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)

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Nov
PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

We have previously reported that the mRNA levels of extracellular matrix (ECM) components including alpha 1(I), alpha 1(III), and alpha 1(IV) collagen chains, laminin B1 and B2 chains, and growth factors including tumor necrosis factor (TNF)-alpha, platelet-derived growth factor (PDGF)-B chain, transforming growth factor (TGF)-beta, and basic fibroblast growth factor (FGF) all increase with age in diabetic glomeruli. The present study was designed to assess whether glomerular expression of these mRNAs in rat diabetic glomeruli is affected by a specific endothelin receptor A antagonist, FR139317. Diabetes was produced by streptozotocin injection, and animals were divided into four groups: untreated diabetic rats, FR139317-treated diabetic rats, control nondiabetic rats, and FR139317-treated control rats. FR139317 treatment was continued for 24 weeks. FR139317 attenuated the rise in creatinine clearance (P < 0.01) and reduced urinary protein excretion (P < 0.01) in diabetic rats, but did not affect blood pressure. FR139317 attenuated the increases in glomerular mRNA levels of alpha 1(I) (P < 0.01), alpha 1(III) (P < 0.01), and alpha 1(IV) (P < 0.01) collagen chains, laminin B1 (P < 0.01) and B2 (P < 0.01) chains, TNF-alpha (P < 0.01), PDGF-B (P < 0.01), TGF-beta (P < 0.001) and basic FGF (P < 0.01) in diabetic rats. However, FR139317 did not affect these mRNA levels in glomeruli of control rats. These findings suggest that FR139317 may be useful in the treatment of diabetic glomerulopathy by reducing mRNA levels of ECM components and growth factors.
Diabetes 1995 Aug
PMID:Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. 762 93

Nitric oxide (NO) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus. beta-Cells express the inducible form of NO synthase (iNOS) and produce large amounts of NO upon exposure to cytokines. iNOS requires the amino acid arginine for NO formation. It has been shown in other cell types that interferon-gamma (IFN gamma) and bacterial lipopolysaccharide induce the enzyme argininosuccinate synthetase (AS), enhancing the capacity of these cells to regenerate arginine from citrulline and maintain NO production in the presence of low arginine concentrations. To characterize the messenger RNA (mRNA) expression of AS in insulin-producing cells, RINm5F cells (RIN cells) were exposed to interleukin-1 beta (IL-1 beta) or to tumor necrosis factor-alpha plus IFN gamma. After 4-6 h, there was a significant and parallel induction of AS and iNOS mRNA. IL-1 beta-induced AS and iNOS mRNA expression was prevented by an inhibitor of the activation factor NF-kappa B pyrrolidine diaminoguanidine, an inhibitor of gene transcription (actinomycin D), and a blocker of protein synthesis (cycloheximide), suggesting coregulation of AS and iNOS by cytokines. RIN cells exposed to IL-1 beta in the presence of citrulline but the absence of arginine had increased AS enzyme activity and produced NO, demonstrating that cytokine-induced AS mRNA expression is accompanied by increased AS activity. Both adult rat islets exposed to IL-1 beta and human pancreatic islets cultured in the presence of IL-1 beta, tumor necrosis factor-alpha, and IFN gamma were able to use citrulline to regenerate arginine and produce NO. Taken as a whole, the present data suggest that regulation of AS activity may play a role in modulation of NO production in both rodent and human insulin-producing cells.
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PMID:Expression of the citrulline-nitric oxide cycle in rodent and human pancreatic beta-cells: induction of argininosuccinate synthetase by cytokines. 762 52

Protective effects of essential fatty acid deficiency (EFAD) on autoimmunity were shown in rodents. Our goal was to investigate the mechanisms of EFAD effects on autoimmune diabetes in nonobese diabetic (NOD) mice. Weanling female mice were randomized between a control diet group and an EFAD diet group, and the development of diabetes and immune response was determined over a 6-month period. The cumulative incidence of diabetes was significantly reduced in the EFAD group (20 vs 68.75% in the control group; p < 0.01), without affecting the insulitis process. Splenocyte reactivity to phytohemagglutinin and anti-CD3 antibody was significantly increased in EFAD-fed mice (p < 0.01). The EFAD group also exhibited a dramatic increase in baseline (29-fold) and antigen-presenting cell (APC)-stimulated (10-fold) T cell responses in syngeneic mixed leukocyte reaction. These responses were associated with a marked increase in splenocyte interleukin-4 (IL-4) production, a reduction in interferon-gamma production, and a down-regulation of CD45RB isoform expression. Macrophages in the EFAD group exerted a reduced suppressive effect on concanavalin A-induced splenocyte proliferation and were found to release increased amounts of tumor necrosis factor-alpha and IL-1 and reduced amounts of prostaglandin E2. These results clearly demonstrate that EFAD prevents diabetes in NOD mice. The data suggest an enhanced activity of Th2-like cells, as well as an effect on APC activity linked to alteration in eicosanoid metabolism.
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PMID:Essential fatty acid deficiency prevents autoimmune diabetes in nonobese diabetic mice through a positive impact on antigen-presenting cells and Th2 lymphocytes. 766 43

