UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to evaluate the effects of resident islet macrophage activation on beta cell function. Treatment of freshly isolated rat islets with TNF-alpha and LPS results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory actions of TNF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expression by beta cells. The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibitory effects on glucose-stimulated insulin secretion by rat islets. Resident macrophages appear to be the source of IL-1, as a 7-day culture of rat islets at 24 degrees C (conditions known to deplete islets of lymphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite production, and the inhibitory effects on insulin secretion. In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1alpha and IL-1beta mRNA expression in rat islets. Immunocytochemical colocalization of IL-1beta with the macrophage-specific marker ED1 was used to provide direct support for resident macrophages as the islet cellular source of IL-1. IL-1beta appears to mediate the inhibitory actions of TNF + LPS on beta cell function as TNF + LPS-induced expression of IL-1beta is fourfold higher than IL-1alpha, and Ab neutralization of IL-1beta prevents TNF + LPS-induced nitrite production by rat islets. These findings support a mechanism by which the activation of resident islet macrophages and the intraislet release of IL-1 may mediate the initial dysfunction and destruction of beta cells during the development of autoimmune diabetes.
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PMID:Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. 951 Jan 67

When aiming at preventing IDDM in man, knowledge of the molecular mechanisms leading to beta cell destruction may facilitate identification of new possible intervention modalities. A model of IDDM pathogenesis in man suggests that cytokines, and IL-1 in particular, are of major importance in the initial events (Nerup et al 1994) (Fig. 1). In vitro rat experiments demonstrated that rhIL-1 beta inhibits beta cell function and induces beta cell death both in isolated islets of Langerhans and in the isolated perfused pancreatic gland. With the long term goal of identifying new modalities capable of preventing IDDM in man, the aim af this review was to investigate the effects of rhIL-1 beta on beta-cell function and viability in normal rats. This review discussed 1) the pharmacokinetics of IL-1 beta in rats as the basis for choice of route of administration and dose of rhIL-1 beta, 2) the effects and molecular mechanisms of IL-1 beta on temperature and food intake used as control parameters for successful injection of rhIL-1 beta in rats, 3) the effects of one or more injection of IL-1 beta on rat beta cell function, 4) the molecular mechanisms leading to IL-1 beta induced beta cell inhibition in vivo, and some possible intervention modalities based on the molecular mechanisms, 5) the effects of IL-1 beta on spontaneous diabetes mellitus in DP BB rats, and 6) the effects and molecular mechanisms of IL-1 beta induced inhibition of thyroid epithelial cell function and aggravated thyroiditis in DP BB rats, compared to the effects of IL-1 beta on rat beta cell function. Finally, this review discussed the effects of IL-1 beta on human beta cells in vitro, and the clinical relevance of these experiments, with special reference to a clinical trial with the aim of preventing IDDM in man. The pharmacokinetic studies suggested that IL-1 beta is distributed according to a two-compartment model with a first-order elimination. Interleukin-1 beta reached all the investigated organs in the rats, was accumulated in kidneys and was excreted in the urine. The data suggested that IL-1 beta also accumulated in the islets of Langerhans. After injection of 4.0 micrograms/kg pathophysiologically relevant concentrations of rhIL-1 beta were reached and intact rhIL-1 beta persisted for up to 5 hrs in plasma. Peripheral injections of IL-1 beta dose-dependently induced fever and anorexia in rats, probably via induction of PGE2 in the brain or in peripheral tissues thereafter passing the blood-brain barrier. Nitric oxide produced by cNOS seems to be a molecular mediator of IL-1 beta induced fever but not of anorexia. Fever and anorexia are well described effects of IL-1 beta in rats, and are as such usefull control parameters of the absorption and biological activity of IL-1 beta after peripheral injection. Injections of rhIL-1 beta to normal, non-diabetes prone rats induced initial beta cell stimulation followed by inhibition, in accordance with in vitro data. Furthermore, induction of peripheral insulin resistance coincided with beta cell inhibition after one daily injection for 5 days, leading to a transient diabetes mellitus-like state, characterized by hyperglycemia and hypoinsulinemia. At this time point, electron-microscopy did not demonstrate beta cell destruction. However, IL-1 beta induced intercellularly edema and microvillous processes on the beta cells, which might be early evidence of apoptosis. The diabetes mellitus-like state was not aggravated if the daily injections were continued beyond 5 days. Daily injections of rhIL-1 beta for 2 to 4 weeks induced formation of blocking IL-1 beta-antibodies in normal rats. Hence, injections exceeding 2 weeks should only be performed using species homologous IL-1 beta. The molecular mechanism of IL-1 beta induced beta cell inhibition in rats in vivo as in vitro, are likely to involve binding of IL-1 beta to the IL-1RtI, since the IL-1RtII is considered to be a decoy receptor. (ABSTRACT TRUNCATED)
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PMID:Interleukin-1 beta induced transient diabetes mellitus in rats. A model of the initial events in the pathogenesis of insulin-dependent diabetes mellitus? 958 1

