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

Cytokines are known to play an important role in autoimmunity and have been suggested to be involved in the pathogenesis of insulin-dependent diabetes (IDDM). In the present study we have measured IL-1, IL-2, IL-4, IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) (using both immunoassays and bioassays) in sera from 50 patients affected by IDDM at the time of clinical diagnosis and 51 age and sex matched controls. Detectable levels of IL-1, IL-2, IL-6 and IFN-gamma were found in the serum of a small percentage of subjects and were not significantly different between patients and controls. IL-4 was detectable in a higher number of both patients and controls and circulating TNF-alpha (greater than 1 U/ml) was found in a percentage of patients (24%) significantly higher than controls (P less than 0.01). Raised levels of TNF-alpha were detectable using an immunoenzymatic assay whereas TNF bioactivity in these samples was negligible. We conclude that the presence of immunoreactive TNF-alpha in the patient's sera may reflect an increased localized production of this cytokine at pancreatic level. However, the measurement in serum of other cytokines does not add information on the role that they may play in the pathogenesis of IDDM.
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PMID:Cytokines in sera from insulin-dependent diabetic patients at diagnosis. 193 94

Recently it has been demonstrated that heat shock protein 70 (hsp70) is induced in pancreatic islet cells during prolonged exposure to interleukin 1 beta (IL-1 beta). It is unclear whether this represents a cellular defense against the noxious action of IL-1 beta or whether hsp70 is involved in the suppressive action of the cytokine. To assess the role for hsp70 in isolated islets exposed to IL-1 beta, hsp70 was purified and introduced into cells of isolated rat pancreatic islets via the liposome technique. Delivery of hsp70 was efficient according to immunoblot analysis, but delivered hsp70 disappeared within 16 h. Hsp70-containing liposomes did not affect protein synthesis, insulin secretion, or islet insulin mRNA content. However, when hsp70 liposome-incubated islets were further exposed to IL-1 beta (25 U/ml) for 16 h, these islets released more insulin in response to glucose stimulation and contained more insulin mRNA than islets incubated with control liposomes and subsequently exposed to the cytokine. No protective effect of liposomes containing bovine serum albumin or ovalbumin were observed. We conclude that hsp70 may protect against IL-1 beta-induced impairment of pancreatic beta-cell function.
Diabetes 1991 Nov
PMID:Liposomal delivery of purified heat shock protein hsp70 into rat pancreatic islets as protection against interleukin 1 beta-induced impaired beta-cell function. 193 3

The endothelium is a regulatory organ that mediates hemostasis, contractility, cellular proliferation, and inflammatory mechanisms in the vessel wall. Injury to the endothelium from hypertension, smoking, hyperlipidemia, and diabetes mellitus disrupts normal regulatory properties and results in abnormal endothelial cell function. Clinically, endothelial cell dysfunction can be manifested as vasospasm, thrombus formation, atherosclerosis, or restenosis. The normal hemostatic properties of the endothelium include the maintenance of a nonadhesive luminal surface, antithrombotic properties, anticoagulant properties, and fibrinolytic properties. The endothelial cell regulates smooth muscle cell contractility by the production of relaxing and constricting factors in response to physiologic stimuli. Endothelial cell injury is also an initial event in the development of atherosclerosis and restenosis by facilitating platelet adhesion and aggregation and by signaling the release of mitogens from platelets, macrophages, and endothelial cells, which stimulate smooth muscle cell proliferation. In addition, endothelial cells undergo morphologic and functional alterations in response to cytokine signals, which may contribute to the pathogenesis of vasculitis and atherosclerosis. In sum, the normal endothelium performs many regulatory functions which become altered when the endothelium is injured.
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PMID:Biology of the impaired endothelium. 195 Nov 6

The Biobreeding Worcester rat provides one of the best models of autoimmune diabetes. Immunopathologic studies of acute diabetes show that the islets are infiltrated by T cells and macrophages. It has been hypothesized that the islets are damaged by the secretion of cytokines such as IL-1 and TNF-alpha and that their function may be altered by IL-6. In this study, we utilized in situ hybridization to determine the expression of the IL-1, TNF, and IL-6 genes within the pancreas of the acute diabetic Biobreeding Worcester rat. These studies showed that cells expressing IL-1, TNF, and IL-6 were present within the islets and in the exocrine pancreas surrounding islets, ducts, and vessels and in an interstitial location. Cells expressing TNF and IL-1 mRNA were present in about 20% of the islets, whereas cells expressing IL-6 were present in about 4% of the islets. Islets containing TNF- or IL-1-positive cells contained about three positive cells per islet whereas only about one IL-6-positive cell was present per islet. In 26% of the islets peri-insular TNF-positive cells were found. Peri-insular IL-1 positive cells were seen in 14% of the islets and 8% showed peri-insular IL-6 positive cells. In nondiabetic 30-day old DP or 90-day-old DR rats intra-islet cytokine gene expression was not seen. Our studies support the view that cytokines are important in beta cell destruction.
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PMID:Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat. 201 34

