Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolic syndrome and type 2 diabetes (T2DM) resulting from sustained hyperglycemia are considered as risk factors for cardiovascular disease (CVD) but the mechanism for their contribution to cardiopathogenesis is not well understood. Hyperglycemia induces nonenzymatic glycation of protein-yielding advanced glycation end products (AGE), which are postulated to stimulate interleukin-6 (IL-6) expression, triggering the liver to secrete tissue necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP) that contribute to CVD pathogenesis. Although the high prevalence of periodontitis among individuals with diabetes is well known by dental researchers, it is relatively unrecognized in the medical community. The expression of the same proinflammatory mediators implicated in hyperglycemia (i.e., IL-6, TNF-alpha, and CRP) have been reported to be associated with periodontal disease and increased risk for CVD. We will review published evidence related to these 2 pathways and offer a consensus.
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PMID:Oral infection, hyperglycemia, and endothelial dysfunction. 1790 6

Endothelin-1 (ET-1) promotes the contractile ability of fibroblasts, essential for wound closure and reconstitution of the dermis. Wound healing is impaired in type 2 diabetic patients (D). We compared the effect of ET-1 on proliferative transforming growth factor (TGFbeta(1)) expression, fibronectin and laminin release), differentiative [alpha-smooth muscle actin (alpha-SMA) expression] and inflammatory [monocyte chemo-attractant protein (MCP-1) and interleukin-6 (IL-6) expression] responses in skin fibroblasts of healthy subjects (C) and D, testing the relative role of ET(A) and ET(B) receptors in mediating these responses. ET-1 did not influence TGFbeta(1), fibronectin or laminin production. alpha-SMA was more abundant and more stimulated in D, as well as MCP-1 and IL-6 expression and release. These effects were prevented by BMS-182874, selective antagonist of ET(A), more abundant than ET(B) in both cell strains and whose expression rose more in D than C upon stimulation with ET-1. This peculiar pattern of responses to ET-1, presumably acquired during the chronic in vivo exposure to hyperglycemia along the natural history of the disease, may partially explain the increased susceptibility of D to chronic ulcerations.
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PMID:Effects of endothelin-1 on fibroblasts from type 2 diabetic patients: Possible role in wound healing and tissue repair. 1836 70

Stress is accompanied by metabolic alterations that could contribute to the etiology of diabetes mellitus, arteriosclerosis, and cardiovascular diseases; however, the mechanisms by which stress affects glucose and lipid metabolism remain to be resolved. Stress-induced effects on neurotransmission and interleukin-1 (IL-1) signaling rapidly produce hyperglycemia by increasing sympathetic outflow. Activation of the sympathetic nervous system can also rapidly stimulate lipolysis and hepatic triglyceride secretion. Furthermore, stress increases serum interleukin-6 (IL-6) and nerve growth factor (NGF) levels by activating neuroendocrine systems. IL-6 and NGF can rapidly increase lipolysis and hepatic triglyceride secretion without inducing hyperglycemia. The sympathetic nervous system does not mediate cytokine-induced hypertriglyceridemia. Thus, the central nervous system plays an important role in regulation of hepatic glucose and lipid metabolism via the sympathetic nervous system and cytokines. (Trends Endocrinol Metab 1997;8:192-197). (c) 1997, Elsevier Science Inc.
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PMID:Stress, acute hyperglycemia, and hyperlipidemia role of the autonomic nervous system and cytokines. 1840 6

Insulin is used to control pro-inflammatory hyperglycemia in critically ill patients. However, recent studies suggest that insulin-induced hypoglycemia may negate its beneficial effects in these patients. It is noteworthy that recent evidence indicates that insulin has anti-inflammatory effects that are independent of controlling hyperglycemia. To date, the mechanism by which insulin directly reduces inflammation has not been elucidated. It is well established that insulin activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling in many cell types. We and others have shown that this pathway negatively regulates LPS-induced signaling and pro-inflammatory cytokine production in monocytic cells. We hypothesized that insulin inhibits inflammation during endotoxemia by activation of the PI3K/Akt pathway. We used a nonhyperglycemic mouse model of endotoxemia to determine the effect of continuous administration of a low dose of human insulin on inflammation and survival. It is noteworthy that insulin treatment induced phosphorylation of Akt in muscle and adipose tissues but did not exacerbate lipopolysaccharide (LPS)-induced hypoglycemia. Insulin decreased plasma levels of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein 1 (MCP1)/JE, and keratinocyte chemoattractant, and decreased mortality. The PI3K inhibitor wortmannin abolished the insulin-mediated activation of Akt and the reduction of chemokine and interleukin-6 levels. We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels.
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PMID:Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. 1844 80

The stress response to surgery is characterized by activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, and by an inflammatory response and hyperglycemia. The aim of the present study was to investigate if preoperative corticosterone could reduce the postoperative systemic stress response, without aggravating hyperglycemia or interfering with activation of the hypothalamic-pituitary-adrenal axis, in a standardized rat model of surgical trauma. We used a standardized experimental model of intestinal resection in the rat. Exogenous corticosterone (8 mg/kg body weight) or vehicle was administered 2 hours before surgery; and postoperative plasma concentrations of interleukin-6, interleukin-10, adrenaline, noradrenaline, glucose, and insulin were determined. Exogenous corticosterone decreased preoperative plasma adrenaline but did not change plasma glucose or insulin levels. Moreover, corticosterone reduced postoperative plasma interleukin-6, catecholamines, and glucose (all P < .001-.05) without any effect on the plasma corticosterone concentration compared with vehicle-treated controls. A preoperative 2-hour exposure of physiologic poststress corticosterone concentrations not only suppressed plasma IL-6 levels but also inhibited surgery-induced adrenaline release and suppressed plasma glucose levels. We hypothesize that glucocorticoids attenuated the inflammatory response in injured tissues that reduced afferent input into brain areas regulating the neuroendocrine response.
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PMID:Preoperative glucocorticoid administration attenuates the systemic stress response and hyperglycemia after surgical trauma in the rat. 1930 63

