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)

We examined the effects of the potassium channel opener KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ) on cardiovascular metabolic syndrome (i.e., syndrome X), in rats. High-fructose diet rats developed hypertension, hypertriglyceridemia, increased total cholesterol/HDL (high-density lipoprotein)-cholesterol ratio, and hyperinsulinemia, KRN4884 (0.3-3.0 mg/kg, twice a day for 14 days, p.o.) alleviated the risk factors in fructose-fed rats. Furthermore, fructose-fed rats exhibited impairment of glucose tolerance and excess insulin secretion when loaded with glucose orally. Treatment with KRN4884 (1.0 mg/kg, twice a day for 14 days, p.o.) improved the glucose intolerance and inhibited hypersecretion of insulin in the glucose-loaded, fructose-fed rats. In contrast, KRN4884 (0.3-1.0 mg/kg, twice a day for 10 days, p.o.) did not affect serum triglyceride, cholesterol, glucose, or insulin concentrations in normal rats. LPL (lipoprotein lipase) activities in skeletal muscle and adipose tissue, and HTGL (hepatic triglyceride lipase) activity in liver were measured after administration of KRN4884 or vehicle twice a day for 14 days in fructose-fed rats. KRN4884 caused a significant increase in LPL activity in muscle and tended to increase LPL activity in adipose tissue in fructose-fed rats. HTGL was decreased in fructose-fed rats as compared with normal controls and was unaffected by KRN4884. These findings suggested that KRN4884 enhances insulin sensitivity and LPL activity, which are related to glucose and lipid metabolism and may be useful for the treatment of syndrome X.
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PMID:Effects of the K+ channel opener KRN4884 on the cardiovascular metabolic syndrome model in rats. 1067 63

Cardiovascular risk factors as well as morbidity and mortality from coronary heart disease among Turkish adults are herein reviewed. Lipids and lipoproteins are in focus, but other relevant risk factors are also discussed. Turks have distinctively low levels of total and high-density lipoprotein (HDL)-cholesterol, associated with high levels of hepatic lipase and fasting triglycerides. In addition, physical inactivity is common in both genders; close to 60% of men have the smoking habit, while obesity is common among Turkish women leading to a high prevalence of hypertension and diabetes in them. These factors probably account for the unanticipated fact that Turkish adults have the pattern of causes of death similar to a developed population, although the process of industrialization is ongoing, the structure of its population is young and overall cholesterol levels are comparatively low. The age-standardized coronary heart disease death rate is estimated to rank among the highest in Europe. The leading independent predictors of coronary events and death [systolic blood pressure, total/HDL-cholesterol ratio, followed by diabetes and (central) obesity] are related to the metabolic syndrome, estimated to prevail in 3-4% of adults aged 30 or over, and to underlie one-eighth of cases of coronary disease. Since several adverse factors exhibit a rising trend, primary and secondary prevention of cardiovascular disease must assume a much higher priority in various issues in Turkey than it currently does.
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PMID:Risk factors and cardiovascular disease in Turkey. 1168 77

BACKGROUND: The purpose of the investigation presented here was to study the effects of insulin therapy in type 2 diabetes mellitus (type 2 DM) not only on glycemic control but also on other components of the metabolic syndrome, including lipid metabolism, blood pressure, and body weight. METHODS: Twelve patients with type 2 DM were studied before and after replacement of sulphonylurea treatment with insulin for 4 months. RESULTS: Insulin therapy resulted in a significant decrease in fasting glucose levels by 26%; glycated hemoglobin decreased by 17% and fructosamine values by 19%. With insulin treatment, fasting plasma triglyceride levels decreased by 28% and total HDL cholesterol and HDL(3) cholesterol increased by 17 and 11%, respectively. Low-density lipoprotein (LDL) cholesterol showed no significant change. The magnitude of postprandial lipemia after ingestion of a standard fatty meal decreased by 38%. Insulin treatment was also accompanied by a 21% increase in lipoprotein lipase (LPL) activity in postheparin plasma and by a 20% increase in cholesteryl ester transfer protein (CETP) activity. Hepatic lipase activity was not changed significantly with insulin. Mean BMI decreased from 28.5+/-4.2 to 28.0+/-3.1 kg/m(2) (P=0.02), which is in keeping with the finding that peripheral insulin levels did not increase and which can be explained by the fact that the insulin regimen was combined with dietary counseling. Accordingly, blood pressure showed no significant change. CONCLUSION: Our study demonstrates that judicious replacement of sulfonylurea treatment with insulin therapy, together with dietary counseling, can result in a simultaneous improvement in the major stigmata of the metabolic syndrome, i.e. a significant improvement in glycemic control and lipid metabolism without unfavorable effects on body weight and blood pressure.
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PMID:Insulin improves fasting and postprandial lipemia in type 2 diabetes. 1206 22