It has been postulated that one of the factors causing immune-mediated pancreatic beta-cell destruction in insulin-dependent diabetes mellitus (IDDM) is interleukin-1 (IL-1). Rat pancreatic islets exposed to human recombinant IL-1 beta (rIL-1 beta) for 48 h in vitro exhibit a markedly reduced glucose-stimulated insulin secretion. Also, a deleterious effect of glucose on beta-cell function, especially under conditions of a reduced beta-cell mass, which may exist in the early phase of IDDM has been suggested. In this study the response of rat pancreatic islets in vitro to a combination of the cytokine and high glucose concentration have therefore been assessed. Thus, islets were cultured for 48 h at either 11.1 or 56 mM glucose with or without 25 U/ml rIL-1 beta. Exposure to the cytokine reduced the islet DNA content at both glucose concentrations by 20-25%. In short-term incubations in the absence of rIL-1 beta after the preceding culture with the cytokine, the glucose-stimulated insulin release was reduced by 70% in islets cultured at 11.1 mM glucose and by only 40% after culture at 56 mM glucose, when compared to the corresponding control islets. The utilization of D-[5-3H]glucose, i.e., the catabolism of glucose in the glycolytic pathway, was the same in all groups of islets. However, the D-[6-14C]glucose oxidation rate, i.e., the metabolism of glucose in the Krebs cycle, was reduced by about 65% in rIL-1 beta exposed islets kept at 11.1 mM glucose and 46% in islets cultured at 56 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism and beta-cell function of rat pancreatic islets exposed to human interleukin-1 beta in the presence of a high glucose concentration. 208 53

Interleukin-1 (IL-1) may be one of the effector molecules involved in the destruction of the pancreatic islet B cells resulting in insulin-dependent diabetes mellitus. Isolated islets exposed to IL-1 show an acutely increased substrate metabolism and insulin release, which is followed by a metabolic and functional suppression. Since an increased cellular uptake of calcium in the islets may be associated with both nutrient-induced insulin release and cell damage, the effects of recombinant IL-1 beta (rIL-beta) on net cellular calcium uptake by isolated rat pancreatic islets were investigated. In short-term experiments the islets were exposed to 25 U/ml rIL-1 beta for 120 min in the presence of 1.7 mM or 16.7 mM glucose, or 16.7 mM glucose plus 5 mM verapamil. In these experiments rIL-1 beta induced an increase both in net cellular uptake of calcium and in insulin release only in the presence of 16.7 mM glucose. The stimulatory effect of rIL-1 beta at 16.7 mM glucose was blocked by verapamil. By long-term experiments, under tissue culture conditions in the presence of 11.1 mM glucose, islet net calcium uptake, insulin release and glucose oxidation were measured at different time points over a 24-h period. During the first 2 h of incubation 25 U/ml rIL-1 beta effected a significant increase of net calcium uptake, insulin release and glucose oxidation. However, after 4-5 h of incubation with the cytokine no such stimulatory effects were seen. After longer incubations with rIL-1 beta all the islet functions studied were suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Short-term exposure of rat pancreatic islets to human interleukin-1 beta increases cellular uptake of calcium. 208 54

Cultured neonatal rat (F344, RT1(1v1)) islets that were devoid of MHC class II (OX6) antigen and antigen-presenting cells were treated with recombinant murine interferon (IFN-gamma) and/or recombinant murine tumor necrosis factor (TNF-alpha) in vitro. The IFN-gamma and TNF-alpha resulted in some disruption of the integrity of the islets by 7 days of culture, but the combination resulted in disaggregation of the islets within 7-8 days. Insulin release into the medium and secretion in response to glucose were adversely affected by the cytokines. The IFN-gamma resulted in expression of class II antigen on about 10% of the endocrine cells after 3-4 days in culture. This effect of IFN-gamma was potentiated by TNF-alpha resulting in 27% of the cells expressing class II antigen. Islets treated with IFN-gamma and TNF-alpha alone or in combination were not rejected in a subsequent transplant underneath the kidney capsule of WF rats (RT1u). We conclude that expression of class II antigen alone is not sufficient to initiate an allogeneic rejection response, but that cytokine-mediated destruction of endocrine cells could be the basis of immune-mediated islet-cell loss in islet-allograft rejection or autoimmune diabetes.
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PMID:Successful allogeneic transplantation of rat islets expressing cytokine-induced major histocompatibility complex class II antigen. 210 45

