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

Recently it has been postulated that interleukin-1 (IL-1) locally released by infiltrating mononuclear cells may destroy the pancreatic B cells during the development of insulin-dependent diabetes mellitus. Since IL-1 is a potent inducer of interleukin-6 (IL-6) in various cells, it is conceivable that IL-6 is a second mediator of the IL-1 action. In the present study the effects of IL-6 alone or in combination with IL-1 were studied on pancreatic islet function in vitro after tissue culture and compared with the effects observed after exposure to IL-1 only. Rat pancreatic islets were cultured in medium RPMI 1640 + 10% calf serum with or without the addition of human recombinant IL-6 (500-5000 pg/ml) for 48 h. The medium insulin accumulation was increased by 40-50% after culture with 500-2000 pg/ml IL-6, but was similar to the controls at 5000 pg/ml. When islets were cultured for 18 h only, also 5000 pg/ml IL-6 stimulated the medium insulin accumulation. IL-6 did not affect the islet insulin content and the rates of islet (pro)insulin and total protein biosynthesis. It inconsistently decreased the islet DNA content. In short-term experiments after 48-h culture with IL-6, there was a dose-dependent inhibition of the glucose-stimulated insulin release. On the other hand, islets cultured with IL-6 (5000 pg/ml) exhibited an elevated glucose oxidation and oxygen uptake, but a lower ATP content at 16.7 mM glucose and an unaffected glucose utilization and glutamine oxidation compared to the controls. This raises the possibility that IL-6 had induced a condition with an increased energy expenditure, resulting in an enhanced mitochondrial metabolism of glucose. Islets cultured with human recombinant IL-1 beta (25 units/ml) showed a strong inhibition of the insulin accumulation in the culture medium and of glucose-stimulated insulin release and a marked decrease in the islet DNA and insulin content. A combination of IL-1 (25 U/ml) + IL-6 (1000 pg/ml) did not alter the inhibitory action of IL-1 alone. The present findings thus show that IL-6 induces a dissociation between insulin secretion and glucose oxidation in islets in vitro. This has not been observed in islets exposed to IL-1, which suggests that IL-6 does not solely mediate the inhibitory effects of IL-1 on islet function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. 240 46

Eighteen patients were treated with escalating doses of recombinant, Escherichia coli-derived human interleukin-6 (IL-6) intravenously every 8 h. Therapy was given for two cycles of 7 days each separated by a week off therapy. Fevers and chills were observed in most patients. Mild renal and liver function abnormalities were noted at higher doses of IL-6. Dose-limiting toxicity was reached at 30 micrograms/kg i.v. every 8 h due to reversible neurotoxicity, but significant rapidly reversible anemia and hyperglycemia were seen at lower doses. Platelet counts, white blood cell counts, and acute phase reactant levels were substantially elevated. No antitumor responses were seen. A maximum tolerated dose of 10 micrograms/kg i.v. every 8 h for two 7-day cycles is recommended for future phase II trials.
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PMID:A phase I trial of intravenous interleukin-6 in patients with advanced cancer. 752 Mar 34

To clarify the mechanism that causes elevation of plasma fibrinogen levels in diabetes, we examined the effect of high concentration of glucose and/or advanced glycosylation end products (AGEs) on the production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by human monocytes. Monocytes isolated from nine healthy volunteers were incubated with glucose, glucose with mannitol, or glucose with AGE-BSA for 24 or 48 h, respectively. IL-6 and TNF-alpha levels of culture supernatants were measured by ELISA methods. IL-6 and TNF-alpha levels of culture supernatants incubated with 22 mM or 33 mM glucose showed considerable increase over basal levels incubated with 11 mM glucose, whereas those levels incubated with high concentration of mannitol showed no increase. These two cytokine levels of culture supernatants, especially IL-6 level, showed synergistic elevation with AGE-BSA concentration. Our serial observation with treatment for lowering glucose levels showed that the diabetics with decreasing plasma fibrinogen levels also showed decrease in plasma IL-6 levels. In this study, we revealed the effect of glucose and AGEs on the production of IL-6 or TNF-alpha by human monocytes. These results suggest that hyperglycemia and AGEs will cause disregulated production of IL-6 and hyperfibrinogenemia in diabetics.
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PMID:The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. 769 4

