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)

Bearing in mind the importance of upper-body obesity for the insulin resistance (or metabolic) syndrome and the abnormalities in free fatty acid metabolism associated with this disorder, the regulation of lipolysis in isolated subcutaneous adipocytes was investigated in 13 72-yr old upper-body obese men with insulin resistance and glucose intolerance and in 10 healthy 72-yr-old men. There was a marked resistance to the lipolytic effect of noradrenaline in the metabolic syndrome due to defects at two different levels in the lipolytic cascade. First, an 80-fold decrease in sensitivity to the beta 2-selective agonist terbutaline (P < 0.001) which could be ascribed to a 50% reduced number of beta 2-receptors (P < 0.005) as determined with radioligand binding. The groups did not differ as regards dobutamine (beta 1) or clonidine (alpha-2) sensitivity, nor beta 1-receptor number. The mRNA levels for beta 1- and beta 2-receptors were similar in the two groups. Second, the maximum stimulated lipolytic rate was markedly reduced in the metabolic syndrome. This was true for isoprenaline (nonselective beta-agonist), forskolin (activating adenylyl cyclase), and dibutyryl cAMP (activating protein kinase). In regression analysis, the observed abnormalities in lipolysis regulation correlated in an independent way with the degree of glucose intolerance (r = -0.67) and beta 2-receptor number with insulin resistance (r = 0.67). In conclusion, the results of this study indicate the existence of lipolytic resistance to catecholamines in the adipose tissue of elderly men with the metabolic syndrome, which may be of importance for impaired insulin action and glucose intolerance. The resistance is located at a posttranscriptional level of beta 2-receptor expression and at the protein kinase-hormone sensitive lipase level.
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PMID:Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. 820 Sep 97

The classic centrally acting antihypertensives such as clonidine, guanfacine and alpha-methyl-DOPA (via its active metabolite alpha-methyl-noradrenaline) induce peripheral sympathoinhibition and a fall in blood pressure as a result of alpha2-adrenoceptor stimulation in the brain stem. These drugs have lost much of their clinical importance because of their unfavourable side-effects (sedation, dry mouth, impotence), which are also mediated by alpha2-adrenoceptors, although in other anatomical regions. Moxonidine and rilmenidine are the examples of a new class of centrally acting antihypertensives, which cause peripheral sympathoinhibition mediated by imidazoline (I1)-receptors in the rostral ventromedulla (RVLM). Their side-effect profile appears to be better than that of clonidine and alpha-methyl-DOPA, probably because of a weaker affinity for alpha2-adrenoceptors. The mode of action, haemodynamic profile, antihypertensive efficacy and adverse reactions of the classic and newer centrally acting antihypertensives are the subject of the present survey. Attention is also paid to other therapeutic applications of centrally acting antihypertensives, such as congestive heart failure and the metabolic syndrome.
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PMID:Centrally acting antihypertensive drugs. Present and future. 1042 8

The metabolic syndrome is characterized by a clustering of cardiovascular risk factors including type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity. Elevated plasma insulin and urinary norepinephrine (noradrenaline) and reduced urinary epinephrine (adrenaline) excretion are associated with obesity in Caucasian populations. We examined the interrelationships between obesity, plasma insulin, and urinary catecholamine excretion in Chinese subjects with various components of the metabolic syndrome. A total of 577 Chinese subjects (aged 38 +/- 10 years; 68% with type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria and 32% healthy subjects) were studied, all of whom had a plasma creatinine less than 150 micromol/L. The blood pressure, height, weight, waist and hip circumference, and fasting plasma glucose, insulin, lipid, and creatinine levels were measured. A 24-hour urine sample was collected for measurement of albumin and catecholamine excretion. The body mass index (BMI) and waist circumference were used as measures of general and central obesity, respectively. The insulin resistance index was estimated by the calculated product of fasting plasma insulin and glucose concentrations. Patients with an increasing number of components of the metabolic syndrome (type 2 diabetes mellitus, hypertension, dyslipidemia, obesity, and/or albuminuria) were more obese, hyperglycemic, dyslipidemic, and albuminuric and had higher blood pressure, plasma insulin, insulin resistance indices, and 24-hour urinary norepinephrine excretion but lower urinary epinephrine output (all P < .005). Increasing quintiles of BMI in the whole population or waist circumference in both sexes were associated with increasing trends for adverse lipid profiles, plasma insulin, insulin resistance indices, and urinary norepinephrine excretion but a decreasing trend for urinary epinephrine output (all P < .001). There were close associations between age, obesity, blood pressure, fasting plasma glucose, lipid, insulin, insulin resistance indices, and urinary catecholamine excretion. Using stepwise multiple regression analysis (all P < .001), 34% of the variability of the BMI and 45% of that of the waist circumference were independently related to gender (waist higher in males and BMI higher in females), increased plasma insulin, triglyceride, and urinary norepinephrine excretion, and decreased high-density lipoprotein (HDL) cholesterol and urinary epinephrine output. In Chinese subjects with different manifestations of the metabolic syndrome, hyperinsulinemia, insulin resistance, elevated norepinephrine, and reduced epinephrine excretion were closely associated with general and central obesity. Based on these findings, we postulate that complex interactions between the insulin and sympathoadrenal systems may lead to the development of obesity and the metabolic syndrome.
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PMID:Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese. 1122 19

