UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
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PMID:Recent advances in the relationship between obesity, inflammation, and insulin resistance. 1661 57

Tumor necrosis factor-alpha (TNF-alpha) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-alpha in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-alpha upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-alpha activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1beta, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-alpha induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-alpha may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.
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PMID:Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters. 1663 16

Interleukin-6 (IL-6, gene symbol IL6) is a proinflammatory cytokine. High circulating IL-6 levels have been associated with insulin resistance and greater risk of type 2 diabetes. Using a linkage disequilibrium (LD)-based approach, we sought to investigate the associations of the common polymorphisms comprehensively defining the genetic variability at the IL6 locus with diabetes risk. We conducted a case-control study of 2691 cases of type 2 diabetes (1692 women and 999 men) and 3237 control subjects (2238 women and 999 men) from the Nurses' Health Study and the Health Professional Follow-up Study. Pairwise LD analysis indicated that all the IL6 polymorphisms (rs2069827, rs1800797, rs1800795, rs1554606, rs2069849, rs2069861 and rs1818879) were in strong LD. We did not find significant associations between IL6 polymorphisms and the risk of type 2 diabetes in women or men, individually or in haplotypes. In addition, none of the IL6 polymorphisms was significantly associated with the plasma levels of IL-6 in the control subjects. Our meta-analysis of 5383 diabetes case and 12 069 controls indicated a null association between the best-studied 5' promoter polymorphism--174G>C (rs1800795)--and diabetes risk. Diversity in adiposity, age and sex could not account for the heterogeneity across different studies. In summary, the data in this study do not support substantial associations between the common polymorphisms in IL6 gene and circulating IL-6 levels and the risk of type 2 diabetes.
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PMID:Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. 1664 65

Genetics, oxidative stress: superoxide anion (O2*-) and hydrogen peroxide (H2O2), endothelial nitric oxide (eNO), lipid peroxides, anti-oxidants, endothelin, angiotensin converting enzyme (ACE) activity, angiotensinII, transforming growth factor-beta (TGF-beta), insulin, homocysteine, asymmetrical dimethyl arginine, proinflammatory cytokines: interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), C-reactive protein (hs-CRP), and long-chain polyunsaturated fatty acids (LCPUFAs), and activity of NAD(P)H oxidase have a role in human essential hypertension. There is a close interaction between endogenous molecules: eNO, endothelin, cytokines, and nutrients: folic acid, L-arginine, tetrahydrobiopterin (H4B), vitamin B6, vitamin B12, vitamin C, and LCPUFAs. Statins mediate some, if not all, of their actions through LCPUFAs, whereas these fatty acids (especially omega-3 fatty acids) suppress cyclo-oxygenase activity and the synthesis of pro-inflammatory cytokines, and activate parasympathetic nervous system, actions that reduce the risk of major vascular events. Some LCPUFAs form precursors to lipoxins and resolvins that have anti-inflammatory actions. Low-grade systemic inflammation seen in hypertension seems to have its origins in the perinatal period and availability of adequate amounts of LCPUFAs during the critical periods of brain growth prevents the development of hypertension. This indicates that preventive strategies aimed at decreasing the incidence of hypertension and its associated conditions such as atherosclerosis, type 2 diabetes, coronary heart disease (CHD), and cardiac failure in adulthood need to be instituted during the perinatal period if they are to be effective.
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PMID:Hypertension as a low-grade systemic inflammatory condition that has its origins in the perinatal period. 1671 19