Increased plasma levels of fibrinogen and C-reactive protein (CRP), as well as leukocytosis, are now established as risk factors for the thromboembolic complications of vascular disease. Chronic inflammation or infection associated with an acute-phase response--notably, periodontal disease and smoking-induced lung damage--are likewise known to increase cardiovascular risk. A common etiologic factor in these conditions may be interleukin-6 (IL-6), acting on hepatocytes to induce acute-phase reactants that increase blood viscosity and promote thrombus formation. Recent evidence that hypertrophied adipocytes release IL-6, and that hyperglycemia evokes IL-6 production by endothelium, may explain why plasma fibrinogen is increased in visceral obesity and poorly controlled diabetes. IL-6 is released by a range of tissues in response to stimulation by the monocyte-derived cytokines interleukin-1 and tumor necrosis factor; by suppressing production of these cytokines, fish oil, alpha-linolenic acid, and pentoxifylline can reduce IL-6 synthesis. Moderate ethanol consumption, as well as sex-hormone replacement, also appear to inhibit IL-6 production or activity. These practical protective measures may be of particular value to patients with pre-existing atheroma and elevated plasma levels of acute-phase reactants. Since IL-6 plays a crucial physiological role in osteoclast generation and activation, these measures may also aid preservation of bone density.
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PMID:Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. 1041 55

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.
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PMID:Insulin resistance and endothelial dysfunction in atherosclerosis: implications and interventions. 1261 87

Several interacting and mutually perpetuating biochemical pathways or systems, such as the polyol pathway, nonenzymatic glycation, oxidative stress, protein kinase Cbeta and the reninangiotensin system, may be activated as a result of sustained hyperglycemia in diabetes. These abnormally activated pathways may in turn influence several vasoactive factors and cytokines, such as vascular endothelial growth factor, interleukin-6, pigment epithelium-derived factor and endostatin, which are important in mediating the functional and structural changes of diabetic retinopathy. Intricate and interacting regulatory mechanisms involving these factors may control their ultimate ability to produce biologically significant effects. A better understanding of these factors and their interactions may assist in the development of adjuvant therapies for the treatment of diabetic retinopathy. (c) 2002 Prous Science. All rights reserved.
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PMID:Pathophysiology of Diabetic Retinopathy. 1267 48

This review discusses the myocardial protective property of the insulin/glucose-insulin-potassium regimen and the mechanisms involved in this beneficial action. Several recent studies suggest that insulin not only is useful to control hyperglycemia and maintain glucose homeostasis but also may have the unique property to protect the myocardium from reperfusion injury and ischemia and prevent apoptosis of myocardial cells. The insulin/glucose-insulin-potassium (GIK) regimen suppresses the production of tumor necrosis factor-alpha, interleukin-6, macrophage migration inhibitory factor and other pro-inflammatory cytokines, and free radicals; and enhances the synthesis of endothelial nitric oxide and anti-inflammatory cytokines interleukin-4 and interleukin-10. Thus, the insulin/GIK regimen brings about its cardioprotective action. This may also explain why the insulin/GIK regimen is useful in sepsis and septic shock, myocardial recovery in acute myocardial infarction, and critical illness. It is suggested that the infusion of adequate amounts of insulin to patients with acute myocardial infarction, congestive heart failure, cardiogenic shock, and critical illness preserves myocardial integrity and function and ensures rapid recovery. In view of the suppressive action of insulin on the synthesis of proinflammatory cytokines and free radicals, it is possible that the insulin/GIK regimen, when used in a timely and appropriate fashion, may also protect other tissues and organs and facilitate in the recovery of patients who are critically ill.
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PMID:Insulin: an endogenous cardioprotector. 1450 50

