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)

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-alpha is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-alpha is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-alpha agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-alpha agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-alpha activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-alpha agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.
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PMID:Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence. 1642 52

Insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defense and is constituted by different barriers (e.g., epithelia, adipose tissue) and different blood and tissue components (e.g., macrophages, neutrophils). This system generates the acute-phase response in which different acute-phase proteins and cytokines are produced in response to different aggressions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e., brain and the immune system). Evolutionary pressures have led to survival of the fittest individuals, those with the genetics that allows the best defense against infection and periods of famine. Evidence is reported according to which gene polymorphisms in the molecules regulating the inflammatory cascade are associated with body composition, insulin action, and characteristics of the metabolic syndrome. The evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-18], or decreased anti-inflammatory molecules (adiponectin, certain TNF-alpha isoforms, soluble CD14, etc.), would lead in westernized countries to chronic inflammation conditions, such as obesity and type 2 diabetes, resulting in cardiovascular disease.
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PMID:Genetic predispositions to low-grade inflammation and type 2 diabetes. 1647 51

Subclinical inflammation is a risk factor for cardiovascular disease. The mechanisms underlying increased levels of inflammatory markers and their changes in response to weight loss are not fully understood yet. It has been proposed that elevated concentrations of C-reactive protein (CRP) are mediated by cytokines produced in adipose tissue. We investigated the changes in circulating CRP after weight reduction, in relation to parameters relevant to the metabolic syndrome. Forty 25- to 35-year-old obese female volunteers participated in an intervention program of dietary education and supervised physical activity for a period of 9 weeks. Anthropological parameters and biochemical measurements (high-sensitivity CRP [hsCRP], plasma lipoproteins, interleukin 6 [IL-6], adiponectin) were analyzed before and after the intervention. Body mass index decreased by more than 7% from 31.5 +/- 4.1 to 29.1 +/- 3.9. Plasma free fatty acid (FFA) concentrations decreased by 30%, high-density lipoprotein cholesterol increased by 8%, and fasting insulin concentrations decreased by 15%. There were no significant changes in either low-density lipoprotein cholesterol or triacylglycerol concentrations. Subcutaneous and visceral adipose tissue mass decreased by 12% and 18%. High-sensitivity CRP concentrations decreased by 30%; however, mean plasma IL-6 and adiponectin concentrations remained unchanged. In linear regression analysis, the changes in plasma hsCRP concentrations were associated with baseline hsCRP concentration, change in triacylglycerols and FFA concentrations, and in waist circumference. The decrease in hsCRP concentration after weight reduction does not appear to be mediated by decreases in circulating IL-6 or adiponectin concentrations; however, change in hsCRP concentration is related to changes in waist circumference and lipid metabolism, reflected by plasma triacylglycerol and FFA levels.
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PMID:The decrease in C-reactive protein concentration after diet and physical activity induced weight reduction is associated with changes in plasma lipids, but not interleukin-6 or adiponectin. 1648 80

Insulin resistance (IR) plays a larger role in the type 1 diabetes mellitus (T1DM) disease process than commonly recognized. Overweight and physical inactivity have increased steadily for the last 20-30 years in children and adolescents in many populations, concurrently with a rising incidence of T1DM. The role of IR in T1DM has only recently been gaining acceptance. This review will focus on how IR influences our current understanding of disease development and metabolic syndrome (MS) in T1DM. Increases in IR by weight gain and sedentarism, associated to decreased beta cell mass by autoimmune process, may disrupt normoglycemia in pre-T1DM individuals. IR may reflect a more aggressive form of autoimmune disease mediated by immuno-inflammatory factors that also mediate beta cell destruction (TNF-alpha and IL-6). These concepts are included in the "accelerator hypothesis". Moreover, family history of T2DM and chronic hyperglycemia (glucotoxicity), occurring after T1DM diagnosis, contribute to decrease peripheral glucose uptake. The onset of diabetic nephropathy (DN) might also contribute to IR and metabolic syndrome (MS) via low-grade inflammation and increased oxidative stress. MS is found between 12 to 40% in T1DM, especially in patients with advanced DN and poor glycemic control. These findings have therapeutic and cardiovascular prognostic implications as children make the transition toward adolescence and young adulthood T1DM.
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PMID:[Insulin resistance and metabolic syndrome in type 1 diabetes mellitus]. 1676 91

Obesity has been linked to cardiovascular disease, hypertension, diabetes and the metabolic syndrome, with elevated markers of systemic inflammation. Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane adhesion molecule involved in leukocyte migration to sites of inflammation. In human obesity, elevated expression of the soluble form of ICAM-1 (sICAM-1) is positively correlated with abdominal fat deposition. Increases in adiposity have also been correlated with macrophage infiltration into adipose tissue. Here we investigate adipose tissue production and transcriptional regulation of ICAM-1 in a mouse model of dietary obesity. After feeding mice a high-fat diet, ICAM-1 expression in serum and adipose tissue was analyzed by ELISA, Northern blotting, real-time quantitative PCR, and flow cytometry. After 6 mo on the high-fat diet, sICAM-1 levels significantly correlated with body weight and abdominal fat mass. ICAM-1 mRNA was expressed in adipose tissue of mice, with significantly higher levels in males than females. After only 3 wk, there were adipose tissue-specific increases in mRNAs for ICAM-1, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in male mice. Analysis of the stromal-vascular fraction of male adipose tissue revealed CD11b-negative cells with increased surface ICAM-1 and CD34. We also found two populations of F4/80+, CD11b+, ICAM-1+ cells, one of which also expressed CD14 and CD11c and was increased in response to a high-fat diet. These results indicate that within 3 wk on a high-fat diet, male mice exhibited significant increases in pro-inflammatory factors and immune cell infiltration in adipose tissue that may represent links between obesity and its associated inflammatory complications.
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PMID:ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice. 1680 3

The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity.
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PMID:Hypothalamic integration of immune function and metabolism. 1687 87

Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases.
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PMID:Molecular mechanisms of insulin resistance and associated diseases. 1695 1

Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (>/=65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21-0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
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PMID:Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study. 1696 11

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and no diabetes were administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data that were obtained from 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml x mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 92 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl; P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the administration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ARB therapy.
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PMID:Insulin resistance, inflammatory biomarkers, and adipokines in patients with chronic kidney disease: effects of angiotensin II blockade. 1713 Feb 63

Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined.
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PMID:Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. 1713 Jun 44


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