Traditional risk factors for coronary artery disease (CAD) predict about 50% of the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined emerging risk factors for CAD, including small, dense low-density lipoprotein (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and low high-density lipoprotein (HDL). An increased number of small, dense LDL particles is often missed when the LDL cholesterol level is normal or borderline elevated. Small, dense LDL particles are present in families with premature CAD and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic syndrome, as defined by ATP III, incorporates a number of the components of these syndromes, including insulin resistance and intra-abdominal fat. Subclinical inflammation and elevated procoagulants also appear to be part of this atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by the liver and increased secretion of large, apolipoprotein (apo) B-100-containing VLDL is the primary metabolic characteristic of most of these patients. The TG in VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate-density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed further, resulting in the generation of LDL. The cholesterol esters in LDL are exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL. Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty acid trapping and retention by adipose tissue may result from a primary defect in the incorporation of free fatty acids into TGs. Alternatively, insulin resistance may promote reduced retention of free fatty acids by adipocytes. Both these abnormalities lead to increased levels of free fatty acids in plasma, increased flux of free fatty acids back to the liver, enhanced production of TGs, decreased proteolysis of apo B-100, and increased VLDL production. Decreased removal of postprandial TGs often accompanies these metabolic abnormalities. Genes regulating the expression of the major players in this metabolic cascade, such as LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the expression of small, dense LDL but these are not the major defects. New candidates for major gene effects have been identified on chromosome 1. Regardless of their fundamental causes, small, dense LDL (compared with normal LDL) particles have a prolonged residence time in plasma, are more susceptible to oxidation because of decreased interaction with the LDL receptor, and enter the arterial wall more easily, where they are retained more readily. Small, dense LDL promotes endothelial dysfunction and enhanced production of procoagulants by endothelial cells. Both in animal models of atherosclerosis and in most human epidemiologic studies and clinical trials, small, dense LDL (particularly when present in increased numbers) appears more atherogenic than normal LDL. Treatment of patients with small, dense LDL particles (particularly when accompanied by low HDL and hypertriglyceridemia) often requires the use of combined lipid-altering drugs to decrease the number of particles and to convert them to larger, more buoyant LDL. The next critical step in further reduction of CAD will be the correct diagnosis and treatment of patients with small, dense LDL and the dyslipidemia that accompanies it.
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PMID:Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. 1241 79

Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.
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PMID:Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet. 1263 74

Excessive weight gain in a subset of intensively treated Diabetes Control and Complications Trial (DCCT) subjects was associated with higher waist to hip ratio; higher triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (ApoB) in the presence of small-dense LDL; and decreased high-density lipoprotein 2 cholesterol (HDL2-C), suggesting that weight gain in these subjects resulted in higher intraabdominal fat (IAF), and an atherosclerotic dyslipidemia mediated through hepatic lipase activity (HL). Objectives were to investigate relationships between IAF, HL, and dyslipidemia and to relate IAF to previous body mass index change during the DCCT. Sixty-one subjects were studied approximately 4 yr after DCCT closeout. IAF was positively related to HL (P < 0.001). IAF positively correlated with logTG (P < 0.001) and ApoB (P < 0.001), and negatively with LDL relative flotation rate (P < 0.001) and logHDL2-C (P = 0.001). HL accounted for most of the relationship between IAF with logHDL2-C and LDL relative flotation rate, and none of the relationship between IAF and logTG or ApoB. DCCT-related body mass index change accounted for a significant portion of logIAF variance measured 4 yr later (P < 0.001). Elevated IAF in subjects with type 1 diabetes was related to an atherosclerotic dyslipidemia similar to that seen in individuals without diabetes who have metabolic syndrome. DCCT-related weight gain positively correlated with subsequent IAF.
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PMID:Visceral obesity, hepatic lipase activity, and dyslipidemia in type 1 diabetes. 1284 91