The beta(3)-adrenergic receptor (beta(3)AR) plays a critical role in lipid metabolism, and thus alterations in its function may be involved in the metabolic syndrome. Indeed, we have found previously that the Trp64Arg amino acid variant of the beta(3)AR is associated with hypertension and higher serum triacylglycerol levels in the Sardinian population. The aim of the present study was to evaluate the effect of the Trp64Arg beta(3)AR variant on the regulation of triacylglycerol levels and blood pressure during the exogenous infusion of noradrenaline. We studied groups of non-diabetic normotensive subjects: eight with the wild-type Trp64Trp beta(3)AR and eight with the Trp64Arg variant. The subjects each received, on two different days (randomized, double-blind fashion), a 4 h infusion of either noradrenaline (0.147 nmol.min(-1).kg(-1)) or Emagel (subjects had fasted for at least 12 h). The only available subject with a homozygous mutant Arg64Arg beta(3)AR was also studied. Blood pressure was measured every 10 min using a sphygmomanometer, and blood samples were taken every 30 min from the contralateral vein for biochemical determinations. After a 4 h noradrenaline infusion, significant increases in diastolic blood pressure (from 83+/-2 to 91+/-3 mmHg; P <0.01) and serum triacylglycerol levels (from 1.69+/-0.4 to 1.79+/-0.6 mmol/l; P <0.05) were observed compared with basal values in subjects with the Trp64Arg beta(3)AR variant, whereas subjects with the Trp64Trp beta(3)AR did not show any significant change over the infusion period. Glycaemia had increased significantly only at the end of the first 1 h of infusion in subjects with the Trp64Arg variant (from 5.0+/-0.1 to 5.8+/-0.3 mmol/l; P <0.05), with no significantly different behaviour compared with those subjects with the Trp64Trp beta(3)AR during the remaining infusion period. The effects of noradrenaline infusion were more marked in the subject with the Arg64Arg variant. In conclusion, our data indicate that the Trp64Arg amino acid variant of the beta(3)AR confers increased sensitivity to the pressure effect of noradrenaline. Moreover, this variant also influences blood triacylglycerol levels and, to a degree, glucose metabolism.
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PMID:The Trp64Arg beta3-adrenergic receptor amino acid variant confers increased sensitivity to the pressor effects of noradrenaline in Sardinian subjects. 1224 39

In many industrialized nations, obesity is now considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as the metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia and hypertension, which are all recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public health problem. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining bodyweight loss. For example, phentermine may result in modest bodyweight loss through suppression of appetite, but potential cardiovascular adverse effects exist and the efficacy is mainly short-term. Sibutramine, an inhibitor of serotonin and norepinephrine (noradrenaline) reuptake, may increase satiety and result in modest bodyweight loss. However, cardiovascular adverse effects may occur in susceptible patients. Nonetheless, sibutramine is one of the few drugs that has been approved by the US Food and Drug Administration (FDA) for bodyweight loss. Orlistat, a lipase inhibitor, is also approved by the FDA for bodyweight loss but may have bothersome gastrointestinal adverse effects, especially among patients who do not adhere to the recommended low-fat diet. Ongoing studies continue to evaluate other drug treatments that may result in bodyweight reduction through a number of different mechanisms. It is anticipated that the development of effective and well tolerated antiobesity drugs will elevate the pharmacologic treatment of obesity to the status of other cardiovascular risk factors and metabolic disorders. This may be especially important given that dyslipidemia, hypertension and type 2 diabetes mellitus are often secondary to, or exacerbated by, obesity.
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PMID:Pharmacotherapy of obesity: currently marketed and upcoming agents. 1472 70

