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

Abnormalities in fatty acid (FA) metabolism underlie the development of insulin resistance and alterations in glucose metabolism, features characteristic of the metabolic syndrome and type 2 diabetes that can result in an increased risk of cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist. AZ 242 dose-dependently reduced the hypertriglyceridemia, hyperinsulinemia, and hyperglycemia of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that treatment with AZ 242 (1 micromol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays, AZ 242 activated human PPARalpha and PPARgamma with EC(50) in the micro molar range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma effect, and caused up-regulation of liver fatty acid binding protein in HepG-2 cells, a PPARalpha-mediated effect. PPARalpha-mediated effects of AZ 242 in vivo were documented by induction of hepatic cytochrome P 450-4A in mice. The results indicate that the dual PPARalpha/gamma agonism of AZ 242 reduces insulin resistance and has beneficial effects on FA and glucose metabolism. This effect profile could provide a suitable therapeutic approach to the treatment of type 2 diabetes, metabolic syndrome, and associated vascular risk factors.
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PMID:AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. 1240 84

At a time when the lipid management guidelines give more and more emphasis to the identification and treatment of high-risk patients with the metabolic syndrome and diabetes, there is an obvious need to balance the known effects of low-density lipoprotein (LDL) lowering with the new evidence of clinical efficacy derived from the adjustment of high-density lipoprotein (HDL) and triglyceride levels. Whereas the statins remain the drug of choice for patients who need to reach the LDL goal, fibrate therapy may represent the best intervention for subjects with atherogenic dyslipidemia and an LDL already close to goal. In addition, the concomitant use of fibrates may significantly reduce cardiovascular risk in patients whose LDL is controlled by statin therapy. In this review, we evaluate the pharmacologic properties of the fibrate drugs, with particular attention to the effects of peroxisome proliferator activated receptor a activation in the control of dyslipidemia as well as in the attenuation of arterial inflammation. Clinical trials of fibrates, such as the Helsinki Heart Study, Veterans Affairs High-density lipoprotein Intervention Trial, Diabetes Atherosclerosis Intervention Study, and Bezafibrate Infarction Prevention trial, have conjured up a scenario for the clinical utility of fibrates and their possible superiority to statins in the management of obese, insulin-resistant, and diabetic patients presenting with near-goal LDL and inappropriate HDL and triglyceride levels.
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PMID:The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. 1502

Metabolic syndrome is characterized by the clustering of a number of metabolic abnormalities in the presence of underlying insulin resistance with a strong association with diabetes and cardiovascular disease morbidity and mortality. The disorder is defined in different ways, but the pathophysiology is attributable to insulin resistance. An increased release of free fatty acids (FFAs) from adipocytes block insulin signal transduction pathway, induce endothelial dysfunction due to increased reactive oxygen species (ROS) generation and oxidative stress. Dyslipidemia, associated with high levels of triglycerides and low concentrations of high density lipoproteins (HDLs), contributes to a proinflammatory state. Inflammation, the key pathogenic component of atherosclerosis, promotes thrombosis, a process that underlies acute coronary event and stroke. Tissue factor, a potent trigger of the coagulation cascade, is increased in diabetes with poor glycemic control. Therapeutic lifestyle changes (weight loss and physical activity) along with pharmacological interventions are recommended to prevent the complications of metabolic syndrome. In addition to statins, metformin, blood pressure lowering medications, interventions to increase HDLs are other important approaches to decrease the risk of cardiovascular disease. Furthermore, the peroxisome proliferator activated receptor (PPAR)-alpha and gamma agonists are potent anti-inflammatory and anti-atherogenic agents that could both improve insulin sensitivity and the long-term cardiovascular risk. In this review we focus on the molecular and pathophysiological basis of metabolic syndrome, which augments diabetes (insulin resistance) and the contribution of neovascularization in the plaque progression in diabetes, leading to rupture and coronary thrombosis.
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PMID:Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. 1691 71

Type-2 diabetes is characterized by obesity-related insulin resistance. Insulin resistance and accompanying hyperinsulinemia have been reported to play an important role in pathogenesis of the metabolic syndrome. Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid, has attracted considerable attention because of its potentially beneficial biological effects. Previous studies showed that dietary CLA alleviates diabetes through improvement of glucose tolerance and insulin-stimulated glucose transport activity in skeletal muscle of diabetic rats. Skeletal muscle plays an important role both in insulin-mediated glucose metabolism and in lipid metabolism. In the present study, we evaluated comprehensively the effect of dietary CLA on the expression of genes related to lipid metabolism and insulin sensitivity in the skeletal muscle of obese, diabetic Zucker rats. After 8 weeks of feeding, expression of lipogenic genes was decreased in tendency, while expression of lipolytic genes was markedly increased by dietary CLA. Additionally, expression of genes-related insulin sensitivity, such as adiponectin receptor 1, was significantly enhanced, and mRNA level of peroxisome proliferator activated receptor-alpha, known as a transcriptional factor related lipid metabolism and insulin signaling in skeletal muscle, was markedly increased in CLA-fed rats. We also showed that dietary CLA significantly decreased the level of tumor necrosis factor-alpha (TNF-alpha), associated with the development of insulin resistance, in the skeletal muscle of Zucker rats. We suppose that the attenuated TNF-alpha accumulation in skeletal muscle may contribute to the alteration of expression of several genes and the alleviation of insulin resistance in CLA-fed Zucker rats.
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PMID:Dietary conjugated linoleic acid lowered tumor necrosis factor-alpha content and altered expression of genes related to lipid metabolism and insulin sensitivity in the skeletal muscle of Zucker rats. 1700 73

Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or "lipid quartet"): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B)--emerged as the greatest "competitor" of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP - Bezafibrate Infarction Prevention study, HHS - Helsinki Heart Study, VAHIT--Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD--Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy--selected on the basis of their safety and effectiveness - may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.
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PMID:Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins. 1700 98

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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PMID:Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. 1751 19

HIV-associated lipodystrophy or lipoatrophy, unreported before the introduction of highly active antiretroviral therapy (HAART), was first described in 1998, and has a prevalence ranging from 18% to 83%. As in genetic lipodystrophy syndromes, fat redistribution may precede the development of metabolic complications (dyslipidemia, insulin resistance) in HIV-infected patients receiving HAART. The pathogenesis of HAART-associated lipodystrophy and metabolic syndrome is complex and a number of factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, and mitochondria. Protease inhibitors are responsible for a decrease in cytoplasmic retinoic-acid protein-1, in low density lipoprotein-receptor-related protein and in peroxisome proliferator activated receptor type-gamma. Nucleoside reverse transcriptase inhibitors, and thymidine analogues, are responsible for mitochondrial dysfunction as demonstrated by a decrease in subcutaneous adipose tissue mitochondrial DNA content. Both phenomena are responsible for a decreased differentiation of adipocytes, increased levels of free fatty acids and lipoatrophy. The increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-6 may further contribute in development of lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid dehydrogenase type-1, which converts inactive cortisone to active cortisol, resulting in increased lipid accumulation in adipocytes and insulin resistance. HAART drugs and inflammatory cytokines are associated with a decrease in adiponectin. The levels of adiponectin and adiponectin-to-leptin ratio correlate positively with insulin resistance in HIV-infected patients with lipodystrophy. HAART-associated metabolic syndrome is an increasingly recognized clinical entity. The atherogenic profile of this syndrome may increase the risk of cardiovascular disease even in young HIV-infected patients. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients receiving HAART.
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PMID:Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome. 1762 54

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. Plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.
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PMID:The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation. 1816 May 87

Despite medical advice, 20-30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3 mg/kg in Sprague Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization, and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 d of life (postnatal d 7), which corroborates with a decrease in gene expression of specific transcription factors such as pancreatic and duodenal homeobox 1, Pax-6, Nkx6.1, and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue weight at weaning (postnatal d 21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as CAAT-enhancer-binding protein-alpha, peroxisome proliferator activated receptor-gamma, and sterol regulatory element binding protein-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high-fat diet, cold intolerance, reduced physical activity, and glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development.
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PMID:Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. 1868 84

Increased renal expression of the angiotensin II, type-1 receptor (AT1R) has been associated with increased blood pressure (BP) and progression of renal disease. We tested whether common medications used to treat hypertension and the metabolic syndrome alter renal AT1R; and whether urine AT1R can be used as a reasonable noninvasive marker of renal levels in the obese Zucker rat, a model for human metabolic syndrome. Immunoblotting revealed that renal and urinary levels of AT1R were significantly higher in obese versus lean rats and correlated (R = 0.62, p < 0.05). Chronic treatment with BP lowering, candesartan, an AT1R antagonist, increased renal levels of AT1R in both lean (282% of lean controls) and obese (178% of obese controls) rats, but decreased urine AT1R levels in obese rats (72% of obese controls). Similarly, chronic treatment with rosiglitazone (RGZ), a peroxisome proliferator activated receptor (subtype gamma) agonist, significantly decreased urine (43% of obese controls) but not renal AT1R (105%) in obese rats. Blood pressure, measured by radiotelemetry, was significantly correlated in untreated and RGZ-treated rats to renal AT1R (R = 0.57, p = 0.0035). Finally, high- (4%) and medium- (0.4%) NaCl diets increased excretion of AT1R in obese rats to approximately 400% of low- (0.04%) NaCl diet. This effect was markedly blunted in lean rats. Overall, we demonstrate increased renal AT1R levels in obese rats. Urine AT1R correlated with renal levels only in the untreated state. Relative salt-sensitivity of AT1R excretion in obese, relative to lean rats, may have implications for both BP and renal disease in the metabolic syndrome.
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PMID:Regulation of angiotensin II type I receptor (AT1R) protein levels in the obese Zucker rat kidney and urine. 1917 59


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