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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
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PMID:Increased oxidative stress in obesity and its impact on metabolic syndrome. 1559

Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States. Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis. Much evidence supports the presence of insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive oxygen (ROS) and nitrogen (RNS) species, which are produced by cellular disturbances in glucose and lipid metabolism. Endothelial dysfunction contributes to impaired insulin action, by altering the transcapillary passage of insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of insulin-stimulated glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in glucose and lipid metabolism develop secondary to the insulin resistance. Vascular damage, which results from lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction.From the clinical standpoint, much experimental evidence supports the concept that therapies that improve insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to insulin enhance vascular endothelial function. There is general agreement that aggressive therapy aimed simultaneously at improving insulin-mediated glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of atherosclerosis. Interventions that 1 correct carbohydrate and lipid metabolism, 2 improve insulin resistance, 3 reduce blood pressure and restore vascular reactivity, and 4 attenuate procoagulant and inflammatory responses in adults with a high risk of developing cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined.
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PMID:Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. 1650 74

The metabolic syndrome, Type II (non-insulin-dependent) diabetes and obesity are associated with endothelial dysfunction and increased plasma concentrations of NEFAs (non-esterified fatty acids; free fatty acids). The present study was undertaken to define the inhibitory effects of saturated NEFAs on EDR (endothelium-dependent relaxation). Experiments were performed in rings of rabbit aorta to establish (i) dose-response relationships, (ii) the effect of chain length, (iii) the effect of the presence of double bonds, (iv) reversibility and time course of inhibition, and (v) the effect on nitric oxide production. Aortic rings were incubated (1 h) with NEFA-albumin complexes derived from lauric (C(12:0)), myristic (C(14:0)), palmitic (C(16:0)), stearic (C(18:0)) and linolenic (C(18:3)) acids. EDR induced by acetylcholine (0.1-10 mumol/l) was measured after pre-contraction with noradrenaline. Inhibition of EDR was dose-dependent (0.5-2 mmol/l NEFA), and the greatest inhibition (51%) was observed with stearic acid (2 mmol/l). Lauric acid had the smallest inhibitory effect. The inhibitory effects were always reversible and were evident after 15 min of incubation. Linolenic acid caused a significantly lower inhibition of EDR than stearic acid. SOD (superoxide dismutase) restored the inhibitory effect caused by NEFAs, suggesting the involvement of ROS (reactive oxygen species) in removing nitric oxide. The nitric oxide concentration measured after exposure of the rings to acetylcholine was lower after incubation with NEFAs than with Krebs buffer alone. This finding is consistent with removal of nitric oxide by ROS. This claim was supported by the demonstration of increased concentrations of nitrated tyrosine in the rings incubated with NEFAs.
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PMID:Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta. 1652 62

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

Metabolic syndrome consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart disease. One of the defects in metabolic syndrome and its associated diseases is excess cellular oxidative stress (mediated by reactive oxygen and nitrogen species, ROS/RNS) and oxidative damage to mitochondrial components, resulting in reduced efficiency of the electron transport chain. Recent evidence indicates that reduced mitochondrial function caused by ROS/RNS membrane oxidation is related to fatigue, a common complaint of MS patients. Lipid replacement therapy (LRT) administered as a nutritional supplement with antioxidants can prevent excess oxidative membrane damage, restore mitochondrial and other cellular membrane functions and reduce fatigue. Recent clinical trials have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. Thus LRT plus antioxidant supplements should be considered for metabolic syndrome patients who suffer to various degrees from fatigue.
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PMID:Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. 1724 17

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle.
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PMID:The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. 1753 Oct 95

