Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect the multitude of cardiovascular risk factors associated with the metabolic syndrome. To achieve maximal effectiveness, an ACC inhibitor should inhibit both the lipogenic tissue isozyme (ACC1) and the oxidative tissue isozyme (ACC2). Herein, we describe the biochemical and acute physiological properties of CP-610431, an isozyme-nonselective ACC inhibitor identified through high throughput inhibition screening, and CP-640186, an analog with improved metabolic stability. CP-610431 inhibited ACC1 and ACC2 with IC50s of approximately 50 nm. Inhibition was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. CP-610431 also inhibited fatty acid synthesis, triglyceride (TG) synthesis, TG secretion, and apolipoprotein B secretion in HepG2 cells (ACC1) with EC50s of 1.6, 1.8, 3.0, and 5.7 microm, without affecting either cholesterol synthesis or apolipoprotein CIII secretion. CP-640186, also inhibited both isozymes with IC50sof approximately 55 nm but was 2-3 times more potent than CP-610431 in inhibiting HepG2 cell fatty acid and TG synthesis. CP-640186 also stimulated fatty acid oxidation in C2C12 cells (ACC2) and in rat epitrochlearis muscle strips with EC50s of 57 nm and 1.3 microm. In rats, CP-640186 lowered hepatic, soleus muscle, quadriceps muscle, and cardiac muscle malonyl-CoA with ED50s of 55, 6, 15, and 8 mg/kg. Consequently, CP-640186 inhibited fatty acid synthesis in rats, CD1 mice, and ob/ob mice with ED50s of 13, 11, and 4 mg/kg, and stimulated rat whole body fatty acid oxidation with an ED50 of approximately 30 mg/kg. Taken together, These observations indicate that isozyme-nonselective ACC inhibition has the potential to favorably affect risk factors associated with the metabolic syndrome.
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PMID:Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. 1284 71

The recent focus on emerging cardiovascular risk factors, such as C-reactive protein, homocysteine, and small, dense low-density lipoprotein (LDL), may give the false impression that the current approach to the assessment of cardiovascular disease risk fails to identify a large section of the high-risk population. On the contrary, the new guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) propose classifying an enormous number of individuals, including people with any form of atherosclerotic disease, diabetes, and a combination of major risk factors, into the category of high risk (>20% likelihood of a major coronary event or stroke in 10 years). Considering the widespread prevalence of the metabolic syndrome-a high-risk condition characterized by mild hypertension, mild dyslipidemia, hyperglycemia, and visceral obesity-we may be faced with the challenge of implementing aggressive risk reduction therapies in as much as 30% of the adult US population. From the point of view of risk assessment, a practical approach is to follow the NCEP guidelines (ie, place patients with diabetes and those with atherosclerotic complications in the highest risk category), apply the Framingham calculation to determine risk in people with common risk factors, and initiate early intervention in people who have familial hypercholesterolemia (LDL cholesterol >200 mg/dL) or a family history of early cardiovascular disease. The emerging risk factors may be useful for further stratifying risk in individuals with intermediate risk and the presence of risk factors not included in the Framingham calculation.
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PMID:A practical approach to risk assessment to prevent coronary artery disease and its complications. 1286 51

The metabolic syndrome may be a common phenotype increasing risk for type 2 diabetes and cardiovascular disease. We assessed the prevalence and characteristics of the metabolic syndrome among population-based samples of 3,224 white subjects attending Framingham Offspring Study (FOS) exam 5 (1991-1995) and 1,081 non-Hispanic white and 1,656 Mexican-American subjects attending the San Antonio Heart Study (SAHS) phase II follow-up exam (1992-1996). Subjects were approximately 50% women, aged 30-79 years, without diabetes, and classified with the metabolic syndrome according to criteria for obesity, dyslipidemia, hyperglycemia, and hypertension proposed by the Third Report of the National Cholesterol Education Program's Adult Treatment Panel (ATP III) or the World Health Organization (WHO). We used regression models to estimate rates across ethnic groups and to assess the association of the metabolic syndrome with insulin resistance and predicted 10-year coronary heart disease (CHD) risk. Among FOS white subjects, the age- and sex-adjusted prevalence of the metabolic syndrome was 24% by both ATP III and WHO criteria; among SAHS non-Hispanic white subjects, 23 and 21%, respectively; and among SAHS Mexican-American subjects, 31 and 30%. Rates were highest among Mexican-American women (ATP III, 33%) and lowest among white women (21%). Subjects with the metabolic syndrome by ATP III criteria had higher age-, sex-, and ethnicity-adjusted levels of fasting insulin (11.3 micro U/ml), homeostasis model assessment of insulin resistance (2.7), and predicted CHD risk (11.8%) than those without the syndrome (5.9 micro U/ml, 1.3, and 6.4%, respectively; all P = 0.0001); differences were similar using WHO criteria. We conclude that the metabolic syndrome typically affects 20-30% of middle-aged adults in the U.S. By any criteria, subjects with the metabolic syndrome are more insulin resistant and at increased predicted risk for CHD versus those without the metabolic syndrome.
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PMID:Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. 1288 36

