Gene/Protein Disease Symptom Drug Enzyme Compound
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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 plays an important role not only in the development and progression of diabetes mellitus but also in the establishment of metabolic syndrome. Improvement of insulin resistance is thus of great importance both in improving glucose metabolism and preventing atherosclerosis. Although HMG-CoA reductase inhibitors appear to favorably affect glucose metabolism, as indicated by the results of a subanalysis in the West of Scotland Coronary Prevention Study (WOSCOPS), their effects on glucose metabolism and insulin resistance have not been thoroughly investigated in animal models. In this study, the effects of atorvastatin on the glucose metabolism and insulin resistance of KK/Ay mice, an animal model of type II diabetes, were investigated. Atorvastatin significantly decreased the non-HDL-cholesterol level in the oral glucose tolerance test, inhibited increase in the 30-min glucose level, decreased plasma insulin levels before and 30 and 60 minutes after glucose loading, and decreased the insulin resistance index, compared with corresponding values in controls, indicating that atorvastatin appeared to improve glucose metabolism by improving insulin resistance. Northern blot analysis revealed decreases in levels of mRNA of sterol regulatory element binding protein-1 (SREBP-1) and glucose-6-phosphatase (G6Pase), and it may play a role in the improvement of glucose metabolism and insulin resistance.
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PMID:Effects of atorvastatin on glucose metabolism and insulin resistance in KK/Ay mice. 1594 17

In this study, we investigated the role of acyl-coenzyme A:diacylglycerol acyltransferase 2 (DGAT2) in glucose and lipid metabolism in obese mice by reducing its expression in liver and fat with an optimized antisense oligonucleotide (ASO). High-fat diet-induced obese (DIO) C57BL/6J mice and ob/ob mice were treated with DGAT2 ASO, control ASO, or saline. DGAT2 ASO treatment reduced DGAT2 messenger RNA (mRNA) levels by more than 75% in both liver and fat but did not change DGAT1 mRNA levels in either of these tissues, which resulted in decreased DGAT activity in liver but not in fat. DGAT2 ASO treatment did not cause significant changes in body weight, adiposity, metabolic rate, insulin sensitivity, or skin microstructure. However, DGAT2 ASO treatment caused a marked reduction in hepatic triglyceride content and improved hepatic steatosis in both models, which was consistent with a dramatic decrease in triglyceride synthesis and an increase in fatty acid oxidation observed in primary mouse hepatocytes treated with DGAT2 ASO. In addition, the treatment lowered hepatic triglyceride secretion rate and plasma triglyceride levels, and improved plasma lipoprotein profile in DIO mice. The positive effects of the DGAT2 ASO were accompanied by a reduction in the mRNA levels of several hepatic lipogenic genes, including SCD1, FAS, ACC1, ACC2, ATP-citrate lyase, glycerol kinase, and HMG-CoA reductase. In conclusion, reduction of DGAT2 expression in obese animals can reduce hepatic lipogenesis and hepatic steatosis as well as attenuate hyperlipidemia, thereby leading to an improvement in metabolic syndrome.
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PMID:Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. 1600 99

The metabolic syndrome and type 2 diabetes mellitus are both becoming more prevalent, and both increase the risk of cardiovascular disease. Many patients are not receiving appropriate treatment for the type of dyslipidemia that commonly occurs in these disorders--the so-called 'atherogenic lipid triad' of high serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome. Hypertriglyceridemia is a strong predictor of coronary heart disease. There is also an inverse relationship between serum levels of HDL-C and triglycerides in diabetic patients, with low serum HDL-C levels possibly representing an independent risk factor for cardiovascular disease. Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL and are less readily cleared. Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels. Even though modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk, therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor. This may leave substantial excess risk for cardiovascular disease in patients with these types of dyslipidemia. The results of recent trials evaluating HMG-CoA reductase inhibitors have been mixed, with two showing no significant effect on cardiovascular outcomes in subgroups of diabetic patients. The recent CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin can reduce cardiovascular events in a trial specifically designed for a diabetic population, though the population had to have at least one other risk factor in addition to diabetes mellitus. Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia that is generally associated with type 2 diabetes mellitus and the metabolic syndrome, as they are usually more effective than HMG-CoA reductase inhibitors for normalizing serum levels of HDL-C and triglycerides. Promising results have been obtained from several trials of fibric acid derivatives including the BIP (Bezafibrate Infarction Prevention) study and the VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial; gemfibrozil). The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, a clinical outcomes trial specifically designed to evaluate fenofibrate in a large population of patients with type 2 diabetes mellitus, many of whom have the metabolic syndrome, is underway. The FIELD trial results should shed light on the efficacy and safety of fenofibrate in reducing cardiovascular morbidity in diabetic and metabolic syndrome patients and on the safety profile of combination therapy with fenofibrate and a HMG-CoA reductase inhibitor.
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PMID:Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. 1625 26

