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)

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.
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PMID:The neuroendocrine control of glucose allocation. 1214 83

It was hypothesized that subjects with metabolic syndrome (hypertension, obesity, hyperlipidemia, diabetes mellitus): (1) develop measurable peripheral edema at moderate altitude and (2) might show differences on erythropoiesis, iron status and vascular endothelial growth factor (VEGF) in comparison to healthy subjects during and after a long-term stay (3-week exposure) at moderate altitude (congruent with 1700 m). Twenty-two male subjects with metabolic syndrome were selected. Baseline investigations (t1) were performed in Innsbruck (500 m). All participants were transferred by bus to 1700 m (Alps) and remained there for 3 weeks with examinations on day 1 (after the first night at altitude, t2), day 4 (t3), day 9 (t4) and day 19 (t5). After returning to Innsbruck, post-altitude examinations were conducted after 7-10 days (t6) and 6-7 weeks (t7), respectively. Body mass was decreased from t1 to t7 (P<0.01). Total body water was decreased at t2 (P<0.01), returned to control level (t3, t4), and was found elevated at t7 (P<0.01). Lean body mass did not change, but body fat decreased during the study (P<0.01). Tissue thickness at the forehead decreased during and after altitude exposure (P<0.01), whereas tissue thickness at the tibia did not alter. Erythropoietin (EPO) was elevated as early as t2 and remained increased until t5. Reticulocyte count was increased at t3 and remained above pre-altitude values. VEGF levels were unchanged. After a 3-week exposure to moderate altitude, patients with metabolic syndrome had reduced their body mass, mainly because of a reduction in body fat. The moderate altitude was found to stimulate erythropoiesis in these patients but this was not sufficient to increase serum VEGF concentration.
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PMID:Austrian Moderate Altitude Study (AMAS 2000) - fluid shifts, erythropoiesis, and angiogenesis in patients with metabolic syndrome at moderate altitude (congruent with 1700 m). 1256 Sep 47

White adipose tissue (WAT) is now recognized as a major endocrine and secretory organ, releasing a wide range of protein factors and signals termed adipokines - in addition to fatty acids and other lipid moieties. A paradigm shift came with the discovery of leptin, a pleiotropic hormone which is a critical signal to the hypothalamus in the control of appetite and energy balance. A number of adipokines, including adiponectin, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor-1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of mild inflammation, and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands; a notable exception is adiponectin, with its anti-inflammatory action, the levels of which fall. WAT may be the main site of inflammation in obesity, increased circulating levels of inflammatory markers reflecting spillover from an 'inflamed' tissue, leading to the obesity-associated pathologies of type 2 diabetes and the metabolic syndrome. From the wide range of adipokines now identified, it is evident that WAT is highly integrated into overall physiological regulation, involving extensive crosstalk with other organs and multiple metabolic systems. Whether major changes in adipokine production in obesity, particularly of those factors linked to inflammation, are unique to this condition, or are a feature of all situations in which there are substantial increases in adipose mass (such as pregnancy, and pre-hibernatory and pre-migratory fattening) requires consideration.
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PMID:Endocrine and signalling role of adipose tissue: new perspectives on fat. 1602 20

Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c(-/-) mice. In contrast to control mice, in the SREBP-1c(-/-) mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.
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PMID:Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. 1604 11

White adipose tissue (WAT) is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. A number of adipokines, including leptin, adiponectin, tumour necrosis factor alpha, IL-1beta (interleukin 1beta), IL-6, monocyte chemotactic protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands (adiponectin, which has anti-inflammatory action is an exception). The elevated production of inflammation-related adipokines is increasingly considered to be important in the development of diseases linked to obesity, particularly Type II diabetes and the metabolic syndrome. WAT is involved in extensive cross-talk with other organs and multiple metabolic systems through the various adipokines.
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PMID:Signalling role of adipose tissue: adipokines and inflammation in obesity. 1624 49

Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin.
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PMID:Obesity, adipokines, and prostate cancer (review). 1646 80