Cytokine effects on permanent cell lines of transformed mouse pancreatic alpha- and beta-cells were compared. The beta-tumor cell 1 (beta TC1) line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat insulin II promoter) produced insulin predominantly, although small quantities of intracellular glucagon (100:1 insulin to glucagon) were detectable by radioimmunoassay. The alpha TC1 line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat preproglucagon promoter) produced not only glucagon but also considerable quantities of insulin (4:1 glucagon to insulin) and preproinsulin mRNA. We therefore cloned alpha TC1 cells and obtained 12 glucagon-producing clonal cell lines that did not produce levels of insulin detectable by radioimmunoassay. Analysis by Northern blotting of total RNA from two lines, alpha TC1 clones 6 and 9, confirmed the absence of preproinsulin mRNA. No somatostatin or pancreatic polypeptide was detected by immunohistochemical staining in alpha TC1 clones 6 or 9 or beta TC1 cells. Rat recombinant gamma-interferon (IFN-gamma; 5-250 U/ml) or mouse recombinant interleukin 1 (IL-1; 1-25 U/ml) individually inhibited DNA synthesis in beta TC1 cells after 3 days of treatment. The two cytokines in combination acted synergistically to further depress DNA synthesis and increase cytotoxicity. In contrast, alpha TC1 clone 9 cells were not sensitive to inhibition of DNA synthesis by each cytokine individually, although glucagon synthesis was inhibited. The combination of these cytokines caused marked inhibition of DNA and glucagon syntheses in alpha TC1 clone 9 cells. alpha TC1 clone 9 cells were somewhat more resistant to the cytotoxic action of the combined cytokines than were beta TC1 cells. Incubation with 50 U/ml IFN-gamma induced class II MHC molecules (I-Ab, I-Ad, and I-Ed) and enhanced the constitutive expression of class I molecules (H-2Kb and H-2Kd) on the cell surfaces of beta TC1, uncloned alpha TC1, and alpha TC1 clones 6 and 9. Thus, these cell lines are heterozygous for MHC alleles derived from both parental strains used in the construction of the transgenic mice [C57BL/6J (H-2b) and DBA/2J (H-2d)]. Class II gene transcription induced by IFN-gamma was confirmed in beta TC1 and alpha TC1 clone 9 cells by Northern blot analysis with A alpha-, A beta-, E alpha, and E beta-DNA probes.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1990 Apr
PMID:Comparison of cytokine effects on mouse pancreatic alpha-cell and beta-cell lines. Viability, secretory function, and MHC antigen expression. 210 69

The effect of the cytokine interleukin-1 beta on the insulin secretory responsiveness of single beta-cells (HIT-T15) was investigated. In the short-term, IL-1 beta induced a dosage-dependent stimulation of insulin release. In contrast, in the long-term, IL-1 beta, inhibited both basal and secretagogue-stimulated insulin secretion. We also demonstrate the simultaneous presence of specific high and low affinity binding sites for IL-1 beta on beta-cells. IL-1 beta, which has been implicated in the pathogenesis of insulin-dependent diabetes, may therefore mediate its opposing effects on beta-cells through a specific plasma membrane receptor.
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PMID:Insulin-secreting beta-cells possess specific receptors for interleukin-1 beta. 213 89

Normal mouse islet cells express low levels of MHC class I molecules and undetectable or extremely low levels of MHC class II molecules. Class I expression was dose-dependently augmented by incubation with interferon-gamma (IFN-gamma) or tumor necrosis factor (TNF). Although neither IFN-gamma nor TNF alone induce class II molecules on islet cells, synergistic interaction of IFN-gamma (200 U/ml) and TNF (200 U/ml) may induce class II expression on approximately 50% of islet cells. Niacinamide and 3-aminobenzamide, both inhibitors of ADP ribosylation and scavengers of free radicals, attenuated the class II expression induced by IFN-gamma and TNF. Twenty millimolar niacinamide and 10 mM 3-aminobenzamide reduced the rates of class II antigen-positive cells to mean +/- SD 3.6 +/- 0.3 and 6.1 +/- 1.9%, respectively. The agents did not affect the cytokine-induced augmentation of class I antigens. The inhibition of class II molecule expression may at least partly account for the preventive effect of niacinamide on autoimmune-associated beta-cell damage in NOD mice.
Diabetes 1990 Sep
PMID:Inhibition of cytokine-induced MHC class II but not class I molecule expression on mouse islet cells by niacinamide and 3-aminobenzamide. 214 88


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