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)

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

This study aimed to clarify whether high-risk premenopausal women have less atherogenic levels of markers of endothelial dysfunction, oxidation, thrombosis and inflammation, and adipokines than high-risk men of the same age. Thus, we studied levels of these markers and their determinants in 207 men and women aged 18 to 39 years with dyslipidemia and a family history of premature coronary heart disease. Women had favorable levels of E and P selectins, tumor necrosis factor alpha, tissue plasminogen activator, plasminogen activator inhibitor 1, thrombomodulin, thiobarbituric acid reactive substances, and adiponectin compared with men, but had higher levels of high-sensitivity C-reactive protein and leptin (all P < .05) and no difference in the L-arginine/asymmetric dimethyl arginine (ADMA) ratio. This ratio was higher among nonusers of hormonal contraception than among users (P = .02). In multivariate analyses, levels of intercellular adhesion molecule 1 and E selectin were associated with cigarette smoking and dietary sucrose (both P < .05), whereas the L-arginine/ADMA ratio was paradoxically associated with smoking (P < .05). Of 17 novel risk markers, 11 were associated with body mass index after adjustment for age, sex, smoking, and percentage of dietary energy from sucrose (regression coefficients, 0.14-0.62; all P < .05). In conclusion, the findings underscore the female advantage regarding determinants of novel risk markers in young adults at risk of coronary heart disease, although some endothelial dysfunction markers (cellular adhesion molecules, L-arginine/ADMA ratio) were not more favorable in women compared with men. Lifestyle factors including body mass index, dietary sucrose, smoking, and hormones were associated with levels of the markers independent of sex with body mass index being the most prominent factor.
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PMID:Do novel risk factors differ between men and women aged 18 to 39 years with a high risk of coronary heart disease? 1722 42

Neuropeptides play a pivotal role in the control of metabolic homeostasis. We aimed to evaluate the release of neuropeptides involved in the control of energy homeostasis in relation to metabolic status in aging humans. The study group consisted of 183 women: 75 centenarians (above 100 yrs old), 26 elderly women (below 70 yrs), 45 younger women (mean 26 yrs) and 37 obese women (mean 41.6 yrs). Fasting plasma concentration of leptin, adiponectin, ghrelin active, neuropeptide Y (NPY) and insulin were measured. Our results showed several differences in the metabolic and neurohormonal status in the centenarian group. The incidence of hypertension, glucose intolerance, insulin resistance and dyslipidemia was lower compared with obese women. Leptin and NPY concentrations were significantly lower than in elderly and obese subjects. Moreover, NPY level was higher than that in the younger group. Plasma adiponectin values were higher than in any of the other group. Insulin levels were significantly lower compared with the young and obese groups. Furthermore, a negative correlation was found between adiponectin and HOMA-IR, and adiponectin and insulin. Ghrelin active concentrations were significantly lower compared with the young subjects. However, ghrelin levels were higher than in obese subjects. We conclude that altered neuropeptide activity in centenarians may play a role in the mechanisms contributing to prolonged survival.
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PMID:Neuroendocrine control of metabolic homeostasis in Polish centenarians. 1722 87

The prevalence of obesity has been increasing dramatically in the last decades in the whole world, not only in industrialized countries but also in developing areas. A major complication of obesity is insulin resistance and type 2 diabetes. Diabetes is also rapidly increasing world-wide--reaching a prevalence in adults of approx. 5-6% in Central Europe and in the US, and more than 50% in specific, genetically prone populations. This article reviews pathogenetic mechanisms linking obesity and type 2 diabetes. Emphasis is placed on the observation that excessive amounts of adipocytes are associated with an impairment of insulin sensitivity, a key feature of the "metabolic syndrome". This is a cluster of metabolic abnormalities such as type 2 diabetes, hypertension and dyslipidemia; all of them are enhanced by the presence of visceral (abdominal) obesity and all contribute to the increased cardiovascular risk observed in these patients. Besides release of free fatty acids, adipocytes secrete substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. Increased turnover of free fatty acids interferes with intracellular metabolism of glucose in the muscle, and they exert lipotoxic effect on pancreatic beta-cells. The pre-receptor metabolism of cortisol is enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. A new class of anti-diabetic drugs (thiazolidinediones, or glitazones) bind to peroxisome proliferator activated receptor (PPAR-gamma) and lower thereby plasma free fatty acids and cytokine production in adipocytes, in addition to a decrease of resistin and an increase in adiponectin observed in animals, resulting in an overall increase in insulin sensitivity and in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance and prevent the development of diabetes should be a reduction in body weight in overweight subjects, and an increase in physical activity. There are now three published randomized controlled trials demonstrating that in high risk individuals, life style changes with modest weight lost, associated with diminished fat intake and an increase in fruit and vegetable consumption result in marked inhibition of the transition from the prediabetic state to manifest type 2 diabetes.
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PMID:From obesity to diabetes. 1724 79

