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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agonism of peroxisome proliferator-activated receptor (PPAR) alpha, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPARalpha agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPARalpha agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg x kg(-1) x day(-1) KRP-101 (n = 5) or vehicle (n = 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPARalpha agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.
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PMID:A novel PPARalpha agonist ameliorates insulin resistance in dogs fed a high-fat diet. 1821 24

Type 2 diabetes mellitus, a global epidemic, is largely attributed to metabolic syndrome and its clustering of cardiovascular risk factors including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The two primary approaches to optimally control risk factors associated with metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with metabolic syndrome and type 2 diabetes is still dismal. Recent evidence suggests premises of the peroxisome proliferator-activated receptor (PPAR) ligands in the combat against type 2 diabetes and metabolic syndrome including obesity and insulin resistance. Three subtypes of the PPAR nuclear fatty acid receptors have been identified: alpha, beta/delta and gamma. PPARalpha is believed to participate in fatty acid uptake (beta- and omega-oxidation) mainly in the liver and heart. PPARbeta/delta is involved in fatty acid oxidation in muscle. PPARgamma is highly expressed in fat to facilitate glucose and lipid uptake, stimulate glucose oxidation, decrease free fatty acid level and ameliorate insulin resistance. Synthetic ligands for PPARalpha and gamma such as fibric acid and thiazolidinediones have been used in patients with type 2 diabetes and pre-diabetic insulin resistance with significantly improved HbA(1c) and glucose levels. In addition, nonhypoglycemic effects may be elicited by PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of PPAR agonists for the incidence of heart disease in metabolic syndrome and type 2 diabetes.
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PMID:Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. 1822 Jun 54

Dyslipidaemia is a common and consistent abnormality in insulin resistant subjects with obesity and type 2 diabetes mellitus associated with increased risk of cardiovascular disease. Lipoprotein metabolism is complex and abnormal plasma concentrations can result from alterations in the rates of production and/or catabolism of diverse lipoprotein particles. Our understandings of the dysregulation and therapeutic regulation of lipoprotein transport in insulin resistant states has relied on the application of advances in stable isotope and modelling methods. Dysregulation of lipoprotein metabolism in these circumstances may be caused by a combination of overproduction of VLDL apolipoprotein (apoB) B-100 and VLDL-apoC-III, decreased catabolism of apoB-containing particles, and increased catabolism of HDL apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance and accumulation of visceral fat. Several pharmacological treatments, such as statins, fibrates or fish oil can correct the dyslipidaemia by diverse kinetic mechanisms of action, including decreased secretion of apoB and apoC-III, and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Newer agents, including insulin sensitizers, cholesterol absorption inhibitors, CETP inhibitors, peroxisome proliferator-activated receptor-delta agonists and endocannabinoid-1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistant states; their mechanisms of action are at present being investigated. Rimonabant is the endocannabinoid receptor blocker shown to decrease cardiometabolic risk in insulin resistant subjects. The complementary mechanisms of action of different agents support the use of combination regimens in treating dyslipoproteinaemia in subjects with central obesity and type 2 diabetes.
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PMID:Pharmacological regulation of dyslipoproteinaemia in insulin resistant states. 1822 Sep 42

The metabolic syndrome (MetS) is defined by a set of metabolic risk factors, including insulin resistance, central obesity, dyslipidemia, hyperglycemia, and hypertension for type 2 diabetes and cardiovascular disease. Although both retrospective and prospective clinical studies have revealed that MetS is associated with chronic renal disease, even with a nondiabetic cause, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs), a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors, may play an important role in the pathogenesis of MetS. All three members of the PPAR nuclear receptor subfamily, PPARalpha, -beta/delta, and -gamma, are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, inflammation, and blood pressure. PPARs have also been implicated in many renal pathophysiological conditions, including diabetic nephropathy and glomerulosclerosis. Ligands for PPARs such as hypolipidemic PPARalpha activators, and antidiabetic thiazolidinedione PPARgamma agonists affect not only diverse aspects of MetS but also renal disease progression. Emerging data suggest that PPARs may be potential therapeutic targets for MetS and its related renal complications. This review focuses on current knowledge of the role of PPARs in MetS and discusses the potential therapeutic utility of PPAR modulators in the treatment of kidney diseases associated with MetS.
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PMID:PPARs and the kidney in metabolic syndrome. 1823 57

Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR-alpha agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR-gamma agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-alpha/gamma agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-delta and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.
PPAR Res 2008
PMID:Should We Use PPAR Agonists to Reduce Cardiovascular Risk? 1828 93

Nuclear hormone receptors, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and the farnesoid X receptor (FXR), are transcription factors involved in the regulation of essential metabolic functions, including glucose and lipid metabolism, reverse cholesterol transport, and the regulation of bile acids. This review summarizes new developments in the use of PPAR, LXR and FXR agonists for the treatment of obesity and cardiovascular diseases, including dyslipidemia and atherosclerosis. Currently available drugs and future areas of research for new therapies are also discussed.
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PMID:Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. 1831 60

