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)

Patients with diabetes mellitus (DM) show an increased susceptibility to bacterial infections due to the presence of neutrophil dysfunction. Susceptibility to tuberculosis has also been reported in such patients, however, the reason remains unclear. This study measured the production of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) by the peripheral monocytes of patients diagnosed with pulmonary tuberculosis accompanied by DM (TB+DM) and patients without DM complications (TB) using age-matched, healthy control subjects for comparison. Also examined was the relationship between cytokine production and DM control. The results were as follows: (1) The production of IL-1 beta, TNF alpha and IL-6 in TB patients was significantly higher than that observed in the healthy control subjects. (2) The production of IL-1 beta, TNF alpha and IL-6 in TB+DM patients was significantly lower than that observed in the TB patients. (3) The production of IL-1 beta and TNF alpha in TB+DM patients with poor control was significantly lower than that observed in the patients with good control. (4) The TNF alpha production had a significant inverse correlation to HbA1c in the TB+DM patients. This study demonstrated that the production of cytokines is impaired in TB+DM patients and suggests a close correlation between tuberculosis immunity and DM.
 ...
PMID:[Case study of interleukin-1 beta, tumor necrosis factor alpha and interleukin-6 production peripheral blood monocytes in patients with diabetes mellitus complicated by pulmonary tuberculosis]. 129 80

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1 beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1 beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1 beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells. 132 36

Nitric oxide has recently been implicated as the effector molecule that mediates IL-1 beta-induced inhibition of glucose-stimulated insulin secretion and beta-cell specific destruction. The pancreatic islet represents a heterogeneous cell population containing both endocrine cells (beta-[insulin], alpha-]glucagon], gamma[somatostatin], and PP-[polypeptide] secreting cells) and non-endocrine cells (fibroblast, macrophage, endothelial, and dendritic cells). The purpose of this investigation was to determine if the beta-cell, which is selectively destroyed during insulin-dependent diabetes mellitus, is both a source of IL-1 beta-induced nitric oxide production and also a site of action of this free radical. Pretreatment of beta-cells, purified by FACS with IL-1 beta results in a 40% inhibition of glucose-stimulated insulin secretion that is prevented by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (NMMA). IL-1 beta induces the formation of nitric oxide by purified beta-cells as evidenced by the accumulation of cGMP, which is blocked by NMMA. IL-1 beta also induces the accumulation of cGMP by the insulinoma cell line Rin-m5F, and both NMMA as well as the protein synthesis inhibitor cycloheximide prevent this cGMP accumulation. Iron-sulfur proteins appear to be intracellular targets of nitric oxide. IL-1 beta induces the formation of an iron-dinitrosyl complex by Rin-m5F cells indicating that nitric oxide mediates the destruction of iron-sulfur clusters of iron containing enzymes. This is further demonstrated by IL-1 beta-induced inhibition of glucose oxidation by purified beta-cells, mitochondrial aconitase activity of dispersed islet cells, and mitochondrial aconitase activity of Rin-m5F cells, all of which are prevented by NMMA. IL-1 beta does not appear to affect FACS-purified alpha-cell metabolic activity or intracellular cGMP levels, suggesting that IL-1 beta does not exert any effect on alpha-cells. These results demonstrate that the islet beta-cell is a source of IL-1 beta-induced nitric oxide production, and that beta-cell mitochondrial iron-sulfur containing enzymes are one site of action of nitric oxide.
 ...
PMID:Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. 133 75

In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin-1 beta (IL-1 beta) gene and for correlations to monocyte (Mo) function in non-related healthy donors and insulin-dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin-dependent diabetes mellitus (IDDM). However, when analysing IDDM patients negative for HLA-DR3 and -DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL-1 beta response. An IL-1 beta allele dosage effect on secretory capacity was observed after LPS-stimulation: 13.4/13.4 kb homozygous individuals secreted significantly more IL-1 beta than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9.4 kb homozygous individuals. Analyses of supernatants from LPS-stimulated Mo cultures from individuals with each TaqI IL-1 beta genotype revealed no differences in the mouse thymocyte co-stimulatory assay when compared on a molar basis, indicating that the TaqI polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. 135 22

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Aug
PMID:Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. 137 15

Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homoeostatic mechanisms. There are two IL-1's (alpha and beta) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis and autoimmune diseases such as nephritis, vasculitis and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak and death occur in animals after a combination of tumour necrosis factor (TNF) and IL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-1-specific receptor antagonist (IL-1ra), which shares 40% conserved amino-acid homology with IL-1 beta, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-1ra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-1ra reduces the spontaneous production of growth factors and proliferation of leukaemic cells. The IL-1ra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel, arthritis and cancer.
 ...
PMID:Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. 139 23