The metabolic syndrome is a main cause for cardiovascular disease and for the accelerating epidemic of chronic renal failure. Previous studies show that 2-hydroxyestradiol (2-HE), an estradiol metabolite with little estrogenic activity, decreases obesity and arterial blood pressure and attenuates the development of renal disease in young, obese, diabetic ZSF1 rats. In humans, however, diabetic renal disease is more frequent and severe in older patients. In vivo, 2-HE is readily converted to 2-methoxyestradiol (2-ME), an estradiol metabolite with no estrogenic activity. Accordingly, one purpose of this study was to determine whether 2-ME would provide benefit in aged rats with a very severe form of diabetic renal disease. Another objective was to determine whether synthetic analogs of estradiol metabolites might be beneficial in diabetic renal disease. To achieve these objectives we examined the effects of 2-ME and its analog 2-ethoxyestradiol (2-EE) in aged (35-week-old), obese ZSF1 rats. Animals were treated for 9 weeks with vehicle (PEG-400, 0.5 microL per hour), 2-ME or 2-EE (18 microg/kg per hour). Metabolic and renal function were measured at weeks 0, 3, 6, and 9, and renal hemodynamics and excretory function were assessed at week 9. Aged ZSF1 rats had elevated levels of glycosylated hemoglobin; increased renal cortical expression of proliferating cell nuclear antigen (PCNA), nuclear factor kappa B (NF-kappaB), and vascular endothelial growth factor (VEGF); glycosuria, hypertension; and proteinuria. 2-ME and 2-EE did not affect obesity or hypertension and had variable effects on glucose homeostasis, yet they attenuated proteinuria; increased renal blood flow and glomerular filtration; and reduced renal cortical expression of PCNA, NFkappaB, and VEGF. We conclude that 2ME and 2EE are strikingly renoprotective even in aged animals with severe diabetic renal disease. The present study warrants further investigation of 2-ME and analogs of estradiol metabolites for treatment of kidney disease associated with the metabolic syndrome.
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PMID:2-Methoxyestradiol and 2-ethoxyestradiol retard the progression of renal disease in aged, obese, diabetic ZSF1 rats. 1726 64

The metabolic syndrome (MS), a condition characterized by several risk factors for coronary artery disease, including obesity, is associated with endothelial dysfunction and oxidative stress. Because proper endothelial function is essential for signaling of certain growth factors (vascular endothelial growth factor, VEGF) we hypothesized that coronary collateral growth (CCG) is impaired in a model of the MS. To test this hypothesis, we stimulated coronary collateral growth in pre-diabetic Zucker obese fatty rats (OZR) and lean littermates (LZR) by using episodic, repetitive ischemia (RI: 40 s left anterior descending arterial occlusion, 24/d for 14 d). Myocardial blood flow (MBF, radioactive microspheres) was measured in the normal (NZ) and collateral-dependent (ischemic) zones (CZ); CCG was assessed as a ratio of CZ/NZ flow (unity represents complete restoration of CZ flow). In LZR, CZ/NZ ratio increased from 0.18 +/- 0.03 to 0.81 +/- 0.07 after RI (P < 0.05). In contrast, in OZR rats CZ/NZ did not increase after RI (0.15 +/- 0.04 vs 0.18 +/- 0.04). To rectify abrogated collateral growth in OZR, we employed VEGF gene therapy (VEGF-transduced, strained-matched, cultured vascular smooth muscle cells [cVSMCs], delivered intracoronary). VEGF therapy modestly but not significantly increased the CZ/NZ ratio after RI (0.16 +/- 0.05 vs 0.33 +/- 0.06). To facilitate VEGF signaling,we reduced oxidative stress by transducing cVSMCs with both ecSOD and VEGF. This increased the CZ/NZ flow ratio after RI to 0.52 +/- 0.04 (p < 0.05 vs. OZR [(0.19 +/- 0.04]) indicating partial restoration of collateral growth. Our results demonstrate that coronary collateral growth is impaired in a model of the metabolic syndrome and that growth factor gene therapy with VEGF is made far more effective when it is coupled to an intervention that reduces oxidative stress.
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PMID:Restoration of coronary collateral growth in the Zucker obese rat: impact of VEGF and ecSOD. 1732 99