Using recently updated guidelines to evaluate and manage lipid disorders is discussed. Coronary heart disease (CHD) is a costly chronic condition associated with significant morbidity and mortality. Epidemiologic data further indicate that dyslipidemia and associated conditions, which may lead to CHD, are grossly undertreated. In 2001, the third National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) released updated guidelines for the evaluation and treatment of lipid disorders. Significant changes to the updated guidelines include designation of a CHD risk equivalent category identifying patients who require aggressive management, recommendation of Framingham-based CHD risk assessment in patients with multiple risk factors, revised target levels for several of the lipids and lipoproteins, and criteria for the identification of patients with the metabolic syndrome. Low-density lipoprotein cholesterol (LDL-C) continues to be the primary target of therapy. In addition, non-high-density lipoprotein cholesterol (HDL-C) is now defined as a secondary treatment target in patients with hypertriglyceridemia. Increased emphasis is placed on the metabolic syndrome, low HDL-C levels, and the presence of multiple and emerging risk factors in guiding the intensity of therapy. The NCEP ATP III guidelines acknowledge challenges in implementing and maintaining patient adherence to both lifestyle changes and pharmacotherapy regimens and provide strategies for increasing treatment success. Implementation of these new guidelines will likely enhance identification, management, and treatment success rates among patients at risk for CHD in the United States.
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PMID:Role of the National Cholesterol Education Program Adult treatment panel III guidelines in managing dyslipidemia. 1290 Oct 24

An opinion poll was carried out during the ALFEDIAM Congress Bordeaux 2003. One hundred and thirty-seven participants (mean age 43.6 +/- 8.3 years/sex Ratio approximately 1) among whom 22.6% run private practices, 51.8% work in hospitals and 21.3% are both private and hospital practitioners, have been questioned about their conception of the prevention of type 2 diabetes. Prediabetes is an acknowledged entity for 61% of the people surveyed. Two thirds use as a diagnostical criterion, moderate fasting hyperglycemia and/or a impaired glucose tolerance. Oral glucose tolerance test (OGTT) is still commonly practised among 51.9% but that is done sparingly only to confirm the diagnosis of diabetes in presence either of several risk factors or of a moderate fasting hyperglycemia. According to 70% of the answers, the detection of diabetes must be repeated every year among at risk subjects aged over 45. The metabolic syndrome is defined according to diverse criteria. The right definition of ATP III is given only in 5% of the cases. As regards the treatment, the combined requirements of physical activity and dietary rules are approved by 97% of the answers. The majority of the persons questioned in the survey consider that a slight loss of weight (less than 5% of the initial weight) is sufficient in a high risk risk individual.On the other hand, opinions are divided as regards the use of drugs at the pre-diabetes stage. Metformin is the only one that is accepted by more than 50% with a rate of 58.4% of positive answers, acarbose and orlistat rating respectively 37.2% and 35%. However a great majority (83.6%) are in favour of the reimbursement of antidiabetic drugs in this indication, for high risk individuals, provided a study has clearly demonstrated the efficiency of the molecule concerned.
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PMID:[French diabetologists' standpoint on the prevention of type 2 diabetes. A survey carried out during the ALFEDIAM Convention Bordeaux 2003]. 1290 21

Three definitions are currently proposed to define metabolic syndrome or insulinresistance syndrome (WHO, EGIR, NCEP-ATP III). These definitions are described and recent epidemiological data assessing the frequency of this syndrome in different populations according to these three definitions are presented. Observational studies indicates an increased cardiovascular morbidity and mortality risk in subjects with metabolic/insulin resistance syndrome. These findings imply to identify these at risk subjects and to define the optimal preventive management strategy.
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PMID:[Metabolic syndrome or insulin resistance syndrome. Recent epidemiological data]. 1291 57