Women with polycystic ovary syndrome (PCOS) have chronic low-level inflammation that can increase the risk of atherogenesis. We measured circulating proatherogenic inflammatory mediators in women with PCOS (8 lean: body mass index, 18-25 kg/m(2); 8 obese: body mass index, 30-40 kg/m(2)) and weight-matched controls (8 lean, 8 obese). Blood samples were obtained fasting and 2 hours after glucose ingestion to measure interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), matrix metalloproteinase-2, plasminogen activator inhibitor-1 (PAI-1), and activated nuclear factor kappaB in mononuclear cells. Truncal fat was determined by dual-energy x-ray absorptiometry. Fasting MCP-1 levels were elevated in lean women with PCOS compared with lean controls (159.9 +/- 14.1 vs 121.2 +/- 5.4 pg/mL, P < .02). Hyperglycemia failed to suppress matrix metalloproteinase-2 in lean women with PCOS compared with lean controls (1.7 +/- 1.2 vs -4.8 +/- 1.6 pg/mL, P < .002). Among women with PCOS, obese individuals exhibited higher fasting sICAM-1 (16.1 +/- 0.8 vs 10.5 +/- 1.0 ng/mL, P < .03) and PAI-1 (6.1 +/- 0.7 vs 3.4 +/- 0.8 ng/mL, P < .03) levels. Trend analysis revealed higher (P < .005) IL-6, sICAM-1, CRP, PAI-1, systolic and diastolic blood pressures, triglycerides, fasting insulin, and homeostasis model assessment of insulin resistance index in women with PCOS compared with weight-matched controls, and the highest levels in the obese regardless of PCOS status. Fasting MCP-1 levels correlated with activated nuclear factor kappaB during hyperglycemia (P < .05) and androstenedione (P < .004). Truncal fat correlated with fasting IL-6 (P < .004), sICAM-1 (P < .006), CRP (P < .0009), and PAI-1 (P < .02). We conclude that both PCOS and obesity contribute to a proatherogenic state; but in women with PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.
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PMID:Evidence of proatherogenic inflammation in polycystic ovary syndrome. 1937 63

Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMPhi). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMPhi (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMPhi gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-kappaB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology.
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PMID:Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae. 1951 43

Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.
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PMID:TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in Ob-ZSF1 model of type 2 diabetes. 1954 15

Thyroid hormone receptor beta (TRbeta also listed as THRB on the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TRbeta agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and glucose intolerance, increased plasma levels of triglycerides, cholesterol, nonesterified fatty acids and interleukin-6. While GC-24 administration to these animals did not affect food ingestion or modified the progression of BW gain, it did increase energy expenditure, eliminating the increase in adiposity without causing cardiac hypertrophy. Fasting hyperglycemia remained unchanged, but treatment with GC-24 improved glucose tolerance by increasing insulin sensitivity, and also normalized plasma triglyceride levels. Plasma cholesterol levels were only partially normalized and liver cholesterol content remained high in the GC-24-treated animals. Gene expression in liver, skeletal muscle, and white adipose tissue was only minimally affected by treatment with GC-24, with the main target being BAT. In conclusion, during high-fat feeding treatment with the TRbeta-selective agonist, GC-24 only partially improves metabolic control probably as a result of accelerating the resting metabolic rate.
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PMID:A TRbeta-selective agonist confers resistance to diet-induced obesity. 1971 19

While global prevalence of obesity continues to increase dramatically, treatment options remain less than optimal. The etiology of obesity is multifactorial, ranging from lifestyle choices such as excess food intake and insufficient physical activity, to use of medications that have weight gain as an undesirable side effect. Economic and political determinants of available foodstuffs and even social networks may also contribute to obesity. Successful management of obesity requires the understanding and acceptance of a new paradigm that identifies obesity as a disease--one defined by waist circumference--that requires treatment. Obesity meets all accepted criteria of a medical disease, including a known etiology, recognized signs and symptoms, and a range of structural and functional changes that culminate in pathologic consequences. Excess adipose tissue acts as an endocrine organ to produce excess free fatty acids, as well as tumor necrosis factor-alpha, interleukin-6, leptin, and plasminogen activator inhibitor-1. These bioactive molecules are associated with hyperinsulinemia, hyperglycemia, insulin resistance, development of diabetes, endothelial damage, and the onset and progression of atherosclerotic lesions. Options for treating obesity include lifestyle modifications (dietary changes, increased physical activity, behavior modification) and, for the morbidly obese, surgery. Lifestyle modification is rarely successful over the long term; therefore, addition of pharmacotherapy should be considered for obese individuals who have difficulty achieving and maintaining weight goals with lifestyle modifications alone. Several weight loss drugs are available for long-term use, with others in various stages of clinical development.
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PMID:Obesity as a disease state: a new paradigm for diagnosis and treatment. 1978 61


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