Obesity, hypertension, dyslipidemia and glucose intolerance cluster in the insulin resistance syndrome. Angiotensin II receptor blockers (ARB) are able to reduce insulin resistance. Furthermore, among ARB, telmisartan displays the property of stimulating PPARgamma. The aim of the study was to examine if and to what extent treatment with irbesartan and telmisartan induces variations in metabolic parameters in insulin resistant, hypertensive subjects. Forty-six non diabetic, obese, insulin-resistant, hypertensive patients took part in the study. They were divided into 2 groups. Group A (23) was submitted to irbesartan 150 mg/day, Group B (23) to telmisartan 80 mg/day for 6 months. Adiponectin, glucose, cholesterol, triglycerides, free fatty acids (FFA), steady-state plasma insulin and glucose (SSPG), 24-hBP were determined at the beginning and at the end of the study. Both irbesartan or telmisartan reduced blood pressure and ameliorated the insulin sensitivity, with increased adiponectin values; in Group B, the amelioration of metabolic parameters was greater than in Group A and the reduction of blood pressure was related with variation of adiponectin levels. Data obtained showed that the antihypertensive action of telmisartan and irbesartan is associated with the amelioration of the metabolic picture. The greater impact on the improvement of the metabolic profile showed by telmisartan and the inverse correlation between adiponectin levels and blood pressure may be partly due to the action as partial PPARgamma agonist displayed by telmisartan.
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PMID:The effects of irbesartan and telmisartan on metabolic parameters and blood pressure in obese, insulin resistant, hypertensive patients. 1725 91

Fasudil, a Rho-kinase inhibitor, may improve insulin signaling. However, its long-term effect on metabolic abnormalities and its preventive effect on diabetic nephropathy are still unknown. We assessed these effects of fasudil in insulin-resistant diabetic rats, comparing them with those of an angiotensin II receptor blocker, olmesartan. Male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka, non-diabetic control, rats at 15 weeks of age were used. OLETF rats were randomized to receive a low or a high dose of fasudil or olmesartan for 25 weeks. To examine the therapeutic effects after the development of diabetes, OLETF rats at 30 weeks of age were given fasudil for 10 weeks. Administration of high-dose fasudil completely suppressed the development of diabetes, obesity, and dyslipidemia and increased serum adiponectin levels in OLETF rats. High-dose olmesartan also decreased hemoglobin A1c and increased serum adiponectin. There was a significant correlation between hemoglobin A1c and serum adiponectin or free fatty acid levels. The treatment with high-dose fasudil ameliorated proteinuria, glomerulosclerosis, renal interstitial fibrosis, and macrophage infiltration in OLETF rats. Olmesartan, even at the low dose, suppressed renal complications. The treatment with fasudil after the development of diabetes improved the metabolic abnormalities in OLETF rats, but could not suppress the progression of nephropathy. We conclude that the long-term treatment with fasudil prevents the development of diabetes, at least in part, by improving adipocyte differentiation in insulin-resistant diabetic rats. Early use of fasudil may prevent diabetic nephropathy.
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PMID:A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. 1733 27