The cardiovascular metabolic syndrome is characterized by the presence of several cardiovascular risk factors, including blood pressure (BP) elevation. We aimed to study the relation between mental stress, plasma catecholamines, BP and BP responses to mental stress in healthy young Caucasian men selected from different levels of screening BP. We included 98 men with high and 22 men with normal screening BP. They were examined at baseline in the laboratory, during a hyperinsulinemic, isoglycemic glucose clamp and during mental stress. At baseline in the laboratory, the men with high screening BP were characterized by elevated BP (p < 0.005) and plasma catecholamines (p < 0.05), but unaltered serum lipid levels compared to men with normal screening BP. After 2 h rest the differences almost disappeared, but could be reproduced during a mental arithmetic stress test. The men with elevated screening BP had significantly higher fasting glucose (p = 0.01) and lower insulin sensitivity (p < 0.005). In a multiple regression model, norepinephrine during mental stress (R2 = 0.10, p < 0.05) was the main variable to retrospectively explain allocation to the normal or high screening BP group. In conclusion, young healthy men with elevated screening BP are characterized by increased sympathetic activity and insulin resistance. Norepinephrine during mental stress is the main variable to explain allocation to the normal or elevated screening BP group. We have shown that one single screening BP measurement predicts insulin resistance and elevated fasting glucose in this cohort.
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PMID:High screening blood pressure is related to sympathetic nervous system activity and insulin resistance in healthy young men. 1518 11

As obese Zucker rats (OZR) manifesting the metabolic syndrome exhibit enhanced vascular adrenergic constriction and potentially an enhanced adrenergic activity vs. lean Zucker rats (LZR), this study tested the hypothesis that OZR exhibit an improved tolerance to progressive hemorrhage. Preliminary experiments indicated that, corrected for body mass, total blood volume was reduced in OZR vs. LZR. Anesthetized LZR and OZR had a cremaster muscle prepared for in situ videomicroscopy and had renal, splanchnic, hindlimb, and skeletal muscle perfusion monitored with flow probes. Arterial pressure, arteriolar reactivity to norepinephrine, and tissue/organ perfusion were monitored after either infusion of phentolamine or successive withdrawals of 10% total blood volume. Phentolamine infusion indicated that regional adrenergic tone under control conditions differs substantially between LZR and OZR, whereas with hemorrhage OZR exhibit decompensation in arterial pressure before LZR. Renal, distal hindlimb, and skeletal muscle perfusion decreased more rapidly and to a greater extent in OZR vs. LZR after hemorrhage. In contrast, hemorrhage-induced reductions in splanchnic perfusion in OZR lagged behind those in LZR, although a similar maximum reduction was ultimately attained. With increasing hemorrhage, cremasteric arteriolar tone increased more in OZR than LZR, and this increase in active tone was entirely due to an elevated adrenergic contribution. Norepinephrine-induced arteriolar constriction was greater in OZR vs. LZR under control conditions and during hemorrhage, with arterioles from OZR demonstrating early closure vs. LZR. These results suggest that a combination of reduced blood volume and elevated peripheral adrenergic constriction contribute to impaired hemorrhage tolerance in OZR.
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PMID:Impaired hemorrhage tolerance in the obese Zucker rat model of metabolic syndrome. 1622 76

Insulin sensitivity decreases for the first time in females at the time of menarche. A much more profound decrease in insulin sensitivity is observed at the end of pregnancy. This physiological insulin resistance is not accompanied by a rise in overall sympathetic activity as reflected in plasma noradrenaline levels, but there is evidence of moderate sympathetic overactivity in muscle and the heart. Pre-eclampsia is characterized by increased insulin resistance, sympathetic overactivity and a particular lipid profile. Thus it is the first manifestation of metabolic syndrome. Women with a history of pre-eclampsia have persistent insulin resistance after pregnancy associated with increased sympathetic activity of the cardiovascular system, and coronary artery disease later in life. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, and inflammation (measured via C-reactive protein) seems to be more strongly related to metabolic syndrome in women than in men. The clinical relevance of these observations remains to be shown. As the key factors of metabolic syndrome, such as insulin resistance and sympathetic overactivity, are closely inter-related, treatment should be aimed at cutting the vicious circle at many points: lifestyle modification (diet, increasing exercise) as a basis of therapy, use of insulin sensitizers (e.g. metformin) to decrease insulin resistance, central sympatholytics (e.g. moxonidine), and AT-receptor blockers or angiotensin-converting enzyme (ACE) inhibitors to overcome sympathetic overactivity, hypertension and inflammation.
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PMID:Insulin resistance and sympathetic overactivity in women. 1633 Oct 99