Insulin-dependent diabetes mellitus is characterized by progressive autoimmune destruction of pancreatic Beta cells mediated by ill-defined effector mechanisms. Experimental data suggest that cytokines, e.g. interleukin 1 and tumor necrosis factor, could play a fundamental role. The aim of this study was to analyze the effect of recombinant IL-1 beta (rIL-1 beta) on both islet functional capacity and morphology, using long-term cultures and various glucose concentrations. Islet cultured with 1 g/l (5.5 mmol/l) glucose maintained normal insulin- secretion and morphology for more than two months. In contrast, islets cultured with 2 g/l (11 mmol/l) glucose showed an altered insulin secretion and a shorter survival (40 days). At 11 g/l (60 mmol/l) glucose, islets died by 2 weeks of culture. rIL-1 beta exerted a cytotoxic effect on islet cells only when added to cultures containing supraphysiological glucose concentrations. But, in the presence of 1 g/l glucose, the addition of rIL-1 beta (40 ng/ml) for prolonged periods (14 days), did not alter islet function. Our results suggest that in auto-immune type I diabetes, IL-1 beta represents an aggravating factor in lesion formation more than a primary pathogenic mechanism.
 ...
PMID:The effects of interleukin-1 on pancreatic beta cell function in vitro depend on the glucose concentration. 147 95

It was recently proposed that the increased levels of modified lipoproteins in diabetic patients may be responsible for the accelerated development of macrovascular complications associated with the disease. Modified lipoproteins are believed to induce the transformation of macrophages into foam cells and, in some cases, to induce endothelial cell damage. In addition, modified lipoproteins trigger an immune response leading to the formation of antibodies and then to the formation of LDL-containing immune complexes. In this review, we summarize the evidence linking LDL glycation and oxidation with intracellular accumulation of cholesterol esters and foam-cell formation, and we discuss their potential for inducing an autoimmune response and the formation of lipoprotein-containing immune complexes. The formation of LDL-ICs seems particularly significant, because these ICs are avidly taken up by macrophages through their Fc receptors and induce not only massive intracellular accumulation of CE but also a paradoxical increase in LDL-receptor expression. Our experimental data suggest that the uptake of LDL-IC is facilitated by RBC adsorption, in agreement with the role of RBC in the adsorption of circulating IC and their delivery to phagocytic cells. In addition, macrophages are activated when ingesting LDL-IC and release IL-1 beta and TNF-alpha, which can contribute to the initiation and progression of an atheromatous lesion by several mechanisms. Although it is difficult to envisage how LDL-IC could initiate an endothelial lesion, it is easy to speculate about their role as cofactors in the initiation and progression of the atherosclerotic process.
Diabetes 1992 Oct
PMID:Immune mechanisms of atherosclerosis in diabetes mellitus. 152 43

Interleukin (IL) 1 is an important mediator of local and systemic disease. Blocking IL-1 using the IL-1 receptor antagonist has reduced the severity of disease in animal models of septic shock, diabetes, graft-vs-host disease, inflammatory bowel disease, and the spontaneous proliferation of leukemia cells. Blocking IL-1 and reduction in the synthesis of IL-1 are important strategies for reducing the progression of inflammatory disease and autoimmune diseases. Nature, however, maintains control over the synthesis of IL-1 by dissociating transcription for translation. In this paper, the basis for the dissociation of IL-1 beta synthesis of mRNA from synthesis of the IL-1 beta protein is reviewed.
 ...
PMID:Dissociation of transcription from translation of human IL-1 beta: induction of steady state mRNA by adherence or recombinant C5a in the absence of translation. 153 18

Previous studies have determined that daily low dose injections of the potent cytokine interleukin-1 beta (IL-1 beta) decreased the frequency of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone (DP) BB rats. In contrast, high dose injections induced an earlier than normal onset. In this study we tested whether the effects of daily human recombinant IL-1 beta injections on leukocyte subsets were associated with its modulation of IDDM onset in BB rats. Prior to the onset of IDDM in DP BB rats, high dose IL-1 beta induced leukocytosis (P less than 0.05), neutrophilia (P less than 0.01), and monocytosis (P less than 0.001). At the onset of IDDM, lymphocyte (P less than 0.01) and neutrophil (P less than 0.001) numbers were increased in high dose treated DP rats but not in rats given saline or low dose IL-1 beta. In 60-day-old diabetes-resistant (DR) BB rats, neurophilia was induced by both low (P less than 0.05) and high (P less than 0.001) dose IL-1 beta without the development of IDDM. At 130 days of age, when the rats were killed, it was discovered that 14/22 (64%) IL-1 beta injected DR rats developed neutralizing IL-1 beta antibodies. Significantly lower neutrophil numbers were observed in high dose DR rats which developed IL-1 beta antibodies compared with those which did not (P = 0.032). Thus, neutrophilia was dissociated from high IL-1 beta acceleration of IDDM onset.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:In vivo effects of interleukin-1 beta on blood leukocytes in BB rats prone or resistant to diabetes. 158 67


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