Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
 ...
PMID:Immune-mediated side-effects of cytokines in humans. 863 83

The macrophage-derived cytokine, interleukin-1 beta (IL-1 beta), has been implicated to play an important role in the autoimmune beta cell lesion of insulin-dependent diabetes mellitus (IDDM) because of its inhibition of insulin secretion, direct cytotoxicity, and alteration of islet cell antigen expression. Because transforming growth factor beta (TGF-beta) has been reported to inhibit IL-1 receptor expression in several lymphoid and progenitor cell lines, to induce IL-1 receptor antagonist protein (IRAP) production in human peripheral blood monocytes, and to antagonize several effects of inflammatory cytokines and because oral tolerance may be mediated in part by TGF-beta released by regulatory T lymphocytes, we investigated whether TGF-beta counteracted the effects of IL-1 beta on islet cells. Islets isolated from Sprague-Dawley rats were cultured with or without recombinant human IL-1 beta and TGF-beta. Accumulated insulin secretion, cytokine-induced cytotoxicity, and islet cell expression of glutamic acid decarboxylase 65 (GAD-65) and heat-shock protein 70 (HSP-70) were measured in this study. We found that (1) IL-1 beta at 50 and 100 pg/ml inhibited insulin secretion by 41.9 +/- 14.8 and 52.6 +/- 3.5% and induced cytotoxicity by 46.5 +/- 17.3 and 54.1 +/- 6.1%, respectively. IL-1 beta at 1000 pg/ml significantly increased HSP-70 expression and decreased GAD-65 expression. (2) TGF-beta at 0.1, 1, 10, and 40 ng/ml had no significant effect on insulin secretion and did not induce cytotoxicity, TGF-beta at 40 ng/ml had no effect on the expression of either HSP-70 or GAD-65. (3) In combination, TGF-beta at 1, 10, and 40 ng/ml did not antagonize the IL-1 beta (50 and 100 pg/ml)-induced inhibition of insulin secretion or cytotoxicity; TGF-beta (40 ng/ml) did not block the effects of IL-1 beta (1000 pg/ml) on HSP-70 or GAD-65 expression. In conclusion, recombinant human TGF-beta does not counteract these effects of recombinant human IL-1 beta on rat pancreatic islet cells.
J Interferon Cytokine Res 1995 Dec
PMID:Recombinant human transforming growth factor beta does not inhibit the effects of interleukin-1 beta on pancreatic islet cells. 874 89

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokine-induced islet beta-cell destruction may be mediated by reactive oxygen intermediates. To determine the possible roles of oxygen free radicals and nitric oxide (NO) as mediators of islet beta-cell destruction, we studied the relationships among cytokine-induced beta-cell destruction, production of malondialdehyde (MDA; an end product of lipid peroxidation), and production of nitrite (the stable end product of NO). The cytokine combination of interleukin-1 beta (50 U/mL), tumor necrosis factor-alpha (10(3) U/mL), and interferon-gamma (10(3) U/mL) induced significant increases in MDA and nitrite and significant decreases in insulin and DNA in islets after 60-h incubation. A novel antioxidant (lazaroid U78518E) significantly inhibited both a strong oxidant. t-butylhydroperoxide, and the combination of cytokines from inducing MDA production, but not from increasing nitrite production in the islets. Also, the lazaroid antioxidant significantly reversed the cytokine-induced decreases in insulin and DNA contents of the islet cultures. In contrast, L-NG-monomethyl arginine, an inhibitor of NO synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in MDA and decreases in insulin and DNA in the islet cultures. In addition, the addition of MDA to the islets produced a dose-dependent decrease in their insulin and DNA contents, and this was only partially prevented by the lazaroid antioxidant. These results suggest that cytokines may be toxic to human islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and aldehyde production in the islets, and that MDA is one of the cytotoxic mediators of cytokine-induced beta-cell destruction.
 ...
PMID:Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production. 878 69