Polymorphonuclear neutrophils (PMN) and monocytes play a role in vascular diseases. Animal experimental models, using deleukocytation or injection of anti-CD11b-anti-CD18 monoclonal antibodies (inhibition of leukocytic adhesion and of interaction with the endothelial cell) have confirmed this role in the ischemia-reperfusion syndrome and in myocardial infarction. In man, increased production of oxygen radicals, PMN release of elastase, increased monocyte formation of tissue factor (TF) and integrins have been noted in coronary artery disease, in chronic arteriopathy of the lower limbs and in association with vascular risk factors such as diabetes. Pharmacological alteration of leukocyte hyperactivity therefore seems to be justified. Pentoxifylline, used with good effect in arteriopathy of the lower limbs, affects numerous leukocytic functions: diminution in adherence and in PMN production of free radicals, diminution in the formation of TF and cytokines (TNF). Gingkolides reduce leukocytic interactions and platelet activation through an anti-PAF (Platelet Activation Factor) action. Aspirin may interfere with free radicals and inhibit TF formation. alpha-tocopherol blocks the activation, by free radicals, of the transcription factor NF k B. By altering the TNF and IL-1 cytokines, leukocytic activation can be controlled. Other cytokines (IL-4, IL-10) have an immunosuppressive action and reduce the formation of TF. The pharmacological targets are therefore multiple. Their use in vascular diseases is only at a very preliminary stage.
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PMID:[Modulators of leukocytic functions]. 960 25

Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.
Diabetes Metab Rev 1998 Jun
PMID:An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. 967 67

Resident macrophages have been suggested to participate in the initiation of beta cell damage during the development of autoimmune diabetes. The purpose of this study was to determine if the endogenous production and release of interleukin 1 (IL-1) in human islets of Langerhans by resident macrophages results in the inhibition of beta cell function. Treatment of human islets with a combination of tumor necrosis factor (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stimulates inducible nitric oxide synthase (iNOS) expression, nitric oxide production, and inhibits glucose-stimulated insulin secretion. The IL-1 receptor antagonist protein (IRAP) prevents TNF + LPS + IFN-gamma-induced iNOS expression and nitrite production, and attenuates the inhibitory effects on glucose-stimulated insulin secretion by human islets. Inhibition of iNOS activity by aminoguanidine also attenuates TNF + LPS + IFN-gamma-induced inhibition of insulin secretion by human islets. These results indicate that the inhibitory effects of TNF + LPS + IFN-gamma are mediated by nitric oxide, produced by the actions of IL-1 released endogenously within human islets. Reverse transcriptase polymerase chain reaction was used to confirm that TNF + LPS + IFN-gamma stimulates the expression of both IL-1alpha and IL-1beta in human islets. Two forms of evidence indicate that resident macrophages are the human islet cellular source of IL-1: culture conditions that deplete islet lymphoid cells prevent TNF + LPS + IFN-gamma-induced iNOS expression, nitric oxide production, and IL-1 mRNA expression by human islets; and IL-1 and the macrophage surface marker CD69 colocalize in human islets treated with TNF + LPS + IFN-gamma as determined by immunohistochemical analysis. Lastly, nitric oxide production is not required for TNF + LPS + IFN-gamma-induced IL-1 release in human islets. However, cellular damage stimulates IL-1 release by islet macrophages. These findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells.
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PMID:IL-1 produced and released endogenously within human islets inhibits beta cell function. 969 Oct 88