Insulin Resistance along with endothelial dysfunction give rise to a constellation of syndromes designated as IRS/MBS metabolic syndrome. Endothelial dysfunction starts early in life much before the development of structural atherosclerosis. Recent insights into vascular biology enable us to understand the molecular mechanisms underlying endothelial dysfunction, and the scope and need for prevention of "pre-clinical" coronary atherosclerosis through lifestyle modification; diet, exercise and stress management. Diminished production of nitric oxide (NO) and/or increased inactivation of NO through oxidative stress (reactive oxygen species ROS and reactive nitrogen species (RNS) are the basis of endothelial dysfunction hence increasing the bioavailability of NO and decreasing its inactivation is the aim of prevention and reversal of endothelial dysfunction. Insulin regulates constitutive NOS gene expression in endothelial cells in vivo; vasodilation is an important component of Insulin-stimulated whole body glucose uptake. Successful strategies are: PPAR alpha and gamma agonists which increase NO production in endothelium; anti-oxidants such as vit. E and C; supplementation with L-arginine, tetrahydrobiopterin-BH4 or sepiapterin (precursor of BH4), SOD mimetic tempol, statins which apart from lowering cholesterol improve NO production, selective beta1 adrenoreceptor antagonists such as nebivolol; suppression of angiotensin-mediated endothelin production by ACE inhibitors and ATR blockers; CB1 receptor blockers, PKCb inhibitors, nitric oxide donors (glyceryl trinitrate and isosorbide dinitrate), dietary supplements of EPA/DHA and regular physical exercise and control of mental stress.
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PMID:Causation, prevention and reversal of vascular endothelial dysfunction. 1805 38

Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)-mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS are responsible for the increased TP-mediated vasoconstriction in OZRs, resulting in impaired functional vasodilation. Eleven-week-old male lean Zucker rats (LZRs) and OZRs were fed normal rat chow or chow containing rosiglitazone (5 mg.kg(-1).day(-1)) for 2 wk. In another set of experiment, LZRs and OZRs were treated with 2 mM tempol (drinking water) for 7-10 days. After the treatments, spinotrapezius muscles were prepared, and arcade arteriolar diameters were measured following muscle stimulation and arachidonic acid (AA) application (10 muM) in the absence and presence of the TP antagonist SQ-29548 (1 muM). OZRs exhibited higher insulin, glucose, triglyceride, and superoxide levels and increased NADPH oxidase activity compared with LZRs. Functional and AA-induced vasodilations were impaired in OZRs. Rosiglitazone treatment improved insulin, glucose, triglyceride, and superoxide levels as well as NADHP oxidase activity in OZRs. Both rosiglitazone and tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 treatment improved vasodilatory responses in nontreated OZRs with no effect in LZRs or treated OZRs. These results suggest that insulin resistance and the resultant increased ROS impair functional dilation in OZRs by increasing TP-mediated vasoconstriction.
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PMID:Insulin resistance and impaired functional vasodilation in obese Zucker rats. 1829 67

The incidence of obesity and non-esterified ('free') fatty acid-associated metabolic disorders such as the metabolic syndrome and diabetes is increasing dramatically in most countries. Although the pathogenesis of these metabolic disorders is complex, there is emerging evidence that ROS (reactive oxygen species) are critically involved in the aberrant signalling and tissue damage observed in this context. Indeed, it is now widely accepted that ROS not only play an important role in physiology, but also contribute to cell and tissue dysfunction. Inappropriate ROS generation may contribute to tissue dysfunction in two ways: (i) dysregulation of redox-sensitive signalling pathways, and (ii) oxidative damage to biological structures (DNA, proteins, lipids, etc.). An important source of ROS is the NOX family of NADPH oxidases. Several NOX isoforms are expressed in the liver and pancreatic beta-cells. There is now evidence that inappropriate activation of NOX enzymes may damage the liver and pancreatic beta-cells. In the context of the metabolic syndrome, the emerging epidemic of non-alcoholic steatohepatitis is thought to be NOX/ROS-dependent and of particular medical relevance. NOX/ROS-dependent beta-cell damage is thought to be involved in glucolipotoxicity and thereby leads to progression from the metabolic syndrome to Type 2 diabetes. Thus understanding the role of NOX enzymes in liver and beta-cell damage should lead to an increased understanding of pathomechanisms in the metabolic syndrome and diabetes and may identify useful targets for novel therapeutic strategies.
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PMID:NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes? 1879 62

The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress determines functional longevity, a rather more descriptive term for the metabolic syndrome is the 'lifestyle-induced metabolic inflexibility and accelerated ageing syndrome'. Ultimately, thriftiness is good for us as long as we have hormetic stimuli; unfortunately, mankind is attempting to remove all hormetic (stressful) stimuli from his environment.
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PMID:Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe? 1937 9


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