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

Non-insulin-dependent (type II) diabetes mellitus is associated with significant abnormalities of lipoprotein metabolism. Control of glycemia rarely completely corrects the alterations in lipid metabolism, suggesting a participation of environmental and genetic factors. The observation that tumor necrosis factor (TNF) can modulate triglyceride metabolism offers a new genetic candidate to be analyzed. Samples of DNA from 91 control subjects and 61 diet-treated type II diabetic patients were analyzed to determine the lipid profile and a possible association with TNF genetic polymorphisms. For TNF restriction fragment length polymorphisms, we used the Nco I restriction enzyme and a TNF-alpha probe obtaining two allelic bands at 10.5 and 5.5 kb. We found a significant association (P < .01) of the 10.5-kb homozygous genotype in type II diabetic subjects with high triglyceride levels. Furthermore, these patients showed significant differences in triglycerides as compared with matched control subjects with the same genotype (P < .001). This study provides support for considering the TNF locus as a susceptibility genetic region in the hypertriglyceridemia of type II diabetes.
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PMID:A tumor necrosis factor-beta polymorphism associated with hypertriglyceridemia in non-insulin-dependent diabetes mellitus. 778 49

Autoimmune destruction of beta-cells in nonobese diabetic (NOD) mice is greatly accelerated by adoptive cotransfer of syngeneic CD4+ and CD8+ T-cells from diabetic animals into newborn NOD mice. We followed, by in situ hybridization, the appearance of mRNA of the tumor necrosis factor (TNF)-alpha gene and, as a marker for activated cytotoxic T-cells, of the serine protease granzyme A gene in the cellular infiltrates generated by cell transfer at birth. Cells expressing the genes for granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer. These numbers gradually increased in the intra-islet infiltrates from day 14 through day 30 after adoptive transfer. Compared with our previous findings in NOD mice developing spontaneous insulin-dependent diabetes mellitus (IDDM) (Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C: Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87:2239-2243, 1990), frequencies of cells with TNF-alpha and granzyme A mRNA were 2- and 12-fold higher, respectively, in transferred IDDM (trIDDM). TNF-alpha mRNA positive cells were predominantly found in the CD4+ T-cell subset of the pancreas-infiltrating cells, whereas granzyme A mRNA positive cells were mainly observed in the CD4- T-cell subset. The effects of the observed enhanced TNF expression upon the pathogenesis of trIDDM are as yet unknown.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jan
PMID:Accelerated beta-cell destruction in adoptively transferred autoimmune diabetes correlates with an increased expression of the genes coding for TNF-alpha and granzyme A in the intra-islet infiltrates. 781 5

Tumour necrosis factor (TNF) has been implicated in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). To investigate a possible role for TNF in IDDM we compared endogenous TNF production in two lines of non-obese diabetic (NOD) mice, NOD/Lt and NOD/WEHI, that have a high and low incidence of diabetes, respectively. Preliminary experiments had shown that the lower syngeneic mixed lymphocyte reaction (SMLR) in NOD/Lt mice could be corrected by TNF-alpha. Plasma TNF-alpha was measured in 8 week-old female non-diabetic mice primed with 1000 units IV of murine interferon gamma (IFN-gamma) followed after 3 hours by 5 micrograms IV of lipopolysaccharide (LPS). Two hours later plasma was collected and TNF measured by ELISA. Plasma TNF in NOD/Lt mice was 9.2 +/- 2.4 ng/ml (mean +/- SEM, n = 16) compared to 2.5 +/- 0.5 ng/ml in NOD/WEHI mice (n = 15) and 7.6 +/- 1.0 ng/ml in BALB/c mice (n = 14). Time course studies demonstrated higher levels of both immunoreactive and bioactive TNF in NOD/Lt compared to NOD/WEHI mice up to 4 hours post-stimulation. A separate group of female NOD/Lt mice had IFN-gamma/LPS-stimulated plasma TNF-alpha measured at 10 weeks and were followed to age 30 weeks. The mean stimulated plasma TNF-alpha level was consistently higher in those mice that developed diabetes compared to those that remained non-diabetic, the difference being significant when mice were 21 weeks of age. These results suggest that endogenous TNF-alpha production may be a trait marker of IDDM susceptibility.
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PMID:Endogenous TNF production differs between high and low diabetes incidence non-obese diabetic (NOD) mice. 785 1

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

Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. 794 48

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

Evaluations of glomerular mRNA levels encoding for PCNA, TNF-alpha, PDGF-A and -B chains, TGF-beta, IGF-I, bFGF, and EGF were made at 4, 12, and 24 wk after injection of STZ in Sprague-Dawley rats. The mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF increased with age in STZ-induced diabetic rats. At 24 wk after STZ injection, mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF were increased 3.8-fold, (P < 0.01), 4.2-fold (P < 0.01), 4.0-fold (P < 0.01), 5.2-fold (P < 0.001), and 3.6-fold (P < 0.01), respectively, in the glomeruli of diabetic rats when compared with control rats. In contrast, mRNA levels for IGF-I, PDGF-A chain, and EGF were not altered in glomeruli from diabetic and control rats throughout the experimental period. Insulin treatment partially ameliorated the increase in mRNA levels for PCNA, TNF-alpha, PDGF-B chain, TGF-beta, and bFGF in the glomeruli of diabetic rats. These data indicate that alterations in growth factor mRNA levels in glomeruli may be a manifestation of diabetic nephropathy, and that hyperglycemia or insulin deficiency may play a role in abnormal growth factor gene regulation.
Diabetes 1993 Mar
PMID:mRNA expression of growth factors in glomeruli from diabetic rats. 809 59

The characteristic three-dimensional cell type organization of islets of Langerhans is perturbed in animal models of diabetes, suggesting that it may be important for islet function. Rat islet cells in culture are able to form aggregates with an architecture similar to native islets (pseudoislets), thus providing a good model to study the molecular basis of islet architecture and its role in islet function. Sorted islet B cells and non-B cells were permanently labeled with two different fluorescent dyes (DiO and DiI), mixed, and allowed to form aggregates during a 5-d culture in the presence or absence of TNF-alpha (100 U/ml), a cytokine suggested to be implicated in the early physiological events leading to insulin-dependent diabetes mellitus. Confocal microscopy of aggregates revealed that TNF-alpha reversibly perturbs the typical segregation between B and non-B cells. Insulin secretion, was altered in the disorganized aggregates, and returned towards normal when pseudoislets had regained their typical architecture. The homotypic adhesion properties of sorted B and non-B cells cultured for 20 h in the presence or absence of TNF-alpha were studied in a short term aggregation assay. TNF-alpha induced a significant rise in Ca(2+)-independent adhesion of B cells (from 24 +/- 1.1% to 44.3 +/- 1.2%; n = 4, P < 0.001). These findings raise the possibility that the increased expression of Ca(2+)-independent adhesion molecules on B cells leads to altered islet architecture, which might be a factor in the perturbation of islet function induced by TNF-alpha.
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PMID:Tumor necrosis factor-alpha modifies adhesion properties of rat islet B cells. 809 44

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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