The cellular and molecular requirements for beta-cell damages in an immune-mediated toxin-induced insulin-dependent diabetes mellitus have been studied in the model of multiple low-dose streptozotocin-induced diabetes in rats and mice. It was found that strain-related susceptibility to diabetes induction correlated with a higher level of IL-2, IFN-gamma, and TNF-alpha production, whereas such differences were not observed when IL-1 and NO production by macrophages were analyzed; elimination of immunoregulatory RT6+T cells that increases IFN-gamma production, enhances susceptibility to MLD-STZ-induced diabetes; mercury-induced Th-2 cells down-regulated the disease; IFN-gamma-mediated macrophage activation to produce proinflammatory cytokines rather than NO is an important event in early diabetogenic effects of invading macrophages; inhibition of IL-1 activity downregulates diabetes induction; and generation of NO in beta cells appears to be important for diabetogenic effects. Taken together, data indicate that MLD-STZ diabetes induced by Th-1 lymphocytes that secrete soluble effector molecules that activate macrophages and promote destruction of beta cells possibly by both nitric oxide and nonnitric oxide-mediated mechanisms.
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PMID:Effector mechanisms in low-dose streptozotocin-induced diabetes. 971 13

Insulin-dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages - insulitis and diabetes - and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non-universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100% of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL-18, IL-12 and TNF-alpha were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL-1 -beta, IL-6 and IFN-gamma, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact-mediated mechanisms of beta cell death.
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PMID:Cellular and molecular changes accompanying the progression from insulitis to diabetes. 993 6

Induction of interleukin 1 activates vascular endothelial and kidney mesangial cells, and increases production of type IV (basement membrane) collagen. Hence, genes within the interleukin 1 gene cluster are potential candidates in the pathogenesis of diabetic nephropathy. In a previously validated case-control study from Northern Ireland, consisting of 95 patients with insulin-dependent (type 1) diabetes and nephropathy (cases) and 96 patients with insulin-dependent (type 1) diabetes without nephropathy (controls), the authors performed PCR-based genotyping of specific DNA polymorphisms within the interleukin 1A, interleukin 1B, interleukin 1 (type 1) receptor and interleukin 1 receptor antagonist genes. The groups were matched for age at onset and duration of diabetes. A statistically significant increase was found in the allele frequency of the interleukin 1B*2 allele in cases compared to controls (chi2=7. 19, df.=1; P=0.007, Pcorr=0.028). The results of this study suggest that the interleukin 1B*2 allele, or a susceptibility factor in linkage disequilibrium with this allele, is associated with diabetic nephropathy in the Northern Ireland population.
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PMID:An interluekin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy. 1004 23

Recent studies suggest that Fas expression on pancreatic beta cells may be important in the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by flow cytometry to directly identify which cells express Fas and Fas ligand (FasL) ex vivo and after in vitro culture with cytokines. Fas expression was not detected on beta cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-gamma was required to achieve sufficient Fas expression and sensitivity for islets to be susceptible to lysis by soluble FasL. In islets isolated from older (>/=125 days) NOD mice, Fas expression was detected on a limited number of beta cells (1-5%). FasL was not detected on beta cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also, both NOD and MRLlpr/lpr islets were equally susceptible to cytokine-induced cell death. This eliminates the possibility that cytokine-treated murine islet cells commit "suicide" due to simultaneous expression of Fas and FasL. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated apoptosis of islet cells. These findings indicate that beta cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated beta cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes.
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PMID:Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. 1041 60

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.
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PMID:[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. 1042 20

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