Large interventional studies have shown that statins may reduce the incidence of type 2 diabetes mellitus. However, it is uncertain whether short-term statin therapy can affect insulin sensitivity in patients with the metabolic syndrome. We evaluated the effect of atorvastatin (10 mg/day) in 10 insulin-resistant subjects (age 40 +/- 12 years, body mass index 33.6 +/- 5.2 kg/m(2), triglycerides 2.84 +/- 1.99 mmol/L [249 +/- 175 mg/dl], glucose 6.06 +/- 0.67 mmol/L [109 +/- 12 mg/dl)] using the homeostasis model assessment (HOMA) index (parameter of insulin resistance derived from fasting glucose and fasting insulin concentrations; 5.7 +/- 2.6) in a randomized placebo-controlled, double-blind, crossover study. Subjects were randomized to receive placebo or atorvastatin, each given for 6 weeks separated by a 6-week wash-out period. At the beginning and end of each treatment phase, the patients underwent an oral glucose tolerance test, a 72-hour continuous glucose measurement, and a detailed lipid determination, including a standardized fat tolerance test. Compared with placebo, atorvastatin resulted in a significant (p = 0.05) reduction in the HOMA index (-21%), fasting C-peptides (-18%), glucose (area under the curve during the oral glucose tolerance test, -7%), and a borderline (p = 0.08) reduction of insulin (-18%). The parameters derived from the continuous 72-hour glucose monitoring did not change. A significant reduction also occurred in the total and low-density lipoprotein cholesterol concentrations, although the fasting and postprandial triglyceride concentrations did not change significantly. However, we found a significant correlation between atorvastatin-induced changes in the HOMA and baseline HOMA and between the atorvastatin-induced changes in triglycerides and insulin concentrations. The free-fatty acid, interleukin-6, and high sensitivity C-reactive protein concentrations did not change. Our data indicated that in insulin-resistant, nondiabetic subjects, 6 weeks of atorvastatin (10 mg/day) resulted in significant improvement in insulin sensitivity.
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PMID:Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome. 1678 23

Interleukin-6 (IL-6) is a pleiotropic cytokine which has been proposed as "cytokine for gerontologists" and linked to age-related metabolic disturbances such as the metabolic syndrome or type 2 diabetes. Polymorphisms located in the promoter region of IL-6 have been reported to be involved in the regulation of IL-6 transcription. This study investigates whether IL-6 promoter variants -174 G/C and -573 G/C are associated with quantitative traits related to the metabolic syndrome (International Diabetes Federation criteria) in a population of normoglycemic subjects (n=878) from the latest KORA survey (KORA S4). Genotyping was performed using MALDI-TOF MS. Besides lower height (p=0.01) the -174 CC genotype was independently associated with lower waist (p=0.002) and hip (p=0.01) circumferences in men. Furthermore, the -174 CC genotype was associated with BMI (p=0.004) when adjusted for waist and hip circumference. The present study does not suggest associations with further components of the metabolic syndrome. The association with height seems to be the central factor indicating an influence of IL-6 on growth through impaired bone metabolism. However, the complex relationships need further investigation.
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PMID:IL-6 promoter polymorphisms and quantitative traits related to the metabolic syndrome in KORA S4. 1679 5

We have investigated the relationships between plasma interleukin-6 (IL-6) levels and insulin sensitivity and insulin secretion in a cohort of Italian-Caucasian glucose-tolerant subjects. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp, and first-phase insulin secretion was measured by intravenous glucose tolerance test. Fasting plasma IL-6 concentration was negatively correlated with the rate of insulin-stimulated glucose disposal (M) (P = 0.001). The correlation remained statistically significant, while attenuated, after adjusting for sex, age, and BMI (P < 0.03); after an additional adjustment for free fatty acids (FFAs), a further attenuation was observed, but statistical significance was maintained (P < 0.044). Fasting plasma IL-6 concentration was positively correlated with first-phase insulin secretion assessed as acute insulin response (AIR) (P = 0.001). The correlation remained significant after adjusting for sex, age, and BMI (P = 0.003). To estimate the independent contribution of plasma IL-6 levels to AIR, we carried out forward stepwise linear regression analysis in a model that included sex, age, BMI, waist-to-hip ratio, FFAs, and insulin-stimulated glucose disposal. Only insulin sensitivity and plasma IL-6 concentration were independently associated with AIR, accounting, respectively, for 19.0 and 5.2% of its variation. These data indicate that IL-6 is associated in a reciprocal manner with the two pathophysiological components of type 2 diabetes, i.e., insulin resistance and insulin secretion.
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PMID:Plasma interleukin-6 levels are independently associated with insulin secretion in a cohort of Italian-Caucasian nondiabetic subjects. 1680 71