All cells must maintain a high ratio of cellular ATP:ADP to survive. Because of the adenylate kinase reaction (2ADP <--> ATP + AMP), AMP rises whenever the ATP:ADP ratio falls, and a high cellular ratio of AMP:ATP is a signal that the energy status of the cell is compromised. The AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is switched on by a rise in the AMP:ATP ratio, via a complex mechanism that results in an exquisitely sensitive system. AMPK is switched on by cellular stresses that either interfere with ATP production (e.g. hypoxia, glucose deprivation, or ischemia) or by stresses that increase ATP consumption (e.g. muscle contraction). It is also activated by hormones that act via Gq-coupled receptors, and by leptin and adiponectin, via mechanisms that remain unclear. Once activated, the system switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes that are not essential for short-term cell survival, such as the synthesis of lipids, carbohydrates, and proteins. The AMPK cascade is the probable target for the antidiabetic drug metformin, and current indications are that it is responsible for many of the beneficial effects of exercise in the treatment and prevention of type 2 diabetes and the metabolic syndrome.
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PMID:Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. 1296 15

Considerable data on the pathophysiology, epidemiology, and treatment of dyslipidemia-induced coronary heart disease (CHD) have accumulated in recent years. These data have been assessed and incorporated into the guidelines of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III). A major focus of the new guidelines is the assessment of the near-term (i.e., 10-yr) risk of experiencing a CHD event and matching the intensity of treatment to this risk. Patients with diabetes and those with a greater than 20% 10-year risk of experiencing a CHD event have been elevated to the risk level of CHD equivalent. The ATP III guidelines also modify several lipid and lipoprotein classifications. A low-density lipoprotein cholesterol (LDL) level below 100 mg/dl is now considered optimum for all individuals. In addition, high-density lipoprotein cholesterol (HDL) and triglyceride cutoff points have been modified to reflect more accurately the risk associated with abnormalities in these lipoproteins. As with the previous guidelines, the primary target of therapy remains LDL. Therapeutic lifestyle changes consisting of diet, weight reduction, and increased physical activity should be included in all treatment regimens. Based on their potent LDL-lowering properties and their proven ability to decrease mortality in a variety of patient populations, statins are generally the first choice for pharmacologic therapy. A secondary target of therapy includes non-HDL goals for patients with high triglyceride levels and the metabolic syndrome, which is characterized by abdominal obesity, elevated triglyceride levels, low HDL levels, and insulin resistance. Management of these secondary targets includes weight reduction and increased physical activity, and treatment of the lipid and nonlipid risk factors. Overall, ATP III represents an aggressive approach to treating dyslipidemia, greatly extending the number of individuals who qualify for treatment.
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PMID:Update on the National Cholesterol Education Program Adult Treatment Panel III guidelines: getting to goal. 1452 36

Dyslipidemia is now recognized as a significant potential adverse event in HIV-positive patients who are on ART. The tide of evidence continues to flow between the shore of HIV being the primary factor behind increased cardiovascular risk in HIV-positive patients, and the ocean of HAART being the primary cause. However, there clearly is an association between long-term infection with HIV and metabolic abnormalities. HIV-infected adults should undergo evaluation and treatment based on the NCEP ATP III guidelines. The NCEP recommends non-pharmacologic interventions be given a thorough trial prior to consideration of drug therapy. The recommendations also stipulate that intensive therapy with lipid-lowering medications should be used in individuals with metabolic syndrome. This includes aggressive treatment of hypertension, diabetes, and dyslipidemia. The NCEP also emphasizes the importance of smoking cessation, weight reduction, increased physical activity, and a salubrious diet. The fundamental message still is that physicians must treat HIV infection first. The choice of ART depends on many patient-specific factors, of which cardiovascular risk is only one.
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PMID:Cardiovascular risk among HIV-positive patients on antiretroviral therapy. 1456 35

The metabolic syndrome is strongly related to visceral obesity and associated with a high risk of cardiovascular morbidity and mortality. Since the original description of Reaven in 1988, several working definitions have been proposed, especially by the World Health Organisation in 1998-99, the National Cholesterol Education Program (NCEP-ATP III) Expert Panel in the United States in 2001 and the European Group for the Study of Insulin Resistance (EGIR) in 2002. The present paper attempts at comparing these various definitions and at reporting epidemiological data both in North America and in Europe, especially in Belgium. The prevalence is generally higher in men than in women and strongly increases with age. Overall, one may estimate that around 20% of adults have a metabolic syndrome, which should therefore be considered as an important public health problem.
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PMID:[Metabolic syndrome: definitions and epidemiological data]. 1457 11


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