White adipose tissue is a key endocrine and secretory organ, releasing multiple adipokines, many of which are linked to inflammation and immunity. During the expansion of adipose tissue mass in obesity there is a major inflammatory response in the tissue with increased expression and release of inflammation-related adipokines, including IL-6, leptin, monocyte chemoattractant protein-1 and TNF-alpha, together with decreased adiponectin production. We proposed in 2004 (Trayhurn & Wood, Br J Nutr 92, 347-355) that inflammation in adipose tissue in obesity is a response to hypoxia in enlarged adipocytes distant from the vasculature. Hypoxia has now been directly demonstrated in adipose tissue of several obese mouse models (ob/ob, KKAy, diet-induced) and molecular studies indicate that the level of the hypoxia-inducible transcription factor, hypoxia-inducible factor-1 alpha, is increased, as is expression of the hypoxia-sensitive marker gene, GLUT1. Cell- culture studies on murine and human adipocytes show that hypoxia (induced by low O2 or chemically) leads to stimulation of the expression and secretion of a number of inflammation-related adipokines, including angiopoietin-like protein 4, IL-6, leptin, macrophage migration inhibitory factor and vascular endothelial growth factor. Hypoxia also stimulates the inflammatory response of macrophages and inhibits adipocyte differentiation from preadipocytes. GLUT1 gene expression, protein level and glucose transport by human adipocytes are markedly increased by hypoxia, indicating that low O2 tension stimulates glucose utilisation. It is suggested that hypoxia has a pervasive effect on adipocyte metabolism and on overall adipose tissue function, underpinning the inflammatory response in the tissue in obesity and the subsequent development of obesity-associated diseases, particularly type 2 diabetes and the metabolic syndrome.
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PMID:Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? 1838 4

The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [P. Poirier, et al., Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss, Arterioscler Thromb Vasc Biol. 26(5), (2006) 968-976.; K. Obunai, S. Jani, G.D. Dangas, Cardiovascular morbidity and mortality of the metabolic syndrome, Med.Clin. North Am., 91(6), (2007) 1169-1184]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [C.F. McTiernan, et al., Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts, Gene Ther, 14(23), (2007) 1613-1622]. However, this high transduction does not necessarily translate into improved efficacy [X. Hao, et al., Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model, Cardiovasc Res., 73(3), (2007) 481-487]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regard to secondary end-points of reduced symptomatology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [P.B. Shah, D.W. Losordo, Non-viral vectors for gene therapy: clinical trials in cardiovascular disease, Adv Genet, 54, (2005) 339-361]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes. Currently, polymeric non-viral gene delivery to cardiac myocardium remains underrepresented. In the past decade several advances in non-viral vector development has demonstrated increased transfection efficiency [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Of these polymers, those that employ lipid modifications to improve transfection or target cardiovascular tissues have proven themselves to be extremely beneficial. Water-soluble lipopolymer (WSLP) consists of a low molecular weight branched PEI (1800) and cholesterol. The cholesterol moiety adds extra condensation by forming stable micellular complexes and was later employed for myocardial gene therapy to exploit the high expression of lipoprotein lipase found within cardiac tissue. Use of WSLP to deliver hypoxia-responsive driven expression of hVEGF to ischemic rabbit myocardium has proven to provide for even better expression in cardiovascular cells than Terplex and has demonstrated a significant reduction in infarct size (13+/-4%, p<0.001) over constitutive VEGF expression (32+/-7%, p=0.007) and sham-injected controls (48+/-7%). A significant reduction in apoptotic values and an increase in capillary growth were also seen in surrounding tissue. Recently, investigations have begun using bioreducible polymers made of poly(amido polyethylenimines) (SS-PAEI). SS-PAEIs breakdown within the cytoplasm through inherent redox mechanisms and provide for high transfection efficiencies (upwards to 60% in cardiovascular cell types) with little to no demonstrable toxicity. In vivo transfections in normoxic and hypoxic rabbit myocardium have proven to exceed those results of WSLP transfections by 2-5 fold [L.V. Christensen, et al., Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery, J Control Release, 118(2), (2007) 254-261]. This new breed of polymer(s) may allow for decreased doses and use of new molecular mechanisms not previously available due to low transfection efficiencies. Little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neo-genesis and provide a new means of investigation for treatment.
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PMID:Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction. 1866 30


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