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

Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.
Diabetes 1994 Nov
PMID:Tumor necrosis factor alpha: a key component of the obesity-diabetes link. 792

Hereditary hemochromatosis is a prevalent inherited disorder with an estimated frequency of homozygosity of 0.2 to 0.45% in Caucasians. The disease is characterized by progressive iron overload until a massive accumulation of body iron occurs. Undetected, the disorder eventually can produce either cirrhosis, diabetes mellitus, cardiac disease, arthritis, or hepatocellular carcinoma or a combination of these manifestations. Early diagnosis and treatment prevents organ damage and normalizes life expectancy. Screening studies to detect hemochromatosis are most effectively accomplished by measurement of the serum iron and total iron binding capacity. Treatment is most effectively performed by frequent phlebotomy until body stores are empty and then 3 to 4 times yearly for life. The basic defect of hemochromatosis appears to increase iron absorption, decrease iron excretion, and produce preferential deposit of iron in hepatic parenchymal cells rather than Kupffer cells. The genetic abnormality of hemochromatosis is located on chromosome 6 in close association with the gene for HLA antigens. Recent speculation postulates that tumor necrosis factor may be involved in the etiology of this disease because of its location on chromosome 6 and its effect upon iron transport.
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PMID:Hereditary hemochromatosis: a prevalent disorder of iron metabolism with an elusive etiology. 794 87

Interstitial cystitis is a syndrome of urinary urgency, frequency and suprapubic pain. We investigated the role of inflammatory mediators in 96 patients with histories and symptoms consistent with interstitial cystitis, and 13 controls from The New York Hospital-Cornell Medical Center, University of Washington and University of California at San Diego. Patients were classified into either group A (meets all criteria of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases for inclusion in research studies), group B (meets all of these criteria but without glomerulations) or an "other" group. A small number of group A patients had detectable interleukin-6 in the urine. Urinary concentrations of tumor necrosis factor, prostaglandins E2, D2 and F2 alpha, and thromboxane B2 were not different among either patient groups or controls. Urine specimens contained inhibitors of the bioactivity of interleukin-6 and tumor necrosis factors but no differences between patients or controls were found. No factors chemotactic for human neutrophils were detected in a small patient sample. Bladder wash fluid concentrations of prostaglandins E2, D2 and F2 alpha, and thromboxane were much lower than urinary levels. Bladder wash fluid interleukin-6 and tumor necrosis factor were not detectable. The results suggest that while a small subset of patients may have elevated levels of interleukin-6 the majority of patients do not appear to have elevated levels of inflammatory mediators in the urine or bladder wash fluid. Evaluation of patient bladder tissue may indicate changes not detectable in urine or bladder wash fluid. Alternatively, other etiologies must be considered in those patients.
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PMID:Inflammatory mediator profile in urine and bladder wash fluid of patients with interstitial cystitis. 801 71

In patients with insulin-dependent (Type 1) diabetes mellitus abnormal endothelial cell proliferation was considered as one of the possible explanations for the occurrence of retinopathy. Since monocyte-derived factors have been proposed to be involved in endothelial cell growth regulations we have measured the effect of monocyte-conditioned medium (MO-CM) on endothelial cell proliferation and the production of Tumor necrosis factor alpha and interleukin 1-beta, cytokines known to alter endothelial cell functions. The effect of MO-CM in 20 patients with Type 1 diabetes and proliferative retinopathy on endothelial cell proliferation estimated on [3H] thymidine incorporation, was lower to that observed with the MO-CM in 20 normal controls but the difference did not reach the statistical level of significance. The basal tumor necrosis factor alpha secretion expressed by monocytes was significantly lower in the MO-CM from Type 1 diabetes patients (median: 0.49, range 0.13-2.86 ng/10(6) monocytes) than in the MO-CM from the control subjects (median: 1.84, range: 0.13-7 ng-10(6) monocytes) p < 0.02. The increase in interleukin 1-beta and in tumor necrosis factor alpha production after lipopolysaccharide stimulation were similar in the 2 groups. A low basal tumor necrosis factor production per monocyte may contribute to the development of the diabetic complications as it is involved in several cellular regulation processes.
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PMID:Monokines and endothelial cell proliferation in patients with diabetes mellitus. 805 34

We have investigated the correlation between different tumor necrosis factor (TNF) and class II major histocompatibility complex alleles in the lipopolysaccharide- or phytohemagglutinin-induced secretion of TNF-alpha and TNF-beta by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals. Significant differences in TNF-alpha secretory capacity between TNF NcoI restriction fragment length polymorphisms, TNFa and TNFc microsatellite alleles and DR alleles were identified. No correlation with TNF-beta secretory capacity was found for any of the markers studied. TNF genotyping allowed us to define four extended HLA haplotypes which correlate with TNF-alpha secretory capacity. Two of these are DR4 positive: DQw8, DR4, TNFB*1, TNFa6, B44, A2 and DQw8, DR4, TNFB*2, TNFa2, B15, A2. Individuals carrying the TNFB*2, TNFa2 haplotype had a higher TNF-alpha secretory capacity than those carrying the TNFB*1, TNFa6 haplotype. In a group of DR3/DR4 heterozygous patients with insulin-dependent diabetes mellitus (IDDM), the frequency of the TNFa2 allele was higher than in HLA-DR matched controls, whereas the TNFa6 allele was more frequent in control individuals. In the DR3/DR4 heterozygous diabetic group 12/26 had the alleles combination DQw8, DR4 (Dw4), C4A3, TNFB*2, TNFa2, B15, whereas only 1/18 controls had this haplotype. This diabetogenic haplotype is identical to the DR4 haplotype which correlates with a higher TNF-alpha response. These observations suggest a direct role for the TNF locus in the pathogenesis of IDDM.
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PMID:Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. 809 42