Prolonged-release (PR) nicotinic acid (niacin) [Niaspan] is an oral, once-daily formulation of the lipid-modifying drug designed to produce less vasodilatory flushing than crystalline immediate-release (IR) nicotinic acid and less hepatotoxicity than previous sustained-release formulations of nicotinic acid.PR nicotinic acid appears to retain the same level of efficacy as crystalline IR nicotinic acid and be better tolerated than older nicotinic acid formulations. Nicotinic acid has beneficial effects on all traditional blood lipid and lipoprotein fractions and is the most effective agent for increasing high-density lipoprotein (HDL)-cholesterol (HDL-C) and reducing lipoprotein(a). The effects of PR nicotinic acid are often additive when used in combination with HMG-CoA reductase inhibitors (statins), making it a useful addition when lipid goals are not achieved with the usual statin monotherapy or when additional correction of a specific lipid abnormality is required. PR nicotinic acid also slows atherosclerotic progression and even appears to produce regression of atherosclerosis in patients on stable statin therapy. PR nicotinic acid is a logical drug choice for treating atherogenic dyslipidaemia commonly associated with type 2 diabetes mellitus and the metabolic syndrome, and has been shown to be effective in patients with diabetes without adversely affecting glycaemic control in the majority of patients. The incidence of vasodilatory flushing with PR nicotinic acid is lower than with IR nicotinic acid and it decreases substantially over time as tolerance develops. To date, there has been no clinically significant hepatotoxicity observed with PR nicotinic acid. Therefore, once-daily PR nicotinic acid appears to maximise the potential benefits of nicotinic acid, while minimising any historical tolerability or safety concerns.
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PMID:Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. 1639 85

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.
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PMID:Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly. 1668 57

Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-alpha. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.
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PMID:Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus. 1720 72

In order to characterize the metabolic syndrome it becomes necessary to establish a number of diagnostic criteria. Because of its impact on cardiovascular morbidity/mortality, considerable attention has been focussed on the dyslipidemia accompanying the metabolic syndrome. The aim of this review is to highlight the fundamental aspects of the pathophysiology, diagnosis, and the treatment of the metabolic syndrome dyslipidemia with recommendations to clinicians. The clinical expression of the metabolic syndrome dyslipidemia is characterized by hypertriglyceridemia and low levels of high-density lipoprotein-cholesterol (HDL-C). In addition, metabolic syndrome dyslipidemia is associated with high levels of apolipoprotein (apo) B-100-rich particles of a particularly atherogenic phenotype (small dense low-density lipoprotein-cholesterol [LDL-C]. High levels of triglyceride-rich particles (very low-density lipoprotein) are also evident both at baseline and in overload situations (postprandial hyperlipidemia). Overall, the 'quantitative' dyslipidemia characterized by hypertriglyceridemia and low levels of HDL-C and the 'qualitative' dyslipidemia characterized by high levels of apo B-100- and triglyceride-rich particles, together with insulin resistance, constitute an atherogenic triad in patients with the metabolic syndrome. The therapeutic management of the metabolic syndrome, regardless of the control of the bodyweight, BP, hyperglycemia or overt diabetes mellitus, aims at maintaining optimum plasma lipid levels. Therapeutic goals are similar to those for high-risk situations because of the coexistence of multiple risk factors. The primary goal in treatment should be achieving an LDL-C level of <100 mg/dL (or <70 mg/dL in cases with established ischemic heart disease or risk equivalents). A further goal is increasing the HDL-C level to >or=40 mg/dL in men or 50 mg/dL in women. A non-HDL-C goal of 130 mg/dL should also be aimed at in cases of hypertriglyceridemia. Lifestyle interventions, such as maintaining an adequate diet, and a physical activity program, constitute an essential part of management. Nevertheless, when pharmacologic therapy becomes necessary, fibrates and HMG-CoA reductase inhibitors (statins) are the most effective drugs in controlling the metabolic syndrome hyperlipidemia, and are thus the drugs of first choice. Fibrates are effective in lowering triglycerides and increasing HDL-C levels, the two most frequent abnormalities associated with the metabolic syndrome, and statins are effective in lowering LDL-C levels, even though hypercholesterolemia occurs less frequently. In addition, the combination of fibrates and statins is highly effective in controlling abnormalities of the lipid profile in patients with the metabolic syndrome.
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PMID:Management of dyslipidemia in the metabolic syndrome: recommendations of the Spanish HDL-Forum. 1735 65