Diabetic neuropathy develops as a result of hyperglycemia-induced local metabolic and microvascular changes in both type I and type II diabetes mellitus. Diabetic neuropathy shows slower impulse conduction, axonal degeneration, and impaired regeneration. Diabetic neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves, causing improper locomotor and visceral organ dysfunctions. The pathogenesis of diabetic neuropathy is complex and involves multiple pathways. Lack of success in preventing neuropathy, even with successful treatment of hyperglycemia, suggests the presence of early mediators between hyperglycemia-induced metabolic and enzymatic changes and functional and structural properties of Schwann cells (SCs) and axons. It is feasible that once activated, such mediators can act independently of the initial metabolic stimulus to modulate SC-axonal communication. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), tumor necrosis factor alpha (TNF-alpha), and transforming growth factor beta (TGF-beta), exhibit pleiotrophic effects on homeostasis of glia and neurons in central, peripheral, and autonomic nervous system. These cytokines are produced locally by resident and infiltrating macrophages, lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons. Metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. Moreover, their regulatory roles in nerve degeneration and regeneration may potentially be utilized for the prevention and/or therapy of diabetic neuropathy.
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PMID:Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. 1466 51

There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.
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PMID:Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. 1498 10

Although epidemiologic studies carried out in Taiwan, Bangladesh, and Sweden have demonstrated a diabetogenic effect of arsenic, the mechanisms remain unclear and require further investigation. This paper reviewed the potential biological mechanisms of arsenic-induced diabetes mellitus based on the current knowledge of the biochemical properties of arsenic. Arsenate can substitute phosphate in the formation of adenosine triphosphate (ATP) and other phosphate intermediates involved in glucose metabolism, which could theoretically slow down the normal metabolism of glucose, interrupt the production of energy, and interfere with the ATP-dependent insulin secretion. However, the concentration of arsenate required for such reaction is high and not physiologically relevant, and these effects may only happen in acute intoxication and may not be effective in subjects chronically exposed to low-dose arsenic. On the other hand, arsenite has high affinity for sulfhydryl groups and thus can form covalent bonds with the disulfide bridges in the molecules of insulin, insulin receptors, glucose transporters (GLUTs), and enzymes involved in glucose metabolism (e.g., pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase). As a result, the normal functions of these molecules can be hampered. However, a direct effect on these molecules caused by arsenite at physiologically relevant concentrations seems unlikely. Recent evidence has shown that treatment of arsenite at lower and physiologically relevant concentrations can stimulate glucose transport, in contrary to an inhibitory effect exerted by phenylarsine oxide (PAO) or by higher doses of arsenite. Induction of oxidative stress and interferences in signal transduction or gene expression by arsenic or by its methylated metabolites are the most possible causes to arsenic-induced diabetes mellitus through mechanisms of induction of insulin resistance and beta cell dysfunction. Recent studies have shown that, in subjects with chronic arsenic exposure, oxidative stress is increased and the expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) is upregulated. Both of these two cytokines have been well known for their effect on the induction of insulin resistance. Arsenite at physiologically relevant concentration also shows inhibitory effect on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor important for activating insulin action. Oxidative stress has been suggested as a major pathogenic link to both insulin resistance and beta cell dysfunction through mechanisms involving activation of nuclear factor-kappaB (NF-kappaB), which is also activated by low levels of arsenic. Although without supportive data, superoxide production induced by arsenic exposure can theoretically impair insulin secretion by interaction with uncoupling protein 2 (UCP2), and oxidative stress can also cause amyloid formation in the pancreas, which could progressively destroy the insulin-secreting beta cells. Individual susceptibility with respect to genetics, nutritional status, health status, detoxification capability, interactions with other trace elements, and the existence of other well-recognized risk factors of diabetes mellitus can influence the toxicity of arsenic on organs involved in glucose metabolism and determine the progression of insulin resistance and impaired insulin secretion to a status of persistent hyperglycemia or diabetes mellitus. In conclusions, insulin resistance and beta cell dysfunction can be induced by chronic arsenic exposure. These defects may be responsible for arsenic-induced diabetes mellitus, but investigations are required to test this hypothesis.
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PMID:The potential biological mechanisms of arsenic-induced diabetes mellitus. 1516 43


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