There is ample evidence from many epidemiological studies that lower urinary tract symptoms (LUTS) and sexual dysfunction are strongly linked, independently of age and comorbidities such as hypertension, diabetes, dyslipidaemia and coronary heart disease. However, a causal link between both conditions is not yet established. Four pathophysiological mechanisms currently support the relationship between LUTS and erectile dysfunction (ED): (i) The nitric oxide synthase (NOS)/NO theory; there is a reduction in NOS-containing nerves in the prostate and bladder/urethra in patients with bladder outlet obstruction (BOO), and that lack of NO or loss of protein kinase G causes ED; (ii) The autonomic hyperactivity and metabolic syndrome hypothesis: benign prostatic hyperplasia (BPH) may be part of the metabolic syndrome, which includes cardiovascular diseases (e.g. hypertension, ischaemic heart disease) and diabetes mellitus, known risk factors for ED. Hypertension, obesity, and hyperinsulinaemia have all been claimed to be associated with an increased sympathetic activity. Increased sympathetic activity is involved in LUTS/BPH and may have a role in ED/sexual dysfunction, with noradrenaline and alpha1-adrenoceptors representing a common link; (iii) the Rho-kinase activation/endothelin pathway; there can be increased Rho-kinase activity, and consequently calcium sensitivity of the contractile machinery, in prostate smooth muscle in BPH, the detrusor in BOO, corpora cavernosa in ED, and in the resistance vessels in hypertension. The actions of several factors beside noradrenaline (e.g. endothelin-1, angiotensin II), possibly involved in the increased smooth muscle activity found in both LUTS/BPH and sexual dysfunction, are dependent on Rho-kinase activity. Thus increased Rho-kinase activity might represent a common link between LUTS and sexual dysfunction; (iv) Pelvic atherosclerosis; animal models mimicking pelvic ischaemia and hypercholesterolaemia show similar smooth muscle alterations of the detrusor and corpora. Pelvic ischaemia may induce the biological modifications described above and may thus represent as well a common link between LUTS and sexual dysfunction. Studies treating one condition (e.g. ED) and measuring the impact on the other (e.g. LUTS) should further contribute to support this common link.
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PMID:Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. 1650 50

The metabolic syndrome, Type II (non-insulin-dependent) diabetes and obesity are associated with endothelial dysfunction and increased plasma concentrations of NEFAs (non-esterified fatty acids; free fatty acids). The present study was undertaken to define the inhibitory effects of saturated NEFAs on EDR (endothelium-dependent relaxation). Experiments were performed in rings of rabbit aorta to establish (i) dose-response relationships, (ii) the effect of chain length, (iii) the effect of the presence of double bonds, (iv) reversibility and time course of inhibition, and (v) the effect on nitric oxide production. Aortic rings were incubated (1 h) with NEFA-albumin complexes derived from lauric (C(12:0)), myristic (C(14:0)), palmitic (C(16:0)), stearic (C(18:0)) and linolenic (C(18:3)) acids. EDR induced by acetylcholine (0.1-10 mumol/l) was measured after pre-contraction with noradrenaline. Inhibition of EDR was dose-dependent (0.5-2 mmol/l NEFA), and the greatest inhibition (51%) was observed with stearic acid (2 mmol/l). Lauric acid had the smallest inhibitory effect. The inhibitory effects were always reversible and were evident after 15 min of incubation. Linolenic acid caused a significantly lower inhibition of EDR than stearic acid. SOD (superoxide dismutase) restored the inhibitory effect caused by NEFAs, suggesting the involvement of ROS (reactive oxygen species) in removing nitric oxide. The nitric oxide concentration measured after exposure of the rings to acetylcholine was lower after incubation with NEFAs than with Krebs buffer alone. This finding is consistent with removal of nitric oxide by ROS. This claim was supported by the demonstration of increased concentrations of nitrated tyrosine in the rings incubated with NEFAs.
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PMID:Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta. 1652 62


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