Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for approximately 4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.
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PMID:Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome. 1601 46

The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02-29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.
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PMID:Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease. 1592 79

Leptin secreted mainly by adipocytes plays an important role in insulin sensitivity in metabolic syndrome. Inducible nitric oxide synthase (iNOS) in 3T3-L1 adipocytes is induced by lipopolysaccharide (LPS) and several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma (IFN-gamma). Because the role of iNOS-derived nitric oxide (NO) in adipocyte function has not been fully clarified, the question that we addressed in the present study was whether iNOS-derived NO is involved in regulation of leptin secretion by adipocytes. Incubation of 3T3-L1 adipocytes for 12h with a mixture of IFN-gamma and LPS caused not only a 55% reduction in leptin secretion and a 52% reduction in leptin mRNA, but also significant induction of iNOS at both protein and mRNA levels. Inhibition of leptin secretion that had been induced by the IFN-gamma-LPS mixture was completely nullified by NOS inhibitors such as Nomega-monomethyl-L-arginine and aminoguanidine. Treatment of adipocytes with NO donors such as an NONOate and S-nitrosoglutathione produced an effect on leptin secretion similar to that of the IFN-gamma-LPS mixture. It is likely therefore that NO mediates downregulation of leptin caused by the IFN-gamma-LPS mixture in 3T3-L1 adipocytes, which suggests an important role for NO in adipocyte functions.
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PMID:Nitric oxide-induced downregulation of leptin production by 3T3-L1 adipocytes. 1644 19

Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. As an oxidant, pathological levels of NO inhibit nearly all enzyme-catalyzed reactions through protein oxidation. However, as a signaling molecule, physiological levels of NO stimulate glucose uptake as well as glucose and fatty acid oxidation in skeletal muscle, heart, liver and adipose tissue; inhibit the synthesis of glucose, glycogen, and fat in target tissues (e.g., liver and adipose); and enhance lipolysis in adipocytes. Thus, an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. The putative underlying mechanisms may involve multiple cyclic guanosine-3',5'-monophosphate-dependent pathways. First, NO stimulates the phosphorylation of adenosine-3',5'-monophosphate-activated protein kinase, resulting in (1) a decreased level of malonyl-CoA via inhibition of acetyl-CoA carboxylase and activation of malonyl-CoA decarboxylase and (2) a decreased expression of genes related to lipogenesis and gluconeogenesis (glycerol-3-phosphate acyltransferase, sterol regulatory element binding protein-1c and phosphoenolpyruvate carboxykinase). Second, NO increases the phosphorylation of hormone-sensitive lipase and perilipins, leading to the translocation of the lipase to the neutral lipid droplets and, hence, the stimulation of lipolysis. Third, NO activates expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, thereby enhancing mitochondrial biogenesis and oxidative phosphorylation. Fourth, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake and product removal via the circulation. Modulation of the arginine-NO pathway through dietary supplementation with L-arginine or L-citrulline may aid in the prevention and treatment of the metabolic syndrome in obese humans and companion animals, and in reducing unfavorable fat mass in animals of agricultural importance.
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PMID:Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. 1652 13

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

In recent years, increasing evidence has been provided that even minor renal dysfunction is a powerful cardiovascular risk factor that induces typical cardiovascular alterations and thus predisposes to coronary heart disease as well as to noncoronary cardiovascular problems. This first had been noted in patients with diabetes but now has been confirmed amply in patients without diabetes as well. Numerous heterogeneous abnormalities have been described in patients with early renal dysfunction (e.g., microalbuminuria, reduced estimated GFR). One final common pathway seems to be endothelial cell dysfunction. The link between albuminuria and generalized endothelial cell dysfunction (as indicated by diminished flow-mediated vasodilation, markers of endothelial cell dysfunction, sloughed off endothelial cells, and high transcapillary albumin escape rate) is unclear. In patients with early renal dysfunction, a long list of classical and nonclassical cardiovascular risk factors have been identified: Elevated asymmetric dimethyl-l-arginine concentrations, markers of microinflammation, oxidative stress, features of metabolic syndrome, abnormal adipokine concentrations, dyslipidemia, inappropriate activation of the renin-angiotensin system, and sympathetic overactivity. The mechanisms that link dysfunction of the kidney and the cardiovascular system are being sought. The most interesting unifying concept, however, is deranged fetal programming linking nephron underdosing to the increased cardiovascular risk.
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PMID:Cross-talk between the kidney and the cardiovascular system. 1682 29