Cytokines have been regarded as effector molecules responsible for beta-cell death and major histocompatibility complex hyperexpression in endocrine pancreas of type I diabetes. However, the mechanism that results in beta-cell-selective destruction has not been elucidated. We demonstrated in this study, using cell lines of transformed mouse beta-cells and alpha-cells, that only pancreatic beta-cells but not alpha-cells produced tumor necrosis factor-alpha when exposed to interleukin-1 beta. Northern blot analysis confirmed the beta-cell-selective expression of tumor necrosis factor-alpha mRNA. Interleukin-1 beta also provoked tumor necrosis factor-alpha mRNA expression in vitro by normal mouse islet cells. Because tumor necrosis factor-alpha has been shown to potentiate beta-cell cytotoxicity of interleukin-1 and interferon-gamma, tumor necrosis factor-alpha produced in situ by beta-cells might be self-destructive. In fact, a low dose of interleukin-1 beta in combination with a low dose of interferon-gamma preferentially injured beta-cells. Hence endogenous tumor necrosis factor-alpha production by beta-cells may be involved in beta-cell-selective destruction in type 1 diabetes.
Diabetes 1993 Jul
PMID:Pancreatic beta-cell-selective production of tumor necrosis factor-alpha induced by interleukin-1. 809 83

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we examined the role of nitric oxide (NO) as a mediator of cytokine-induced islet beta-cell destruction in a rat insulinoma cell line (RINm5F). The cytokine combination of interleukin-1 beta (IL-1 beta; 10 U/ml), tumor necrosis factor-alpha (10(3) U/ml), and interferon-gamma (10(3) U/ml) induced DNA fragmentation (first detected at 6 h), mitochondrial damage (by 12 h), and death (by 24 h) of RIN cells, whereas the individual cytokines did not have these destructive effects. Also, the cytokine combination of IL-1 beta, tumor necrosis factor-alpha, and interferon-gamma induced a 10-fold increase in NO production by RIN cells, and L-NG-monomethyl arginine, an inhibitor of NO synthase, produced a dose-dependent inhibition of cytokine-induced NO production, DNA fragmentation, and cell destruction. However, IL-1 beta, acting alone, induced a 7-fold increase in NO production without causing DNA fragmentation, mitochondrial damage, or cell destruction. In addition, nicotinamide, a known inhibitor of ADP ribosylation and scavenger of oxygen free radicals, inhibited cytokine-induced DNA fragmentation and cell destruction without affecting NO production. We conclude that stimulation of NO production may be a necessary, but not sufficient, condition for cytokine-induced destruction of islet beta-cells.
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PMID:Mechanisms of cytokine-induced destruction of rat insulinoma cells: the role of nitric oxide. 811 36

The macrophage-derived cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) have direct effects on pancreatic beta cells and have been hypothesized to play important roles in the autoimmune beta cell lesion of type I diabetes because of two major effects on beta cells: altered insulin secretion and beta cell cytotoxicity. High doses of IL-1 are cytotoxic to beta cells and strongly inhibit insulin release; high-dose IL-1 plus TNF acts synergically to suppress further the insulin release. In contrast, we observed that the predominant effect of low-dose IL-1 and TNF when administered separately was the stimulation of insulin release. We therefore asked whether the combination of low-dose IL-1 plus TNF would act synergistically to stimulate or suppress insulin release. Studies were performed on cultured rat islets and both insulin release and cytotoxicity (51Cr release) were measured. After 2 days of culture, increasing doses of IL-1-25, 50, 75 and 100 ng/l--caused progressively increased cytotoxicity and impaired insulin release. In contrast, the lowest dose of IL-1 tested, 10 ng/l, increased insulin release but was still slightly cytotoxic. Tumor necrosis factor at doses of 10, 25, 62.5, 75 and 100 micrograms/l also was slightly cytotoxic but increased insulin release. The augmented insulin release declined progressively with increasing TNF dose. However the combination of insulin stimulatory doses of IL-1 (10 ng/l) and TNF (62.5 micrograms/l) suppressed insulin release. The effects of these two cytokines on insulin release demonstrated a similar pattern after 4 and 6 days of culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression. 813 Aug 98

Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.
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PMID:Tumor necrosis factor alpha inhibits signaling from the insulin receptor. 819 47

Several studies have implicated tumor necrosis factor (TNF)-alpha in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In the present study we analyzed the first reported TNF-alpha gene polymorphism in relation to IDDM. We have made frequence analysis and tested in vitro lipopolysaccharide (LPS)-induced TNF-alpha secretion. A significant difference in allele frequency was observed between patients and controls (p = 0.03). However, a very strong association of the uncommon TNF2 allele was observed with the HLA-B8, -DR3 alleles. The relative risk (RR) of TNF2 was 2.2 compared to a RR of 3.1 for DR3. One reason for this difference was the identification of the TNF1 allele on the otherwise strongly IDDM-associated HLA-DR3 haplotype: DQB1*0201, DQA1*0501, DRB1*0301, TNFc2, TNFB*2, TNFa1, TNFb5, B18. Thus, the IDDM-associated TNF2 allele had no DR3-independent value as a disease marker. The LPS-induced TNF-alpha production by human monocytes in relation to genotypes demonstrated that TNF1/2 heterozygous individuals had higher, though not statistically significantly (p = 0.08) levels than TNF1-homozygous subjects. However, this difference was rather small, unlikely to be of biological significance and based on the present material we cannot establish the functional importance of this polymorphism.
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PMID:No independent association between a tumor necrosis factor-alpha promotor region polymorphism and insulin-dependent diabetes mellitus. 822 82


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