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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolic syndrome is a cluster of cardiovascular risk factors such as hypertriglyceridemia, hypertension, insulin resistance, based on visceral fat accumulation. Hyperuricemia is also thought as a one of the complications of metabolic syndrome. Hyperinsulinemia caused by insulin resistance induces the low excretion type hyperuricemia. In contrast visceral fat accumulation itself causes the hypersynthetic type hyperuricemia through increased fatty acid influx into the liver. Recently hyperuricemia is suggested to play a causal role for the metabolic syndrome. Xanthine oxido-reductase, a key enzyme of uric acid metabolism was indicated as one of regulatory factors in adipocyte differentiation. These studies may shed a new light on the understanding of the relationship between hyperuricemia and metabolic syndrome.
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PMID:[Relationship between hyperuricemia and metabolic syndrome]. 1840 29

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11beta-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11beta-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 microM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11beta-HSD1 inhibitor PF-877423. 11beta-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11beta-HSD1 oxo-reductase activity (from nil on day 0 to 5.9+/-1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11beta-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11beta-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.
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PMID:A novel selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis. 1843 59

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.
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PMID:7-oxysterols modulate glucocorticoid activity in adipocytes through competition for 11beta-hydroxysteroid dehydrogenase type. 1902 97

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown etiology and is considered to be the most common endocrine disorder in women of reproductive age. Two meta-analyses are presented here concerning the association of Plasminogen Activator Inhibitor 1 (PAI-1) 4G/5G polymorphism and the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with the risk of developing PCOS. Seven studies were included concerning PAI-1 (1538 cases, 710 controls) and six studies concerning MTHFR C677T (223 cases, 392 controls). Overall, a significant association was found for PAI-1, with the odds ratio (OR) for 4G carriers versus 5G homozygotes being equal to 1.600 (95% CI 1.052, 2.434) with strong evidence for dominant inheritance. There was however a large between-studies variability (I(2) = 67.3%). No evidence was found for association of MTHFR C677T polymorphism with PCOS (OR for the TT+CT versus CC comparison equal to 0.940 with 95% CI 0.561, 1.575). No evidence of publication bias was found in these meta-analyses. PAI-1 4G/5G polymorphism seems to be associated with the risk of developing PCOS. Further studies are needed in order to investigate the etiologic mechanism behind this association, as well as the interrelations with other components of the metabolic syndrome (hypertension, diabetes, etc.).
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PMID:Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome. 2270 71

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is a key enzyme in the conversion of cortisone to the functional glucocorticoid hormone cortisol. This activation has been implicated in several human disorders, notably the metabolic syndrome where 11 beta-HSD1 has been identified as a novel target for potential therapeutic drugs. Recent crystal structures have revealed the presence of a pronounced hydrophobic surface patch lying on two helices at the C-terminus. The physiological significance of this region has been attributed to facilitating substrate access by allowing interactions with the endoplasmic reticulum membrane. Here, we report that single mutations that alter the hydrophobicity of this patch (I275E, L266E, F278E, and L279E in the human enzyme and I275E, Y266E, F278E, and L279E in the guinea pig enzyme) result in greatly increased yields of soluble protein on expression in E. coli. Kinetic analyses of both reductase and dehydrogenase reactions indicate that the F278E mutant has unaltered K(m) values for steroids and an unaltered or increased k(cat). Analytical ultracentrifugation shows that this mutation also decreases aggregation of both the human and guinea pig enzymes, resulting in greater monodispersity. One of the mutants (guinea pig F278E) has proven easy to crystallize and has been shown to have a virtually identical structure to that previously reported for the wild-type enzyme. The human F278E enzyme is shown to be a suitable background for analyzing the effects of naturally occurring mutations (R137C, K187N) on enzyme activity and stability. Hence, the F278E mutants should be useful for many future biochemical and biophysical studies of the enzyme.
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PMID:Mutations of key hydrophobic surface residues of 11 beta-hydroxysteroid dehydrogenase type 1 increase solubility and monodispersity in a bacterial expression system. 1950 61