It has been recently reported that activation of PPAR-delta, by specific agonists or genetic manipulation, alleviates dyslipidemia, hyperglycemia, and insulin resistance in animal models of obesity and type 2 diabetes. The purpose of the present study was to determine whether the PPAR-delta agonist has a direct effect on adipokines in visceral adipose tissue of rats and in cultured adipocytes. We examined the expression of visfatin, adiponectin, and resistin mRNA in visceral adipose tissue of Wistar rats fed a high-fat diet and 3T3-L1 adipocytes treated with PPAR-delta agonist (L-165041). Body weight and biochemical measurements were performed. Rats fed a high-fat diet showed a greater increase in body weight than those fed a standard diet (P<0.05), and treatment with L-165041 (10 mg/kg/day) significantly decreased weight gain (P<0.05). The concentration of total cholesterol was lower, and HDL cholesterol was higher in L-165041-treated rats (P<0.05). In the visceral adipose tissue of L-165041-treated rats, visfatin and adiponectin mRNA levels significantly increased compared to those of the untreated rats (P<0.05). However, the expression of resistin decreased in the L-165041-treated rats. Furthermore, in cultured 3T3-L1 adipocytes, the level of visfatin and adiponectin mRNA was up-regulated in response to L-165041 treatment for nine days. By contrast, resistin mRNA levels were down-regulated by L-165041 treatment. The present study provides a novel evidence to suggest that the PPAR-delta agonist has regulatory effects on a variety of adipokines, and these effects might explain some of their metabolic function.
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PMID:Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. 1741 7

Protease inhibitors, as part of highly active anti-retroviral therapy (HAART), have significantly increased the lifespan of human immunodeficiency virus (HIV) infected patients. Several deleterious side effects including dyslipidemia and lipodystrophy, however, have been observed with HAART. Women are at a higher risk of developing adipose tissue alterations and these alterations have different characteristics as compared to men. We have previously demonstrated that in mice the HIV protease inhibitor, ritonavir, caused a reduction in weight gain in females, but had no effect on male mice. In the present study, we examined the potential causes of this difference in weight gain. Low-density lipoprotein receptor (LDL-R) null mice or wild-type C57BL/6 mice, were administered 15 mug/ml ritonavir or vehicle (0.01% ethanol) in the drinking water for 6 weeks. The percent of total body weight gained during the treatment period was measured and confirmed that female LDL-R gained significantly less weight with ritonavir treatment than males. In wild type mice, however, there was no effect of ritonavir treatment in either sex. Despite the weight loss in LDL-R null mice, ritonavir increased food intake, but no difference was observed in gonadal fat weight. Serum leptin levels were significantly lower in females. Ritonavir further suppressed leptin levels in (p < 0.05). Ritonavir did not alter serum adiponectin levels in either gender. To determine the source of these differences, female mice were ovariectomized remove the gonadal sex hormones. Ovariectomy prevented the weight loss induced by ritonavir (p < 0.05). Furthermore, leptin levels were no longer suppressed by ritonavir (p < 0.05). This study demonstrates that gonadal factors in females influence the hormonal control of weight gain changes induced by HIV protease inhibitors in an environment of elevated cholesterol.
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PMID:Gender-specific effects of HIV protease inhibitors on body mass in mice. 1747 47

Diabetic patients have a 3-fold higher risk of developing atherosclerosis and its clinical complications as compared to non-diabetic individuals. Part of the cardiovascular risk associated with diabetes is probably due to genetic determinants influencing both glucose homeostasis and the development of atherosclerosis. However, type 2 diabetes frequently coexists with other cardiovascular risk factors like arterial hypertension, central obesity and dyslipidemia. Genetic variability affecting many areas such as lipid and energy metabolisms, hypertension and haemodynamic mechanisms, blood clotting homeostasis, inflammation, and matrix turnover in the vascular wall will have an impact on the development of macrovascular complications in diabetic patients. Adiponectin is abundantly secreted by adipocytes. It plays important roles in lipid and glucose metabolisms and has direct anti-inflammatory and anti-atherogenic effects. In this review, we summarize recent data from the literature suggesting an implication of allelic variations of the adiponectin gene (ADIPOQ) in the genetic determinants of cardiovascular disease in diabetic subjects.
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PMID:Adiponectin gene and cardiovascular risk in type 2 diabetic patients: a review of evidences. 1750 21

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.
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PMID:Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. 1759 67


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