The Finnish DPS (Diabetes Prevention Study) demonstrated that lifestyle intervention, aimed at increasing physical activity, improving diet, and decreasing body weight, reduced the incidence of type 2 diabetes in individuals with overweight and impaired glucose tolerance by 58%. Here, we studied which immunological markers at baseline predicted subsequent type 2 diabetes and whether there are immunologically defined subsets of subjects who are more or less responsive to the protective effects of lifestyle intervention. We randomly assigned 522 participants to a control group (n = 257) or a lifestyle intervention group (n = 265). Immunological parameters at baseline included high-sensitivity C-reactive protein (CRP), serum amyloid A, interleukin-6, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage migration inhibitory factor (MIF), and soluble intercellular adhesion molecule. In the control group, CRP was the best immunological predictor for progression to overt type 2 diabetes. In the intervention group, progression to type 2 diabetes was significantly higher in subjects with the highest RANTES concentrations and was lower in subjects with the highest MIF levels. Ratios of RANTES to MIF in the upper tertile were highly predictive of incident type 2 diabetes in the intervention group (P = 0.006), whereas the association was less pronounced in the control group (P = 0.088). Thus, systemic concentrations of immune mediators appear to be associated with the progression to type 2 diabetes and the prevention of type 2 diabetes by lifestyle changes.
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PMID:Systemic immune mediators and lifestyle changes in the prevention of type 2 diabetes: results from the Finnish Diabetes Prevention Study. 1687 99

We previously reported the association between the activating enhancer-binding protein-2beta (AP-2beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with the disease-susceptible allele of AP-2beta showed stronger expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study we demonstrated that overexpression of AP-2beta in 3T3-L1 adipocytes decreased the expression and secretion of adiponectin and increased those of interleukin-6 (IL-6). Interestingly, the effects of AP-2beta on the expressions of adiponectin and IL-6 and the mechanisms by which AP-2beta modulated their expressions were different. We found that the promoter activity of adiponectin gene was inhibited by AP-2beta overexpression and enhanced by knockdown of endogenous AP-2beta, whereas IL-6 was unaffected. Electrophoretic mobility shift assays revealed the existence of putative responsive elements for AP-2beta and NF-YA in human and mouse adiponectin promoter regions, and mutation of this AP-2beta binding site abolished the inhibitory effect of AP-2beta. Furthermore, chromatin immunoprecipitation assays demonstrated that AP-2beta and NF-YA competitively bind to the same region of the adiponectin promoter. Our results clearly demonstrated that AP-2beta directly inhibits adiponectin gene expression by displacing NF-YA and binding to its promoter. We conclude that AP-2beta might modulate the expression of adiponectin by directly inhibiting its transcriptional activity.
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PMID:Transcription factor activating enhancer-binding protein-2beta. A negative regulator of adiponectin gene expression. 1695 17

Elevated plasma interleukin-6 (IL-6) is associated with coronary heart disease (CHD), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). We and others have described an association between the human interleukin-6 -174G>C gene variant and body mass index (BMI). Within our previous sample of subjects with T2DM, we measured plasma IL-6 and grouped subjects by the WHO-defined metabolic syndrome, in order to study the association between the -174G>C gene variant, plasma IL-6 and the metabolic syndrome (and component parts). Genotype was obtained in 571 Caucasian subjects with plasma IL-6 measures. There was a significant association between genotype and plasma IL-6 (GG vs GC vs CC: 3.23+/-0.93 pg/ml vs 3.42+/-0.95 pg/ml vs 4.16+/-1.18 pg/ml, p=0.02; for GG/GC vs CC p=0.008). No interactions were observed between genotype and the individual components of the metabolic syndrome in determining plasma IL-6. Increased plasma IL-6 was also associated with the number of components (none vs 1 vs 2 vs > or =3: 2.67+/-0.71 pg/ml vs 2.97+/-0.94 pg/ml vs 4.07+/-1.13 pg/ml, p<0.0001). Within the sample, 76% of CC compared to 56% of GG subjects had the metabolic syndrome (p=0.007). Further analysis of association between the genotype and the components of the metabolic syndrome revealed no further associations than that with BMI previously described. The association of this gene variant with the metabolic syndrome is intimately linked with obesity per se. Further prospective work is required to explore the effect of this gene variant in relation to obesity, the metabolic syndrome and 'prediabetes'.
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PMID:Association between plasma IL-6, the IL6 -174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus. 1712 52

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