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)

Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. A survey of tissue distribution revealed that MIF expression is not limited to T lymphocytes, but exists in several other tissues; however, its presence in adipose tissue has never been investigated. In this study, we examined the expression of MIF in adipose tissue using the rat epididymal fat pad and murine 3T3-L1 adipocytes. Northern and Western blot analyses revealed the expression of MIF mRNA and MIF protein, respectively, in both the fat pad and the adipocyte cell line. In immunohistochemistry, a positive staining reaction with an anti-rat MIF antibody was detected largely in the cytosol of adipocytes of the epididymal fat pad. To examine the production and release of MIF by adipocytes, we examined its content in the culture medium of the 3T3-L1 adipocytes. The results showed that MIF content was 1.6 +/- 0.48 ng/ml (mean +/- SD) after 24 hr culture, and the content was increased up to 9.7 +/- 2.8 ng/ml by stimulation with TNF-alpha (50 nM). Since TNF-alpha produced in adipocytes is known to induce insulin resistance, the results suggest the possibility that MIF plays an important role in the mechanism of insulin resistance often observed in obesity and diabetes via regulation of TNF-alpha expression.
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PMID:Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-alpha. 919 42

The diabetes-resistant BioBreeding (DR-BB) rat, derived from diabetes-prone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone BioBreeding (DP-BB) rat. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play a role in the development of KRV-induced diabetes in DR-BB rats. Seventy-eight percent of DR-BB rats treated with KRV and poly(I:C) develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP) in KRV and poly(I:C)-treated DR-BB rats results in the near-complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1beta revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets. Measurement of CD4+ T cell-derived cytokines revealed that IL-2 and IFN-gamma cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 do not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and poly(I:C) resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic beta cells, culminating in the development of insulin-dependent diabetes mellitus.
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PMID:Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant BioBreeding rats. 920 Apr 87

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
Diabetes 1997 Sep
PMID:Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. 928 59

TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man. Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPARgamma/ RXR complex is shown by the fact that similar effects are observed with other PPARgamma/RXR ligands such as 15 deoxy Delta12,14PGJ2 and LG268. The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions.
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PMID:Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. 931 88

Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
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PMID:Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. 933 2

The potential role of tumour necrosis factors (TNFs) in autoimmunity and insulin-dependent diabetes mellitus (IDDM) led us to determine in vitro TNF-alpha and lymphotoxin-alpha (LT-alpha, TNF-beta) production in IDDM patients according to TNF polymorphism. LT-alpha production of peripheral blood mononuclear cells (PBMC) was lower in diabetic subjects (m = 0.30 +/- 0.2 ng.10(-6) cells) than controls (m = 0.68 +/- 0.3 ng.10(-6) cells, p < 0.05), and early age-at-onset was correlated with low LT-alpha production (rs = 0.8, p = 0.0006). TNF-alpha production was the same in patients and controls, but patients with HbA1c > or = 8% had a higher TNF-alpha production (m = 3.05 +/- 1.2 ng.10(-6) cells) than those with HbA1c < 8% (m = 1.31 +/- 0.33 ng.10(-6) cells, p < 0.05). A study of the microsatellite TNFa region close to the LTA gene showed that the presence of the TNFa1 allele in HLA-(DR3) subjects was associated with increased risk of IDDM. TNFa1-positive subjects (both patients and controls) also had lower LT-alpha production than other subjects. These results indicate that low LT-alpha production is an additional risk factor for IDDM and that poor glycaemic control in patients is associated with enhanced PBMC TNF-alpha production which causes an imbalance between TNF-alpha and LT-alpha production in IDDM patient.
Diabetes Metab 1997 Sep
PMID:Influence of metabolic and genetic factors on tumour necrosis factor-alpha and lymphotoxin-alpha production in insulin-dependent diabetes mellitus. 934 42

Tumor necrosis factor (TNF)-alpha may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of TNF-alpha-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rats were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After approximately 10 days, rats were infused with TNF-alpha for 4-5 days, producing a plasma concentration of 632 +/- 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a submaximal (24 micromol x kg[-1] x min[-1]) and maximal insulin infusion rate (240 micromol x kg[-1] x min[-1]). TNF-alpha infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 +/- 10 vs. 141 +/- 4 micromol x kg[-1] x min[-1], P < 0.05), maximal GDR (175 +/- 8 vs. 267 +/- 6 micromol x kg[-1] x min[-1], P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 +/- 39 vs. 406 +/- 32 fmol ATP/fmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 +/- 24 vs. 48 +/- 6 micromol/l, P < 0.05) and free fatty acid (FFA) concentration (2.56 +/- 0.76 vs. 0.87 +/- 0.13 mmol/l, P < 0.01). Troglitazone treatment completely prevented the TNF-alpha-induced decline in submaximal GDR (133 +/- 16 vs. 141 +/- 4 micromol x kg[-1] x min[-1], NS) and maximal GDR (271 +/- 19 vs. 267 +/- 6 micromol x kg[-1] x min[-1], NS). The hyperlipidemia was partially corrected by troglitazone (1.53 +/- 0.28 vs. 0.87 +/- 0.13 mmol/l, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug. Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-alpha plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove useful in its treatment.
Diabetes 1997 Nov
PMID:TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. 935 12

