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

Insulin resistance is an important issue in the understanding of the metabolic syndrome. Clinical insulin resistance is usually defined by reduced insulin-mediated uptake of glucose in skeletal muscle. However, new studies have shown that liver and fat cells may also develop insulin resistance in subjects with the metabolic syndrome, specifically when these subjects are hyperglycaemic. New investigations also indicate that the endothelial cell itself can be insulin-resistant, reduced blood flow and increased peripheral resistance as the outcome. Insulin resistance may not only induce hyperglycaemia, but also dyslipidaemia (increased plasma levels of free fatty acids and triglyceride, and reduced plasma HDL levels) and arterial hypertension. All these variables may provoke arteriosclerosis and ischaemic heart disease. Specifically, abdominal adiposity seems to be responsible for insulin resistance in subjects with the metabolic syndrome. The mechanism could be intracellular accumulation of acyl CoA and triglyceride. However, an increased production of peptides from the adipose tissue, such as TNF alpha and reduced production of adiponectine may also play a role. The mechanism by which FFA and triglyceride, together with the peptides mentioned, may induce insulin resistance at a cellular level, resulting in reduced glucose transport and intracellular glucose processing, is still being discussed. A change in the insulin signalling cascade is one possibility, but the results so far have been contradictory. Another possibility is, of course, that the cellular accumulation of acyl CoA itself intervenes with gene expression and with phosphorylation of proteins.
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PMID:[Insulin resistance: organ manifestations and cellular mechanisms]. 1198 54

Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappa B activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome.
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PMID:A novel pathway to the manifestations of metabolic syndrome. 1498 Dec 9

Long-term observation studies on metabolic syndrome have disclosed that accumulation of clinical features in the syndrome indicated poor prognosis in the subjects. High sensitivity CRP(hs CRP) is generally increased in the obese subjects due to increased TNF alpha and IL-6 in adipose tissue. Hs CRP is also elevated in hypertensive and diabetic subjects. Hs CRP is increased in the subjects with low HDL-cholesterol and high triglyceride. The West of Scotland Coronary Prevention Study indicated that metabolic syndrome with or without hs CRP more than 3 mg/l predicted definite differences in prognosis for future cardiac outcomes.
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PMID:[Enhanced prognostic information by determining hs CRP on metabolic syndrome]. 1520 52

The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance. Obesity also leads to a proinflammatory and prothrombotic state that potentiates atherosclerosis. Pathways leading directly from adiposity to the genesis of dyslipidemia and hypertension have been elucidated. Recent knowledge implies a role for fat-derived "adipokines," including TNF alpha and adiponectin, as pathogenic contributors or protective factors. Current therapies include diet and exercise as well as agents indicated for the treatment of individual components of the syndrome. Future therapies may accrue from the aggressive pursuit of newer molecular drug targets that have the potential to prevent or treat multiple aspects of the metabolic syndrome.
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PMID:Metabolic syndrome: a clinical and molecular perspective. 1566 May 1

Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.
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PMID:The anti-inflammatory effect of exercise. 1577 55

Mexican Americans (MA) exhibit high risk for the insulin resistance syndrome characterized by subclinical inflammation and greater risk for type 2 diabetes compared with non-Hispanic white (NHW) adults. The reasons for this phenomenon remain obscure. Because the inflammatory cytokine, tumor necrosis factor-alpha (TNF alpha), is associated with insulin resistance in various models of obesity and diabetes, we sought to determine whether circulating concentrations of this cytokine and its soluble receptors are higher in MA than NHW, and also to determine if the TNF alpha system is related to the lower insulin sensitivity in MA. Fasting blood samples were used to determine concentrations of TNF alpha, soluble TNF receptors 1 (sTNFR1) and 2 (sTNFR2) in the same 13 MA (7 women, 6 men, age=27.0+/-2.0 years, BMI=23.0+/-0.7) and 13 NHW (7 women, 6 men, age=24.8+/-1.5 years, BMI=22.8+/-0.6) previously shown to exhibit differences in insulin sensitivity. Circulating TNF alpha was significantly higher (3.11+/-0.38 vs. 2.10+/-0.24 pg/ml, p<0.05) and sTNFR2 was significantly lower (1324+/-85 vs. 1925+/-127 pg/ml, p<0.05) among MA compared with NHW subjects. Soluble TNFR1 was not different between groups (MA: 970+/-111 pg/ml vs. NHW: 1218+/-73 pg/ml, p=0.07). TNF alpha, sTNFR1 and sTNFR2 were not correlated with HOMA-IR when the two groups were analyzed in aggregate. This study documents higher circulating TNF alpha concentrations in non-obese, non-diabetic MA, a population group at increased risk for the metabolic syndrome and the untoward effects of sub-clinical inflammation. The clinical implications of this difference, if any, are not yet known.
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PMID:Circulating tumor necrosis factor alpha is higher in non-obese, non-diabetic Mexican Americans compared to non-Hispanic white adults. 1578 8

