Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is associated not only with the classic cardiovascular risk factors of hypertension and dyslipidemia, but also with several disorders of coagulation and fibrinolysis. Elevated concentrations of the fibrinolytic inhibitor plasminogen activator inhibitor-1 are associated with insulin resistance. In experimental systems, increased expression and secretion of plasminogen activator inhibitor-1 by hepatocyte and endothelial cell lines can be induced by insulin, proinsulin-like molecules, triglyceride-rich lipoproteins and oxidized LDL, as well as by inducing insulin resistance in isolated hepatocytes. Concentrations of the endothelial cell protein von Willebrand factor are elevated in insulin-resistant states, suggesting that abnormalities of capillary endothelium, as well as those reported for endothelium-dependent vasodilatation, may play a role in the etiology of insulin resistance. Levels of a third coagulation factor, fibrinogen, are elevated in insulin-resistant subjects, an association that suggests a possible role for acute-phase cytokines in the abnormalities of coagulation and endothelial function. It is proposed that the recent observations of secretion of interleukin-6 by adipose tissue, combined with the actions of adipose tissue-expressed tumor necrosis factor-alpha in obesity-induced insulin resistance, could underlie the associations of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease.
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PMID:Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? 1018 59

Highly-active antiretroviral therapy (HAART) has lead to a dramatic decrease in the morbidity of patients infected with the human immunodeficiency virus (HIV). However, metabolic side effects, including lipodystrophy-associated (LD-associated) dyslipidemia, have been reported in patients treated with antiretroviral therapy. This study was designed to determine whether successful HAART was responsible for a dysregulation in the homeostasis of tumor necrosis factor-alpha (TNF-alpha), a cytokine involved in lipid metabolism. Cytokine production was assessed at the single cell level by flow cytometry after a short-term stimulation of peripheral blood T cells from HIV-infected (HIV(+)) patients who were followed during 18 months of HAART. A dramatic polarization to TNF-alpha synthesis of both CD4 and CD8 T cells was observed in all patients. Because it was previously shown that TNF-alpha synthesis by T cells was highly controlled by apoptosis, concomitant synthesis of TNF-alpha and priming for apoptosis were also analyzed. The accumulation of T cells primed for TNF-alpha synthesis is related to their escape from activation-induced apoptosis, partly due to the cosynthesis of interleukin-2 (IL-2) and TNF-alpha. Interestingly, we observed that LD is associated with a more dramatic TNF-alpha dysregulation, and positive correlations were found between the absolute number of TNF-alpha CD8 T-cell precursors and lipid parameters usually altered in LD including cholesterol, triglycerides, and the atherogenic ratio apolipoprotein B (apoB)/apoA1. Observations from the study indicate that HAART dysregulates homeostasis of TNF-alpha synthesis and suggest that this proinflammatory response induced by efficient antiretroviral therapy is a risk factor of LD development in HIV(+) patients.
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PMID:Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. 1080 87

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.
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PMID:Gene polymorphisms in the TNF locus and the risk of myocardial infarction. 1111 69

The pathophysiology of coronary atherosclerosis is complex and multifactorial. The probability of the development of symptomatic coronary heart disease may be predicted by standard risk factor stratification involving hypertension, dyslipidemia, age, positive family history, and diabetes. However, risk factor stratification has been demonstrated to have significant limitations in the individual patient, which has generated a search for more specific and sensitive markers. Evidence is increasing that atherosclerosis is a disease characterized by inflammation, beginning with the earliest identifiable lesion (fatty streak) to the advanced vulnerable plaque. Clinical markers of inflammation, including C-reactive protein, modified low-density lipoprotein, homocysteine, tumor necrosis factor, and thermogenicity, have been identified as emerging risk factors that may add prognostic information in patient management. This review centers on inflammation as a potential pathogenetic factor in atherosclerosis and the role that clinical markers may play in the identification of patients at risk.
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PMID:Atherosclerosis and inflammation. 1182 71

Insulin resistance is associated with hypertension, obesity, dyslipidemia, and type 2 diabetes. It is well known that tumor necrosis factor (TNF)-alpha is one of the factors linked to obesity-induced insulin resistance; however, there have been no reports on the role of TNF-alpha in insulin resistance in nonobese insulin-resistant hypertensives. We tested the hypothesis that TNF-alpha affects insulin resistance in nonobese insulin-resistant hypertensive fructose-fed rats (FFR) and that a TNF-alpha--converting enzyme (TACE) inhibitor that blocks TNF-alpha secretion improves insulin resistance in FFR. Six-week-old male Sprague-Dawley rats were fed either standard chow (control) or fructose-rich chow (FFR) for 6 weeks. For the last two weeks of a six-week period of either diet, the rats were treated with a vehicle (control or FFR) or a TACE inhibitor (100 mg/kg/d of KB-R7785; FFR+TACE-I) in peritoneal injection. At the age of 12 weeks, insulin sensitivity was assessed in all conscious rats by the euglycemic hyperinsulinemic glucose clamp technique. While FFR had higher blood pressure than the control rats (P<0.01), the TACE inhibitor did not change blood pressure. Insulin sensitivity (M-value) was reduced in FFR compared with that in the control rats (16.7 +/- 1.1 mg/kg per min and 10.3 +/- 0.6 mg/kg per min in the control rats and FFR, respectively, P<0.001), and the TACE inhibitor improved insulin sensitivity to the level of the control rats (14.3 +/- 1.2 mg/kg per min in FFR+TACE-I, P<0.01). These data indicate that TNF-alpha plays a major role in insulin resistance in nonobese insulin-resistant models and also suggest that TACE would be a good target for controlling insulin resistance not only in obese models but also in nonobese insulin-resistant models.
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PMID:Effect of TNF-alpha--converting enzyme inhibitor on insulin resistance in fructose-fed rats. 1188 11

Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension. Obesity, especially visceral adiposity, is negatively correlated with insulin sensitivity. The release of free fatty acids from adipocytes can block insulin-signaling pathways and lead to insulin resistance. In addition, recently identified adipocyte-specific chemical messengers, the adipocytokines, such as tumor necrosis factor-alpha, adiponectin, and resistin, appear to modulate the underlying insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or type 2 diabetes can result. The thiazolidinediones are potent peroxisome proliferator-activated receptor-gamma agonists and directly improve insulin resistance and glycemic control in patients with type 2 diabetes. Increasing evidence supports the early use of thiazolidinediones for preventing, delaying, or treating diabetes by improving insulin sensitivity and beta-cell insulin secretion.
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PMID:Insulin resistance as the core defect in type 2 diabetes mellitus. 1223 Oct 73

Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-alpha, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.
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PMID:An adipocentric view of signaling and intracellular trafficking. 1239 77

Insulin resistance and/or compensatory hyperinsulinemia are associated with hypertension, obesity, dyslipidemia, and glucose intolerance. Insulin resistance and hyperinsulinemia are considered to increase blood pressure through sympathetic nervous system activation, renin-angiotensin system stimulation, and vascular smooth muscle cell proliferation. Leptin, magnesium ions, nitric oxide, endothelin, peroxisome proliferator-activated receptor gamma, and tumor necrosis factor-alpha also modulate blood pressure. Decreasing insulin resistance by lifestyle modification including diet, weight loss, and physical exercise has been shown to reduce blood pressure. Angiotensin-converting enzyme inhibitors have a beneficial effect on insulin resistance. On the other hand, the angiotensin II antagonist, losartan, does not affect insulin sensitivity. The selective alpha1-blockers have a favorable metabolic profile producing increases in insulin sensitivity. A short-acting type calcium channel blocker seems to decrease insulin sensitivity. On the other hand, long-acting type calcium channel blockers improve insulin sensitivity. Thiazide diuretics and most of the beta-blockers decrease insulin sensitivity. Vasodilatory beta-blockers have been reported to improve insulin sensitivity. Use of low-dose diuretics avoids the adverse effects seen with conventional doses.
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PMID:Hypertension and insulin disorders. 1241 78

Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-a in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome.
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PMID:Insulin resistance in HIV-related lipodystrophy. 1264 10

The simultaneous presence of various cardiovascular risk factors in the same individual is not rare, even in the pediatric age group. The clustering of risk factors can be termed insulin resistance syndrome (IRS) because of the putative central role of tissue insulin insensitivity in the background of the inter-related metabolic disturbances. Fasting hyperinsulinemia, impaired glucose tolerance, dyslipidemia, and hypertension are considered to represent the basic abnormalities of IRS. The most prevalent related disturbances are increased plasma levels of plasminogen activator inhibitor-1, fibrinogen, uric acid, homocysteine, and C-reactive protein, as well as visceral adiposity, microalbuminuria, disturbed essential fatty acid metabolism, low availability of lipid-soluble antioxidant vitamins, and enhanced expression of tumor necrosis factor-alpha in adipose tissues. Certain genetic abnormalities have been associated with IRS, but explain only a small part of the variability in insulin resistance. The exact prevalence of IRS in children remains to be defined; it was found to be 9% in one survey among children with obesity seeking medical attention. Modification of lifestyle, i.e. reduction of energy intake and enhancement of physical activity, are unquestionable prerequisites for long-term success in the management of IRS. In at least two randomized controlled studies, metformin proved to be clinically effective in increasing insulin sensitivity in hyperinsulinemic, nondiabetic adolescents. Thiazolidinediones have been successfully tested for the treatment of insulin resistance in adults, but not in children as yet. Prevention of the development of IRS in children is obviously of great significance for the health status of the community. However, the efficacy of various preventive approaches should be investigated further in carefully designed controlled trials.
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PMID:Insulin resistance syndrome in children : pathophysiology and potential management strategies. 1271 16


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