Mice that express influenza hemagglutinin under control of the rat insulin promoter (INS-HA) as well as a class II major histocompatibility complex (MHC)-restricted HA-specific transgenic TCR (TCR-HA), develop early insulitis with huge infiltrates, but progress late and irregularly to diabetes. Initially, in these mice, INS-HA modulates the reactivity of antigen-specific lymphocytes, such that outside the pancreas they do not cause lethal shock like their naive counterparts in single transgenic TCR-HA mice, when stimulated with high doses of antigen. Inside the pancreas, the antigen-specific cells do not initially attack the islet cells, and produce some IFN-gamma as well as IL-10 and IL-4. Spontaneous progression to diabetes, which can be accelerated by cyclophosphamide injection, is accompanied by a 10-fold increase in IFN-gamma and a 3-fold decrease in IL-10 and IL-4 production by the locally residing antigen-specific T cells. Also, total islets from non-diabetic mice contain more TNF-alpha, compared with diabetic mice. This scenario is consistent with the view that beta cell destruction depends upon the increased production of certain pro-inflammatory cytokines by infiltrating T cells. Our inability to detect Fas expression on beta cells, but not on lymphoid cells, in diabetic and non-diabetic mice, puts some constraints on the role of Fas in beta cell destruction.
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PMID:Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model. 942 42

In the pathomechanism of the thyroid associated ophthalmopathy (TAO) the inflammatory cytokines produced by infiltrating lymphocytes of the retroorbital tissues are involved. The activated lymphocytes have been shown to secrete a number of cytokines including tumour necrosis factor-alpha, interleukin-1 and interferon-gamma. The widely used immunosuppressive therapies have potential serious side effects. The pentoxifylline (Ptx) is known to have effect on production of cytokines. The aim of this study was to investigate the effect of Ptx on expression of HLA-DR molecules and production of glycosaminoglycan of human retroorbital tissue cultures and potential efficacy in patients with TAO. It was found that pentoxifylline (Ptx) was able to inhibit significantly the HLA-DR expression and glycosaminoglycan synthesis induced by inflammatory cytokines including TNF-alpha, IFN-gamma and IL-1. Ten patients with untreated moderate severe ophthalmopathy (8 female and 2 male) were excluded from steroid treatment due diabetes mellitus and psychiatric disease. Classification of eye changes was made by NOSPECS categories and total eye score. All patients were euthyroid during the study and was no remarkable difference in thyroid function and eye symptoms. Before and during Ptx therapy the laboratory parameters were also determined including glycosaminoglycan. TNF-alpha, anti-TSH-receptor, anti-eye muscle, anti-thyroglobulin and anti-thyroid peroxidase antibodies in the patients'sera. It was found a remarkable improvement in the eye symptoms in eight of ten patients. The levels of glycosaminoglycan (uronic acid) and TNF-alpha gradually decreased in eight patients who considered to be responders. The levels of uronic acid in plasma of the responders were found to be significantly lower after Ptx treatment. Before Ptx therapy the TNF-alpha in the sera was not different remarkably in non-responders and responders. After 4 weeks Ptx treatment the TNF-alpha decreased significantly in responders compared to non-responders (20.9 +/- 4.8 pg/ml v. s. 28.3 +/- 6.1 pg/ml) (p < 0.01). The titre of anti-eye muscle antibodies were found to be lower at the end of observation, however, the anti-thyroid antibodies were not changed remarkably. It was concluded that Ptx in the majority of patients (8/10) has a beneficial effect on inflammatory symptoms of TAO and laboratory parameters and suggested to use as an additive therapy, however, further comparative studies are required for final evaluation of Ptx in the treatment of TAO.
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PMID:[Immunomodulatory effect of pentoxifylline in Graves ophthalmopathy]. 943 36

The purpose of this study was to evaluate the effects of resident islet macrophage activation on beta cell function. Treatment of freshly isolated rat islets with TNF-alpha and LPS results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory actions of TNF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expression by beta cells. The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibitory effects on glucose-stimulated insulin secretion by rat islets. Resident macrophages appear to be the source of IL-1, as a 7-day culture of rat islets at 24 degrees C (conditions known to deplete islets of lymphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite production, and the inhibitory effects on insulin secretion. In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1alpha and IL-1beta mRNA expression in rat islets. Immunocytochemical colocalization of IL-1beta with the macrophage-specific marker ED1 was used to provide direct support for resident macrophages as the islet cellular source of IL-1. IL-1beta appears to mediate the inhibitory actions of TNF + LPS on beta cell function as TNF + LPS-induced expression of IL-1beta is fourfold higher than IL-1alpha, and Ab neutralization of IL-1beta prevents TNF + LPS-induced nitrite production by rat islets. These findings support a mechanism by which the activation of resident islet macrophages and the intraislet release of IL-1 may mediate the initial dysfunction and destruction of beta cells during the development of autoimmune diabetes.
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PMID:Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. 951 Jan 67


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