The distribution of fat in obese persons is related to the risk of developing various metabolic disorders, such as glucose intolerance, dyslipidemia and hypertension, and the combination of these conditions is known as the metabolic syndrome. The aim of this study was to investigate the role of subcutaneous fat in regulating insulin resistance and its influence on TNF-alpha expression in visceral fat, by using mice that were subjected to subcutaneous lipectomy with or without subsequent fat transplantation. After partial subcutaneous lipectomy, mice showed significantly greater accumulation of visceral fat compared with sham-operated control mice. Lipectomy led to higher plasma insulin and lower plasma glucose levels after loading with glucose and insulin, respectively, compared with the levels in control mice. Insulin-induced phosphorylation of IRS-1 was decreased in the skeletal muscles of lipectomized mice. Subcutaneous transplantation of fat pads into lipectomized mice reversed the above-mentioned changes indicating insulin resistance in these animals. The fat storage area of adipocytes and TNF- alpha expression by adipocytes in visceral fat were significantly higher in the lipectomized mice than in controls, while subcutaneous transplantation of fat reduced both the fat storage area and TNF-alpha expression. The insulin resistance of lipectomized mice was also ameliorated by systemic neutralization of TNF-alpha activity using a specific antibody. These findings obtained in mice subjected to subcutaneous lipectomy with/without subsequent fat transplantation indicate that subcutaneous fat regulates systemic insulin sensitivity, possibly through altering fat storage and the expression of TNF-alpha by adipocytes in visceral fat. The balance between accumulation of subcutaneous fat and visceral fat may be important with respect to the occurrence of systemic insulin resistance in the metabolic syndrome.
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PMID:Subcutaneous fat modulates insulin sensitivity in mice by regulating TNF-alpha expression in visceral fat. 1707 71

Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARgamma receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA < or = 2 than patients with HOMA > 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 microU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.
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PMID:Insulin resistance and hepatitis C. 1713 67

The pathogenesis of NASH is being unraveled by studies of animal models and humans with this disorder. The necro-inflammatory component of NASH appears to be modulated by interactions among various factors (for example cytokines, hormones, neurotransmitters) that regulate the biological activity of TNF- and other proinflammatory (Th-1) cytokines. Hepatic necroinflammation is necessary, but not sufficient, for progression to cirrhosis. Factors such as leptin inducible factors (for example, noradrenaline), that regulate the activity of profibrogenic cytokines, such as IL-10 and TGF-beta, dictate the extent of fibrosis that occurs during liver injury. A better understanding of how these and other soluble and cell associated factors regulate the phenotypes of different types of liver cells should help us to develop rationale treatments for NASH and other disorders in the metabolic syndrome.
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PMID:The role of cytokines in non-alcoholic steatohepatitis. A review. 1720 49

Adipose tissue is an active and complex endocrine organ that secretes numerous bioactive substances, including hormones, growth factors, and cytokines. Central obesity, one of the components of metabolic syndrome, is a cardiometabolic risk factor associated with a state of chronic inflammation and coagulation, one in which the expression of certain adipocytokines, including tumor necrosis factor-alpha (TNF-(alpha), interleukin (IL)-6, and plasminogen activator inhibitor-1 (PAI-1) is more abundantly increased, while adiponectin expression is decreased. TNF-alpha initiates and organizes inflammatory changes in vascular tissue. IL-6, an inflammatory cytokine directly implicated in atherogenesis, exerts pleiotropic effects on a variety of tissues. An increased concentration of PAI-1, an important regulator of the endogenous fibrinolytic system, promotes continued clotting. Adiponectin, on the other hand, has potent vasculoprotective, angiogenic, anti-inflammatory, and antiatherogenic properties. Adiponectin levels are low in obese individuals and increase when weight is lost, thereby serving as a marker for cardioprotection. Weight loss has long been promoted as a means to reduce the risk of type 2 diabetes and cardiovascular disease; for example, exercise and a hypocaloric diet have been shown to decrease PAI-1 levels. Weight loss drugs, such as orlistat, a lipase inhibitor, and sibutramine, a serotonin and norepinephrine reuptake inhibitor, have both been shown to produce a decrease in C-reactive protein levels and an increase in serum adiponectin. Rimonabant, a selective cannabinoid 1 receptor antagonist in Phase III studies, also has been shown to increase adiponectin levels. These agents may play a role in the regulation of adipocytokines, which may directly affect the risk for cardiometabolic disease.
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PMID:The relation of adipose tissue to cardiometabolic risk. 1720 62


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