LDL (low-density lipoprotein) is the major carrier of cholesterol in human plasma, and as such is intimately involved in the process of atherosclerosis. The lipoprotein class comprises a number of distinct subfractions, and is commonly divided into large, intermediate and small sized particles. Small, dense LDLs are held to be particularly atherogenic, since these particles are retained preferentially by the artery wall, are readily oxidized and carry an enzyme believed to have an important role in atherosclerosis, i.e. lipoprotein-associated phospholipase A(2). Generation of small, dense LDL occurs by intravascular lipoprotein remodelling as a result of disturbances such as Type II diabetes, metabolic syndrome, renal disease and pre-eclampsia. The key predisposing factor is the development of hypertriglyceridaemia, in particular elevation in the plasma concentration of large, triacylglycerol-rich VLDL (very-low-density lipoprotein). This leads to the formation of slowly metabolized LDL particles (5-day residence time), which are subject to exchange processes that remove cholesteryl ester from the particle core and replace it with triacylglycerol. LDL, so altered, is a potential substrate for hepatic lipase; if the activity of the enzyme is high enough, lipolysis will generate smaller, denser particles. Correction of the dyslipidaemia associated with small, dense LDL is possible using fibrates and statins, and this may contribute to the clinical benefits seen with these drugs. Fibrates act to lower plasma triacylglycerol (VLDL) levels, and so correct the underlying metabolic disturbance. Statins remove VLDL particles via receptor-mediated pathways and reduce the residence time (and hence limit the potential for remodelling) of LDL in the circulation.
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PMID:Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. 1450 81

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.
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PMID:Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase. 1471 11

The prevalence of obesity has become increasingly common worldwide, in particular western countries. Obesity, together with insulin resistance, leads to metabolic syndrome in which other coronary risk factors including hyperlipidemia and hypertension cluster in one individual. Hyperlipidemia in metabolic syndrome is characterized increased triglyceride(TG), decreased HDL-C, and small dense LDL, called dyslipidemic triad. Dyslipidemia is attributable to increased flux of free fatty acids to the liver, which promotes TG synthesis, thus VLDL production. Increased VLDL, together with decreased lipoprotein lipase activity due to insulin resistance, causes accumulation of TG-rich lipoproteins, including proatherogenic remnants. Further, increased activities of cholesteryl ester transfer protein and hepatic triglyceride lipase results in low HDL-C and small dense LDL. Initial treatment should be directed to modify life style(weight loss and increased physical activity). Then, pharmacological intervention should be considered when the initial treatment is not fully successful. Fibrate derivatives are considered to be ideal to correct dyslipidemic triad. In addition, potent statins(HMG-CoA reductase inhibitor) can be alternative in metabolic syndrome subjects with elevated LDL-C levels.
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PMID:[Dyslipidemia in metabolic syndrome]. 1520 47

Postheparin plasma hepatic lipase (HL) activity has been shown to correlate with features of the metabolic syndrome and type 2 diabetes in humans. We examined HL postheparin plasma enzyme activity, hepatocyte mRNA, and protein mass in the insulin-resistant, fructose-fed Syrian golden hamster, and the response of the insulin-sensitizing peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Male Syrian golden hamsters were treated for 5 weeks with 1) normal diet (DIET group), 2) 60% fructose diet (FRUC group), or 3) 60% fructose and rosiglitazone (20 mmol . kg(-1) . day(-1)) (FRUC+RSG group). Hepatocyte HL mRNA, protein mass, and postheparin plasma HL activity were increased in FRUC compared with DIET hamsters. FRUC+RSG hamsters had partial normalization of HL mRNA, mass, and activity. There was a shift in the size of LDL particles from large to small in FRUC animals and a shift back to large LDL size in FRUC+RSG. This is the first demonstration that HL hepatocyte mRNA, mass, and plasma enzymatic activity increase concomitantly with induction of an insulin-resistant state and can be partially normalized by treatment with an insulin sensitizer. The increase in HL in insulin-resistant states may play an important role in the typical dyslipidemia of these conditions, and reduction of HL could explain some of the beneficial effects of insulin sensitizers on the plasma lipid profile.
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PMID:Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone. 1550 70


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