The metabolic syndrome increases the risk of atherothrombotic cardiovascular disease (CVD) and diabetes. In turn, diabetes promotes the development of atheroma and is regarded as a coronary heart disease risk equivalent. A multifactorial therapeutic strategy is advocated for patients with the metabolic syndrome to improve cardiovascular risk factor profiles and to reduce the chances of developing type 2 diabetes. Individual components of the syndrome must be addressed using safe, efficacious, and cost-effective measures. There is general agreement that lifestyle modifications, including control of body weight, avoidance of central adiposity, adoption of an antiatherogenic diet, and regular physical activity, are crucial. However, as the magnitude of the individual components of the metabolic syndrome increases with time, lifestyle measures are often insufficient. An individual with metabolic syndrome will often require drug treatment for hyperglycemia, atherogenic dyslipidemia, and high blood pressure, together with antiplatelet therapy. Reducing the need for polypharmacy is an increasingly important consideration for clinicians and the pharmaceutical industry; to date, no single therapy has emerged that targets the root cause(s) of the syndrome. HMG-CoA reductase inhibitors are important agents that reduce CVD morbidity and mortality, in people with impaired fasting glucose or metabolic syndrome. Selective cannabinoid receptor antagonists appear promising because they improve or attenuate several key defects of the syndrome. Thiazolidinediones and metformin are presently licensed for treatment of type 2 diabetes but may prove to have a broader role in future. Novel insulin-sensitizing drugs are under investigation. Drugs that act to prevent or reverse endothelial dysfunction may be of particular utility in preventing cardiovascular disease, especially if initiated before tissue damage has become irreversible. Insulin therapy, which has antiinflammatory and endothelial protective properties, has been shown to reduce morbidity and mortality in high-risk nondiabetic patients during critical illness. Potential synergy between different classes of drugs with metabolic and/or cardiovascular protective properties merits further investigation.
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PMID:Prevention of cardiovascular complications of the metabolic syndrome: focus on pharmacotherapy. 1837 Jul 50

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
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PMID:Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. 1915 24

Hypertension and dyslipidemia frequently coexist in patients with progressive insulin resistance and thus constitute metabolic syndrome. We sought to determine the merits of combining an angiotensin II receptor blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor in treating this pathological condition. Five-week-old Otsuka Long-Evans Tokushima Fatty rats, a model of metabolic syndrome, were untreated or treated with olmesartan 3 mg kg(-1) per day, pravastatin 30 mg kg(-1) per day or their combination for 25 weeks. Long-Evans Tokushima Otsuka rats served as normal controls. The antihypertensive effect of olmesartan and the lipid-lowering properties of pravastatin were both augmented by the combination. The oral glucose tolerance test revealed that only the combined treatment significantly reduced the area under the time-glucose curve, which was accompanied by augmented adiponectin messenger RNA expression in epididymal adipose tissue. Although the total cardiac endothelial nitric oxide synthetase (eNOS) content did not significantly differ among the groups, the combined treatment significantly increased the content of dihydrofolate reductase, a key eNOS coupler. Dihydroethidium staining of the aorta showed that the combination most significantly attenuated superoxide production. Moreover, Azan-Mallory staining revealed that the combination most significantly limited the perivascular fibrosis and wall thickening of intramyocardial coronary arteries. In conclusion, the combination of olmesartan and pravastatin augmented adiponectin expression in white adipose tissue and improved glucose tolerance in a rat model of metabolic syndrome, which was associated with more significant ameliorations of cardiovascular redox state and remodeling than those by treatments with either agent alone.
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PMID:Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model. 1946 50


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