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

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile saline (n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.
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PMID:Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. 1200 57

It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type 2 diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free fatty acid flux and inhibition of insulin action via Randle's effect in insulin-sensitive tissues. Recent data do not entirely support this hypothesis. As such, two new paradigms have emerged that may explain the established links between adiposity and disease. (A) Three lines of evidence support the ectopic fat storage syndrome. First, failure to develop adequate adipose tissue mass in either mice or humans, also known as lipodystrophy, results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle, and the pancreatic insulin-secreting beta cell. Second, most obese patients also shunt lipid into the skeletal muscle, the liver, and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver correlates highly with insulin resistance. Third, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and thus to accommodate an increased energy influx. Taken together, these three observations support the acquired lipodystrophy hypothesis as a link between adiposity and insulin resistance. (B) The endocrine paradigm developed in parallel with the ectopic fat storage syndrome hypothesis. Adipose tissue secretes a variety of endocrine hormones, such as leptin, interleukin-6, angiotensin II, adiponectin (also called ACRP30 and adipoQ), and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. These two new paradigms provide a framework to advance our understanding of the pathophysiology of the insulin-resistance syndrome.
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PMID:Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. 1207 64

This study was undertaken to review the links between maternal nutrition, offspring's birth weight and the propensity to early insulin resistance and high diabetes rates in Indian adults. Studies included a comparison of maternal size and nutrition with birth weights in Pune, India, and Southampton, UK. In Pune, the growth, insulin resistance and blood pressure of four-year-old children were assessed. Adults >40 years of age, who were resident in rural areas, were compared with adults living in urban areas for size, glucose handling, lipid status and blood pressure. Newly diagnosed diabetic adults living in urban areas were also monitored. Height, weight, head, waist and hip circumferences, skin-fold measurements and blood pressure were routinely measured. Fasting glucose, insulin, total and high-density lipoprotein cholesterol and triglycerides were linked to the glucose and insulin responses during glucose tolerance tests. Cytokine levels were measured in plasma samples of urban and rural adults. Indian babies were lighter, thinner, shorter and had a relatively lower lean tissue mass than the Caucasian babies. However, the subcutaneous fat measurements of these babies were comparable to those of the white Caucasian babies. The Indian mothers were small, but relatively fat mothers produced larger babies. Maternal intake of green vegetables, fruit and milk, and their circulating folate and vitamin C levels, predicted larger fetal size. Rapid childhood growth promoted insulin resistance and higher blood pressure. Rural adults were thin, with a 4% prevalence of diabetes and a 14% prevalence of hypertension, but the risks increased within the normal body mass index (BMI) range. Type 2 diabetes was common in urban adults younger than 35 years of age. Although the average BMI was 23.9 kg m(-2), central obesity and thin limbs were noteworthy. Levels of interleukin-6 and tumour necrosis factor-a were markedly increased in urban dwellers. Hence, there is evidence of a remarkably powerful, intergenerational effect on body size and total and central adiposity. Indians are highly susceptible to insulin resistance and cardiovascular risks, with babies being born small but relatively fat. Insulin resistance is amplified by rapid childhood growth. Dietary factors seem to have profound long-term metabolic influences in pregnancy. Overcrowding with infections and central obesity may amplify cytokine-induced insulin resistance and early diabetes in Indian adults with a low BMI.
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PMID:The lifecycle effects of nutrition and body size on adult adiposity, diabetes and cardiovascular disease. 1216 75

Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology. Since advanced glycation end products (AGEs; AGE-albumin) and in particular carboxymethyllysine (CML) are known to play a central role in diabetic nephropathy, we studied the activation of nuclear factor kappaB (NF-kappaB) in tubular epithelial cells in vivo and in vitro by AGE-albumin and CML. Urine samples from healthy control subjects (n = 50) and type 2 diabetic patients (n = 100) were collected and tested for excretion of CML and the presence of proximal tubular epithelial cells (pTECs). CML excretion was significantly higher in diabetic patients than in healthy control subjects (P < 0.0001) and correlated with the degree of albuminuria (r = 0.7, P < 0.0001), while there was no correlation between CML excretion and HbA(1c) (r = 0.03, P = 0.76). Urine sediments from 20 of 100 patients contained pTECs, evidenced by cytokeratin 18 positivity, while healthy control subjects (n = 50) showed none (P < 0.0001). Activated NF-kappaB could be detected in the nuclear region of excreted pTECs in 8 of 20 patients with pTECs in the urine sediment (40%). Five of eight NF-kappaBp65 antigen-positive cells stained positive for interleukin-6 (IL-6) antigen (62%), while only one of the NF-kappaB-negative cells showed IL-6 positivity. pTECs in the urine sediment correlated positively with albuminuria (r = 0.57, P < 0.0001) and CML excretion (r = 0.55, P < 0.0001). Immunohistochemistry in diabetic rat kidneys and a human diabetic kidney confirmed strong expression of NF-kappaB in tubular cells. To further prove an AGE/CML-induced NF-kappaB activation in pTECs, NF-kappaB activation was studied in cultured human pTECs by electrophoretic mobility shift assays (EMSAs) and Western blot. Stimulation of NF-kappaB binding activity was dose dependent and was one-half maximal at 250 nmol/l AGE-albumin or CML and time dependent at a maximum of activation after 4 days. Functional relevance of the observed NF-kappaB activation was demonstrated in pTECs transfected with a NF-kappaB-driven luciferase reporter plasmid and was associated with an increased release of IL-6 into the supernatant. The AGE- and CML-dependent activation of NF-kappaBp65 and NF-kappaB-dependent IL-6 expression could be inhibited using the soluble form of the receptor for AGEs (RAGE) (soluble RAGE [sRAGE]), RAGE-specific antibody, or the antioxidant thioctic acid. In addition transcriptional activity and IL-6 release from transfected cells could be inhibited by overexpression of the NF-kappaB-specific inhibitor kappaBalpha. The findings that excreted pTECs demonstrate activated NF-kappaB and IL-6 antigen and that AGE-albumin and CML lead to a perpetuated activation of NF-kappaB in vitro infer that a perpetuated increase in proinflammtory gene products, such as IL-6, plays a role in damaging the renal tubule.
Diabetes 2002 Dec
PMID:Activation of tubular epithelial cells in diabetic nephropathy. 1245 11

Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.
Diabetes 2003 Feb
PMID:The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity. 1254 Jun 35

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.
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PMID:Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. 1256 Mar 30

The low affinity A(2B) adenosine receptor, like any other adenosine receptor subtype, belongs to the super-family of seven transmembrane domain protein-coupled receptors (7TMs GPCR) and is classified by the GPCR database in the family of rhodopsin like receptors (Class A of GPCR). It has been cloned from various species, including rat and human, and its sequences are highly similar across species, ranging from 85% identity between human and mouse and 95% identity between rat and mouse. The A(2B)receptors show a ubiquitous distribution, the highest levels are present in cecum, colon and bladder, followed by blood vessels, lung, eye and mast cells. Through A(2B) receptors adenosine seems to cause mast cells degranulation, vasodilation, cardiac fibroblast proliferation, inhibition of Tumor Necrosis Factor (TNF-alpha), increased synthesis of interleukin-6 (IL-6), stimulation of Cl(-) secretion in intestinal epithelia and hepatic glucose production. Hence, A(2B) adenosine receptor agonists could be useful in the treatment of cardiac diseases like hypertension or myocardial infarction and in the management of septic shock, while antagonists may serve as novel drugs for asthma, Alzheimer's disease, cystic fibrosis and type-II diabetes. No potent and selective A(2B) agonists have been reported so far; 5'-N-ethylcarboxamidoadenosine (NECA) is one of the most active. The monosubstitution on N(6)-position of adenosine is well tolerated and that position appears to be a useful site for increasing A(2B) potency. Among substituents in 2-position of adenosine only 1-alkynyl chains are effective for A(2B) potency. In particular, the (S)-2-hydroxypropynyl substituents brought about the highest activity demonstrating that the A(2B) receptors discriminate between (R) and (S) diastereomers. Hence, (S)-2-phenylhydroxypropynylNECA (PHPNECA), with an EC(50) = 0.22 micro M, proved to be the most potent A(2B) agonist reported so far. Classical antagonists for adenosine receptors are alkylxanthines which show considerable potency at A(2B) receptors. Para substituted 1,3-dialkyl-8-phenylxanthines possess high affinity in binding assays; the 3-unsubstituted 1-alkyl analogues resulted more A(2B) selective with the 8-[4-[(N-(2-hydroxyethyl)carboxamidomethyl)oxy]phenyl]-1-propylxanthine (60) showing the highest affinity (K(i) = 1.2 nM) and selectivity (A(1)/A(2B) = 60, A(2A)/A(2B) = 1,790, A(3)/A(2B) = 360). Among non-xanthine derivatives very promising are substituted purines, in which combination of appropriate substituents in 2-, 8-, and 9-position could lead to very potent and selective A(2B) antagonists.
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PMID:Medicinal chemistry and pharmacology of A2B adenosine receptors. 1257 Jul 60

Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position -174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians - a population with high rates of insulin resistance and T2DM - and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (-174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P=0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P=0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P=0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians.
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PMID:The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. 1258 29

Current research suggests that insulin resistance is associated with endothelial dysfunction, which is considered an early but significant step in the pathogenesis of atherosclerosis. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Insulin-sensitizing agents--specifically, thiazolidinediones (TZDs)--may be useful for preventing or mitigating endothelial dysfunction. In vitro and clinical data show that TZDs can limit thrombotic, inflammatory, and oxidative changes that contribute to endothelial dysfunction. For example, TZDs have been shown to lower blood levels of plasminogen activator inhibitor-1, a prothrombotic substance, in patients with diabetes or insulin resistance. In obese patients, TZD treatment can improve vascular reactivity and reduce monocyte expression of nuclear factor kappa-B, a transcription factor that contributes to inflammation and oxidative damage. In patients with overt diabetes or insulin resistance, TZD treatment can lower blood levels of C-reactive protein and interleukin-6, markers of inflammation and cardiovascular risk. These beneficial effects of TZDs may help to decrease the risk of vascular damage and atherosclerosis in patients with insulin resistance or diabetes.
Diabetes Technol Ther 2002
PMID:Insulin resistance and endothelial dysfunction in atherosclerosis: implications and interventions. 1261 87

The effects of two third-generation monophasic combined oral contraceptives (COC) and a postmenopausal hormone replacement therapy (HRT) consisting of 2 mg 17 beta-oestradiol on the plasma level of the acute-phase indicator C-reactive protein (CRP) and other acute-phase reactants were analysed. Two studies were conducted: (1) a randomised, open-label study with two different oral contraceptive preparations with an equal dose of ethinylestradiol (30 micrograms) and a different progestogen, either 75 micrograms gestodene (GSD-EE) or 150 micrograms desogestrel (DSG-EE); blood samples of 39 young women were analysed before and after 3, 6, 12 treatment cycles; (2) a randomised, blinded placebo-controlled study with 2 mg 17 beta-oestradiol in postmenopausal women with non-insulin-dependent diabetes mellitus without signs of cardiac involvement; blood samples of 38 women were analysed before and after 6 weeks of treatment. The plasma concentration of CRP increased strongly during oral contraceptive use for both preparations; the increase persisted over 12 cycles. The already elevated CRP in postmenopausal diabetic women showed a moderate increase after 6 weeks of treatment with 17 beta-oestradiol. CRP increases during oral contraceptive use were associated with changes in some other acute-phase proteins (fibrinogen, ceruloplasmin, von Willebrand factor [vWF]) originating from the liver and vessel wall, but not in others (interleukin-6 [IL-6], serum amyloid A [SAA]). The results demonstrate an increase in a specific set of acute-phase reactants caused by oestrogen-containing preparations. It is proposed that the pro-inflammatory effect of oestrogens should be checked for a relationship with the increased risk of thromboembolism for both oral contraceptive and HRT.
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PMID:Pro-inflammatory effects of oestrogens during use of oral contraceptives and hormone replacement treatment. 1261 83


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