The early nephropathy in obese, diabetic, dyslipidemic (ZS) rats is characterized by tubular lipid accumulation and pervasive inflammation, two critically interrelated events. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL) in vitro, change their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX-1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of ICAM-1 and focal adhesion kinase, which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor peroxisome proliferator-activated receptor-delta. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti-LOX-1 antibody. The data support the concept that tubular LOX-1 activation driven by lipid oxidants in the preurine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulointerstitial injury of obesity, diabetes, and dyslipidemia.
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PMID:LOX-1 and inflammation: a new mechanism for renal injury in obesity and diabetes. 1832 20

Trials have revealed that cardiovascular risk is not uniform in the population, but is distributed in a "risk pyramid." Diabetic patients with prior cardiovascular disease (CVD) are at greatest risk. Nondiabetic patients with CVD, diabetic patients without CVD, and subjects with the metabolic syndrome form the next three risk categories. The presence of insulin resistance-related metabolic abnormalities is a common denominator in this risk pyramid. Insulin resistance is a core defect in type 2 diabetes and the metabolic syndrome. Because insulin resistance may cause the atherogenic dyslipidemia that is commonly associated with these conditions, therapeutic strategies that combat insulin resistance could substantially reduce cardiovascular risk. Evidence suggests that defects in mitochondrial oxidative phosphorylation (which may be inherited, age related, or lifestyle acquired) may play a critical role in the pathogenesis of insulin resistance. Reduced mitochondrial oxidative phosphorylation can be partially reversed by improved diet, increased exercise, and administration of peroxisome proliferator-activated receptor-alpha agonists (omega-3 fatty acids and fibrates). Statin therapy has demonstrated clinical benefits in insulin-resistant patients but residual cardiovascular risk remains elevated. Fibrates also improve the lipid profile and reduce cardiovascular risk in a variety of insulin-resistant populations. Affected individuals should be targeted for therapeutic lifestyle intervention. Patients with atherogenic dyslipidemia who have developed insulin resistance, the metabolic syndrome, or type 2 diabetes should receive more intensive interventions including, where appropriate, statin-fibrate combination therapy, to comprehensively modify the lipid profile together with aggressive control of blood pressure and glucose to minimize risk in this very high-risk population.
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PMID:New concepts in dyslipidemia in the metabolic syndrome and diabetes. 1837 Jul 48

In many traditional schools of medicine it is claimed that a balanced modulation of several targets can provide a superior therapeutic effect and decrease in side effect profile compared to a single action from a single selective ligand, especially in the treatment of certain chronic and complex diseases, such as diabetes and obesity. Diabetes and obesity have a multi-factorial basis involving both genetic and environmental risk factors. A wide array of medicinal plants and their active constituents play a role in the prevention and treatment of diabetes. Salacia roots have been used in Ayurvedic medicine for diabetes and obesity since antiquity, and have been extensively consumed in Japan, the United States and other countries as a food supplement for the prevention of obesity and diabetes. Recent pharmacological studies have demonstrated that Salacia roots modulate multiple targets: peroxisome proliferator-activated receptor-alpha-mediated lipogenic gene transcription, angiotensin II/angiotensin II type 1 receptor, alpha-glucosidase, aldose reductase and pancreatic lipase. These multi-target actions may mainly contribute to Salacia root-induced improvement of type 2 diabetes and obesity-associated hyperglycemia, dyslipidemia and related cardiovascular complications seen in humans and rodents. The results of bioassay-guided identification indicate that mangiferin, salacinol, kotalanol and kotalagenin 16-acetate are at least in part responsible for these multi-target regulatory activities of Salacia roots. The evidence suggests that this unique traditional medicine fulfills a multiple-target strategy in the prevention and treatment of diabetes and obesity. Although toxicological studies have suggested minimal adverse effects of the herbal medicine in rodents, a clinical trial is crucial to further confirm the safety of Salacia roots. In addition, further mechanistic studies are necessary in order to allow a better understanding of how use of Salacia root may interact with other therapeutic interventions.
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PMID:Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity. 1843 91

Cardiovascular disease (CVD) is the leading cause of death in the United States and many parts of the world. Potentially modifiable risk factors for CVD include tobacco use, physical inactivity, hypertension, elevated low-density lipoprotein cholesterol, and a cluster of interrelated metabolic risk factors. Over the last several decades, efforts to prevent or treat CVD risk factors have resulted in significantly lower rates of CVD-related mortality. However, many patients never achieve adequate control of CVD risk factors even when these factors have been identified. In addition, the growing prevalence of obesity and type 2 diabetes mellitus (DM) threatens to undermine the improvements in CVD that have been achieved. In the United States, approximately two thirds of adults are overweight or obese, and even modest excess body weight is associated with a significantly increased risk of CVD-related mortality. Lifestyle interventions to promote weight loss reduce the risk of CVD-related illness but are difficult for patients to sustain over long periods of time. The increased incidence of obesity has also contributed to significant increases in the prevalence of other important CVD risk factors, including hypertension, dyslipidemia, insulin resistance, and type 2 DM. Pharmacologic therapies are currently available to address individual CVD risk factors, and others are being evaluated, including endocannabinoid receptor antagonists, inhibitors of peroxisome proliferator-activated receptor subtypes alpha and gamma, and several agents that modulate the activity of glucagon-like peptide-1. The new agents have the potential to significantly improve several CVD risk factors with a single medication and may provide clinicians with several new strategies to reduce the long-term risk of CVD.
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PMID:Cardiovascular disease and modifiable cardiometabolic risk factors. 1845 39


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