrease of body weight gain and body fat mass compared with nontreated animals as demonstrated by dual-energy X-ray absorptiometry analysis. In addition, plasma insulin levels and glucose tolerance were significantly lowered by 20HE treatment. These changes were accompanied by the reduced hepatic expression of PEPCK and G6Pase and increased adiponectin production by visceral fat tissue. These studies demonstrate the anti-obesity and anti-diabetic effects of 20HE and begin to elucidate its putative cellular targets both in vitro and in vivo.
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PMID:20-Hydroxyecdysone decreases weight and hyperglycemia in a diet-induced obesity mice model. 1912 84

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

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

Hyperglycemia is common after acute stroke. In the acute phase of stroke (within 24h), rats with permanent cerebral ischemia developed higher fasting blood glucose and insulin levels in association with up-regulation of hepatic gluconeogenic gene expression, including phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase. In addition, hepatic gluconeogenesis-associated positive regulators, such as FoxO1, CAATT/enhancer-binding proteins (C/EBPs), and cAMP responsive element-binding protein (CREB), were up-regulated. For insulin signaling transduction, phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS1) at the tyrosine residue, Akt, and AMP-activated protein kinase (AMPK), were attenuated in the liver, while negative regulators of insulin action, including phosphorylation of p38, c-Jun N-terminal kinase (JNK), and insulin receptor substrate-1 (IRS1) at the serine residue, were increased. In addition, the brains of rats with stroke exhibited a reduction in phosphorylation of IRS1 at the tyrosine residue and Akt. Circulating cortisol, glucagon, C-reactive protein (CRP), monocyte chemoattractant protein 1 (MCP-1), and resistin levels were elevated, but adiponectin was reduced. Our data suggest that cerebral ischemic insults might modify intracellular and extracellular environments, favoring hepatic gluconeogenesis and the consequences of hyperglycemia.
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PMID:Hyperglycemia is associated with enhanced gluconeogenesis in a rat model of permanent cerebral ischemia. 2327 76


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