To clarify the mechanism that causes elevation of plasma fibrinogen levels in diabetes, we examined the effect of high concentration of glucose and/or advanced glycosylation end products (AGEs) on the production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by human monocytes. Monocytes isolated from nine healthy volunteers were incubated with glucose, glucose with mannitol, or glucose with AGE-BSA for 24 or 48 h, respectively. IL-6 and TNF-alpha levels of culture supernatants were measured by ELISA methods. IL-6 and TNF-alpha levels of culture supernatants incubated with 22 mM or 33 mM glucose showed considerable increase over basal levels incubated with 11 mM glucose, whereas those levels incubated with high concentration of mannitol showed no increase. These two cytokine levels of culture supernatants, especially IL-6 level, showed synergistic elevation with AGE-BSA concentration. Our serial observation with treatment for lowering glucose levels showed that the diabetics with decreasing plasma fibrinogen levels also showed decrease in plasma IL-6 levels. In this study, we revealed the effect of glucose and AGEs on the production of IL-6 or TNF-alpha by human monocytes. These results suggest that hyperglycemia and AGEs will cause disregulated production of IL-6 and hyperfibrinogenemia in diabetics.
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PMID:The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. 769 4

We measured serum levels of tumor necrosis factor-alpha (TNF-alpha) in 48 children with insulin-dependent diabetes mellitus (IDDM), divided into two groups according to disease duration (group I < 6 months and group II > 3 years): group I 15 patients, aged 2.2-13.7 years, and group II 33 patients, aged 4.5-25.5 years. Thirty-six age- and sex-matched healthy subjects served as controls. TNF-alpha levels were measured by immunoradiometric assay. We found that TNF-alpha levels were lower in all IDDM patients (29.65 +/- 3.83 pg/ml) than in controls (74.74 +/- 10.17 pg/ml) (p < 0.0001), as well as in group I (24.07 +/- 3.65 pg/ml) and group II (32.16 +/- 5.29 pg/ml) as compared to controls (p < 0.001). TNF-alpha levels were significantly lower in patients with antibodies than in those without antibodies and in controls. Similar results were found in longstanding IDDM patients. No correlation was found between serum TNF-alpha and chronologic age, duration of disease, metabolic control, insulin requirement and HLA typing. During a 1-year follow-up study in 12 group I patients no significant variations in TNF-alpha levels were observed. It has been reported that the administration of exogenous TNF suppresses the development of diabetes in nonobese diabetic mice, low producers of endogenous TNF. The results suggest that aberrant TNF-alpha synthesis may contribute to immune dysregulation thus favoring the development of autoimmune diseases.
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PMID:Low serum levels of tumor necrosis factor-alpha in insulin-dependent diabetic children. 778 51

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

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of beta-cell destruction by which expression of ICAM-1 on beta-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic beta-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet beta-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jul
PMID:Expression of intercellular adhesion molecule 1 on pancreatic beta-cells accelerates beta-cell destruction by cytotoxic T-cells in murine autoimmune diabetes. 778 42

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

We retrospectively analyzed the clinical presentation of non-insulin-dependent diabetes mellitus (NIDDM) in patients with idiopathic interstitial pneumonia (IIP). Between 1977 to 1993, 75 patients with IIP were admitted to our hospital. None had previously received corticosteroids. To compare the incidence of NIDDM with other pulmonary diseases and the degree of obesity, we randomly selected 200 patients without IIP who were admitted to our hospital in 1992 and 160 healthy subjects. We analyzed weight indices using two methods, body mass index and weight as a percentage of ideal body weight. Eighteen patients (24.0%) with IIP and 9 patients (4.5%) in the disease control group had NIDDM (p < 0.001). As the incidence of NIDDM is approximately 10% in Japan, it was suggested that these IIP patients showed a high prevalence of accompanying NIDDM. Among females, patients with IIP showed a strong tendency toward obesity compared with the healthy control subjects (p < 0.001), but this was not noted among males. Female patients with NIDDM showed a strong tendency toward obesity compared to those without NIDDM, but this was not noted among males. Although the correlation between IIP and NIDDM is unclear, we noted recent reports that advanced glycation and products can stimulate macrophages to secrete tumor necrosis factor and interleukin-1 in vitro, and can stimulate free radical generation by early glycation products in vitro. These cytokines and oxygen radicals may play a role in the pathogenesis or induction of IIP.
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PMID:[Clinical study of patients with idiopathic interstitial pneumonia accompanied by diabetes mellitus]. 785 68


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