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), one of the isoforms of the 11beta-hydroxysteroid dehydrogenase enzymes, acts as an oxo-reductase to reactivate cortisone to cortisol, plays a critical role in tissue-specific corticosteroid reactions, and is therefore a key molecule associated with the development of metabolic syndrome. We investigated whether variations in the 11beta-HSD1 gene correlated with metabolic syndrome. We performed case-control study using a population-based urban Japanese cohort. Among 3005 urban residents, we examined 431 subjects diagnosed with metabolic syndrome according to the Japanese definition and 777 subjects with none of metabolic syndrome criteria as control. We genotyped three single nucleotide polymorphisms (SNPs) (+9410T>A, +17925C>T, +27447G>C) across the 11beta-HSD1 gene in them and analyzed the associations of SNPs and haplotypes with metabolic syndrome. The +9410A allele showed a tendency to metabolic syndrome (OR=1.5, 95%C.I., 1.0-2.2; P=0.041 and Bonferroni corrected P=0.123) without statistical significance. However, we could not find any significant association between metabolic syndrome and SNPs in the 11beta-HSD1 gene. Our findings indicate that polymorphisms and haplotypes in the 11beta-HSD1 gene are not significantly associated with metabolic syndrome in the Japanese population.
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PMID:Association study of 11beta-hydroxysteroid dehydrogenase type 1 gene polymorphisms and metabolic syndrome in urban Japanese cohort. 1953 62

The AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. As the name suggests, the AMPK is activated by increased intracellular concentrations of AMP, and is generally described as a "metabolite-sensing kinase" and when activated initiates steps to conserve cellular energy. Although there is a strong link between the activity of the AMPK and metabolic control in muscle cells, the activity of the AMPK in endothelial cells can be regulated by stimuli that affect cellular ATP levels, such as hypoxia as well as by fluid shear stress, Ca(2+)-elevating agonists, and hormones such as adiponectin. To date the AMPK in endothelial cells has been implicated in the regulation of fatty acid oxidation, small G protein activity and nitric oxide production as well as inflammation and angiogenesis. Moreover, there is evidence indicating that the activation of the AMPK may help to prevent the vascular complications associated with the metabolic syndrome.
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PMID:Activation and signaling by the AMP-activated protein kinase in endothelial cells. 1960 89

The inclusion of coronary heart disease (CHD) risk equivalents in the highest CHD risk category, in addition to the lowest low-density lipoprotein cholesterol (LDL-C) targets, has dramatically increased the number of persons eligible for highly effective risk reduction and lipid-lowering treatment. Two such high-risk groups are persons with diabetes and those with metabolic syndrome. These patients typically have a number of lipid and nonlipid risk factors that require aggressive intervention. In patients with diabetes, treatment with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors ("statins") to lower LDL-C levels and improve other lipid measures has been shown to produce protective benefits at least equal to those observed in nondiabetic patients. Although metabolic syndrome is not yet recognized as a CHD risk equivalent and use of Framingham risk scoring may not place some patients with the syndrome in the highest risk category, there is accumulating evidence that these patients are at very elevated risk and should be treated aggressively. Particular problems in risk assessment arise in immigrant groups such as South Asians, in whom traditional risk assessment may be inaccurate. In this article, Dr Deedwania examines the clinical evidence regarding cardiovascular risk associated with diabetes and metabolic syndrome and discusses current therapeutic options. Two case reports are presented, followed by roundtable discussions among the contributors to this Special Report.
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PMID:Treating dyslipidemia in high-risk patients: case reviews and discussion. 1966 72

Metabolic syndrome (MetS) are consist of central obesity, diabetes, dyslipidemia and hypertension. Previous studies have reported possible association of migraine and MetS were reviewed. Migraine is a prevalent disabling disorder and have been regarded as an episodic and functional disorder. However, recent evidence suggests that in some cases, the disease may follow a chronic and progressive course. On the basis of available evidence, obesity is considered to be associated with migraine frequency and progression. The association between diabetes and migraine is unclear. Similarly, association of migraine with hypertension is also unclear. Female migraineurs commonly have an unfavorable cholesterol profile, i.e. one with high total cholesterol and low HDL levels. Obesity can be considered as a proinflammatory state in which increased inflammatory mediators, vascular hyperreactivity, plasma calcitonin gene-related peptide (CGRP) concentrations and decreased adiponectin concentrations are observed. These alterations can cause an increase in the frequency of migraine attacks developed of central sensitization, and thereafter, chronic migraine. Migraine and obesity may share some neurobiological abnormalities. Orexins modulate both pain and metabolism. Dysfunction in the orexin pathways seems to be a risk factor for both conditions. The methylene-tetrahydrofolate reductase (MTHFR) gene and the angiotensin converting enzyme (ACE) gene exhibit polymorphism. C677Tmutation in the MTHFR gene and the D-allele of the ACE gene are the shared risk factors for the development of migraine and cardiovascular disease. Certain beta-blockers, Ca blockers, ACE inhibitors, and angionten II receptor blocker (ARB) have excellent efficacy in migraine prophylaxis. The pharmacological mechanism of these agents do not seem to stand on their antihypertensive effect, but the other mechanism of action. Appropriate meal, sleep, and exercise are important for the management of MetS and migraine headaches.
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PMID:[Metabolic syndrome and prevention of migraine headache]. 1988 41

Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes.
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PMID:11beta-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development. 2001 40


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