The present study aims to characterize the role of the citrulline-nitric oxide cycle in the response of adult human and rat pancreatic islets to cytokines. Citrulline (0.1-1.0 mM) or arginine (0.1-1.0 mM) led to a similar dose dependent nitric oxide (NO) production by rat islets exposed to interleukin 1 beta (IL-1 beta) or human islets exposed to IL-1 beta + tumour necrosis factor alpha (TNF-alpha) + interferon gamma (IFN-gamma). In the absence of citrulline or arginine cytokines failed to induce NO production. Cytokines induced argininosuccinate synthetase activity in both species. Studies of IL-1 beta exposed rat islets revealed both NO-dependent and NO-independent effects: (1) IL-1 beta inhibits glucose-induced insulin release even in the absence of NO synthesis, but this inhibition is more severe when the presence of citrulline or arginine enables NO production; (2) NO formation in the presence of arginine or citrulline is necessary for cytokine-induced inhibition of protein biosynthesis. In conclusion, the citrulline-NO cycle enables rodent and human islet of Langerhans to regenerate arginine from citrulline and maintain NO production, thus contributing to islet functional inhibition. Considering that arginine availability may be limiting for NO production in vivo, the citrulline-NO cycle may be important for the regulation of NO production during insulitis in early insulin-dependent diabetes mellitus.
Cytokine 1996 Aug
PMID:Role of the citrulline-nitric oxide cycle in the functional response of adult human and rodent pancreatic islets to cytokines. 889 40

Adipocytes produce a variety of molecules that are capable of functioning in both a paracrine and autocrine fashion. Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. This finding has led to the idea that TNF produced by adipocytes functions as a local "adipostat" to limit fat accumulation. Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. These findings raise the possibility that pharmacological inhibition of TNF may provide a novel therapeutic target to treat patients with NIDDM.
Cytokine Growth Factor Rev 1996 Aug
PMID:Inhibition of insulin receptor signaling by TNF: potential role in obesity and non-insulin-dependent diabetes mellitus. 889 94

To assess the clinical value of determination of the interferon (IFN)-producing capacity of patients, IFN production induced by Sendai virus (HVJ) in vitro was measured in cell cultures of whole blood from patients with various diseases. IFN production in patients with lung cancer, myelodysplastic syndromes, noninsulin-dependent diabetes mellitus, pulmonary tuberculosis, and asymptomatic HIV-1 infection was lower than that in healthy persons. Furthermore, periodic measurements of IFN production revealed decreasing IFN producing capacities in patients with lung cancer with progression of the tumor stage. However, increased IFN-producing capacities were observed in patients with tuberculosis after standard therapy. Further experiments showed that the main type of IFN induced in whole blood cultures was IFN-alpha, and decreased IFN production in patients did not result from a decreased number of leukocytes but rather from an impairment of cellular IFN production. The evaluation of IFN production in whole blood cell cultures may be a feasible method of assessing the impaired immune status.
J Interferon Cytokine Res 1996 Nov
PMID:Determination of interferon-alpha-producing capacity in whole blood cultures from patients with various diseases and from healthy persons. 893 66

Cytokines produced by mononuclear leukocytes infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokines may damage islet beta-cells by inducing oxygen free radical production in the beta-cells. Lipid peroxidation and aldehyde production are measures of oxygen free radical-mediated cell injury. In the current study, we used a HPLC technique to measure levels of different aldehydes produced in rat islets incubated with cytokines. The cytokine combination of interleukin-1beta (10 U/ml), tumor necrosis factor-alpha (10(3) U/ml), and interferon-gamma (10(3) U/ml), and the oxidant, t-butylhydroperoxide, induced significant increases in islet levels of the same aldehydes: butanal, pentanal, 4-hydroxynonenal (4-HNE), and hexanal. Cytokine-induced aldehyde production was associated with islet beta-cell destruction. Thus, cytokine-induced increases in malondialdehyde (MDA; at 4 h) and 4-HNE (at 8 h) preceded islet cell destruction (at 16 h), and the addition of 4-HNE, hexanal, MDA, and pentanal (1-200 microM) to th islets, but not other aldehydes at similar concentrations, produced dose-dependent destruction of islet beta-cells. Furthermore, an antioxidant (lazaroid U78518E) prevented cytokine-induced increases in 4-HNE, hexanal, and MDA and significantly inhibited cytokine-induced decreases in insulin and DNA in the islets. In contrast, N(G)-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in 4-HNE, hexanal, and MDA or decreases in insulin and DNA in the islets. These results suggest that cytokines may damage islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and, consequently, the formation of cytotoxic aldehydes in the islet cells.
 ...
PMID:Destruction of rat pancreatic islet beta-cells by cytokines involves the production of cytotoxic aldehydes. 894 Mar 48

Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) in animal models. We extend this therapy to non-insulin-dependent diabetes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow transplantation that also prevented IDDM in animal models. An i.p. or i.v. injection of streptococcal preparation (OK-432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT) in KK-Ay mice for more than 32 h regardless of the glucose loading routes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FBG and GTT for more than 4 wks without body weight loss. The improvement of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induced by OK-432 and BCG, IL-1 alpha, TNF alpha and lymphotoxin significantly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFN gamma did not. There were no differences between the OK-432-treated KK-Ay mice and control in histology of the pancreas, degree of insulin-induced decrease in blood glucose levels, and muscle glycogen synthase activities. As to insulin secretion, there is a tendency that the OK-432-treatment less that 1 week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels. Thus, cytokine-inducers improved FBG and glucose tolerance of NIDDM animals probably via cytokines. The results imply a role of the cytokines in glucose tolerance of NIDDM, although precise immune and metabolic mechanisms remain to be elucidated.
 ...
PMID:Improvement of glucose tolerance with immunomodulators on type 2 diabetic animals. 901 38

Cytokine induced pancreatic beta-cell destruction seen in Type 1 diabetes and islet graft rejection involves multiple intracellular signaling pathways that directly or indirectly lead to inflammatory damage or programmed cell death. IL-1beta has been shown to stimulate the 12-lipoxygenase pathway product 12-HETE, in RIN m5F cells; however, the precise role of 12-LO activation in mediating cytokine effects is not clear. Since the stress-activated protein kinase, JNK, has been linked to cytokine mediated inflammatory actions, we studied the effect of two LO products, 12-HETE and 15-HETE, on JNK activity. We demonstrate that 1 nM 12-HETE stimulates JNK activity, while 1 nM 15-HETE, the 15-lipoxygenase pathway product, does not. These results suggest 12-HETE is a novel upstream signal for IL-1beta induced JNK activation in RIN m5F cells.
 ...
PMID:The stress-activated c-Jun protein kinase (JNK) is stimulated by lipoxygenase pathway product 12-HETE in RIN m5F cells. 901

A CA-repeat polymorphism within the first intron of the interferon (IFN)-gamma gene was analyzed. This polymorphism was recently demonstrated to be associated with insulin-dependent diabetes mellitus (IDDM) in Japanese subjects. We typed 266 IDDM patients and 195 control subjects of Danish Caucasoid origin. No significant differences in allele or genotype frequencies between patients and control were observed. In addition, we typed 168 IDDM and 110 control subjects of Finnish origin. A significant disease association of the studied IFN-gamma allelic pattern was found (p = 0.029). Analysis of data according to HLA-DQB1 susceptibility status did not reveal heterogeneity of risk at the IFN-gamma locus in either of the populations. Fifty-five Danish and 94 Finnish IDDM multiplex families with at least two affected siblings (660 individuals) were typed to test for transmission disequilibrium (TDT). No evidence for overall transmission disequilibrium using either an allele-wise (p = 0.42; combined data) or a genotype-wise analysis (p = 0.21; combined data) could be detected. Thus, the modest significance level observed in the Finnish case-control study and the failure to replicate it by the TDT provide little support for the hypothesis that the IFN-gamma gene microsatellite is associated with IDDM.
J Interferon Cytokine Res 1997 Feb
PMID:Analysis of an interferon-gamma gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish Study Group of Diabetes in Childhood. 905 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>