1. Chronic feeding with a high-fat diet can cause metabolic syndrome in rodents similar to humans, but the role of saturated versus unsaturated fats in vascular tension remains unclear. 2. The present study shows that rats on a diet rich in either saturated or unsaturated fat had higher blood pressure compared with chow-fed rats (approximately 130 vs 100 mmHg, respectively), along with hyperlipidaemia and insulin resistance. Compared with responses of phenylephrine-preconstricted artery segments from chow-fed rats, vasorelaxation of isolated renal arteries from high-fat fed rats was reduced substantially (> 50%) in response to acetylcholine (0.01-10 micromol/L) and moderately to nitroprusside (>or=1 micromol/L) at low concentrations. Acetylcholine-induced vasorelaxation of arteries from high-fat fed rats was also more sensitive to inhibition by the nitric oxide (NO) synthase inhibitors NG-nitro-L-arginine and methylene blue. 3. In human umbilical vein endothelial cells, the production of NO and endothelin-1 was significantly inhibited by unsaturated fatty acids. In comparison, saturated fatty acids stimulated endothelin-1 production without altering NO production. 4. The data indicate that both saturated and unsaturated high-fat feeding may result in an increase in blood pressure owing to reduced endothelium-dependent vasorelaxation in the arterial system. The impaired endothelium-dependent vasorelaxation induced by saturated and unsaturated fatty acids may involve different mechanisms.
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PMID:High-fat feeding reduces endothelium-dependent vasodilation in rats: differential mechanisms for saturated and unsaturated fatty acids? 1689 44

Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase (eNOS) in vascular endothelium, resulting in increased production of nitric oxide (NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells (BAEC) in primary culture (assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time- and dose-dependent manner. Production of NO in response to ghrelin (100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys3)-GHRP-6 (selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering (si) RNA (but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser473) and eNOS (Akt phosphorylation site Ser1179) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein (MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.
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PMID:Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. 1710 60

Partially inconsistent data exist on mutual relations between nontraditional atherosclerotic risk factors, including the magnitude of insulin resistance (IR), as well as on their relevance for atherogenesis in the metabolic syndrome. Subjects exhibiting combined impaired fasting glucose and impaired glucose tolerance (IFG/IGT) are exposed to an exceptionally high risk for atherogenesis and development of type 2 diabetes mellitus. Because of islet Beta-cell dysfunction, the usefulness of commonly used indices of IR is limited in IFG/IGT. Our aim was to assess the relationship between extent of angiographic coronary artery disease (CAD) and nontraditional atherosclerotic risk factors (including IR by a clamp-based golden standard method) in IFG/IGT. Fifty-three subjects (32 men, 21 women; mean age, 55 +/- 11 years) with stable angina, preserved left ventricular systolic function, and IFG/IGT were divided into 3 groups: group A (no coronary stenoses >50%, n = 22), group B (1-vessel CAD, n = 15), and group C (2/3-vessel CAD, n = 16). Insulin sensitivity was quantified by a hyperinsulinemic euglycemic clamp technique and expressed as M. M value, plasma homocysteine (Hcy) level, and asymmetric dimethyl-L-arginine (ADMA)/L-arginine ratio were independent determinants of CAD extent as shown by forward stepwise discriminant function analysis. Compared with group A (M = 32.7 +/- 9.3 micromol/kg fat-free mass [FFM] per minute; Hcy, 8.1 +/- 1.4 micromol/L), lower M and higher Hcy levels were found in group B (M = 16.9 +/- 8.2 micromol/kg FFM per minute, P < .001; Hcy, 11.2 +/- 2.9 micromol/L, P = .003) and C (M = 16.4 +/- 7.8 micromol/kg FFM per minute, P < .001; Hcy, 12.8 +/- 3.9 micromol/L, P < .001). The ADMA/L-arginine ratio was increased in group C (0.0078 +/- 0.0011) compared with group A (0.0063 +/- 0.0013, P = .03) and B (0.0058 +/- 0.0012, P = .01). Multivariate correlates (P < .05) of plasma Hcy concentrations were M (beta = -.34 +/- .12, P = .008), creatinine clearance (beta = -.23 +/- .10, P = .03) and fasting insulin (beta = .25 +/- .12, P = .04). This indicates an additive contribution of IR, plasma Hcy, and elevated ADMA/L-arginine ratio to the extent of angiographic CAD in combined IFG/IGT.
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PMID:Nontraditional atherosclerotic risk factors and extent of coronary atherosclerosis in patients with combined impaired fasting glucose and impaired glucose tolerance. 1716 Dec 29

Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 microM) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg.kg(-1).day(-1)), enalapril (30 mg.kg(-1).day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome.
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PMID:EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR. 1722 56


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