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

Tumor necrosis factor beta (TNF-beta) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-beta in the regulation of inflammation and type 1 diabetes, we produced transgenic mice in which the murine TNF-beta gene was regulated by the rat insulin II promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-beta in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes.
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PMID:Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. 127 67

Tumor necrosis factor (TNF) is a protein hormone implicated in the development of septic shock and other pathologic states. However, complexities inherent in detecting TNF synthesis by individual tissues have left the precise origins of this protein undefined. In addition, the possibility that localized TNF production may contribute to the pathogenesis of organ-specific diseases such as type I diabetes has not been explored in vivo. We have developed a transgenic mouse line bearing a reporter gene construct in which the TNF coding sequence and introns are replaced by a chloramphenicol acetyltransferase (CAT) coding sequence. In normal transgenic animals, CAT activity is expressed only in the thymus. When endotoxin is administered to the animals, CAT activity is also evident in kidney, heart, islets of Langerhans, spleen, lung, fallopian tubes, and uterus, but not in other organs. The biosynthesis of CAT in vivo correlated with tissue capacity to secrete TNF in vitro. Thus, TNF was secreted by all the tissues that expressed CAT, including lung, spleen, thymus, uterus/fallopian tubes, pancreatic islets, renal glomeruli, and cultured cardiac cells after exposure to endotoxin.
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PMID:The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. 152 26

Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Oct
PMID:Role of cytokines in inducing hyperlipidemia. 152 45

Endothelial cells form the luminal vascular surface and thus have a central role in the regulation of coagulation. One important way in which endothelial cells control the clotting system is by regulating the expression of binding sites for anticoagulant and procoagulant factors on the cell surface. In the quiescent state, endothelial cells maintain blood fluidity by promoting the activity of numerous anticoagulant pathways, including the protein C/protein S pathway. After activation, as can be brought about by cytokines, the balance of endothelial properties can be tipped to favor clot formation through coordinated induction of procoagulant and suppression of anticoagulant mechanisms. Tumor necrosis factor suppresses the endothelial anticoagulant cofactor thrombomodulin and induces expression of the procoagulant cofactor tissue factor. Working in concert, these changes can allow fibrin formation to proceed in an inflamed focus but maintain blood fluidity in the surrounding area of normal vasculature. Recent studies suggest that similar changes in endothelial coagulant properties can be induced by advanced glycosylation end products, proteins modified by glucose that accumulate in the vasculature at a rapid rate in diabetic subjects, indicating the potential relevance of these mechanisms in diabetic vascular disease.
Diabetes Care 1991 Feb
PMID:Endothelium and regulation of coagulation. 206 Apr 25

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
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PMID:Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. 767 83

Tumor necrosis factor (TNF) bioactivity was assessed in culture media conditioned with uterine cells collected from control or diabetic rats on days 5 and 8 of pregnancy. On both days, diabetic uterine cells released significantly more biologically active TNF than did control cells, and this activity was significantly decreased by the addition of anti-TNF-alpha antibodies but not by the addition of normal IgG when WEHI 164 cells were used as a target. When uterine tissues from day 5 or day 8 pregnant diabetic rats were tested by Northern blot analysis, TNF-alpha mRNAs were twofold more abundant than in control samples, but the difference was not statistically significant (P = 0.086 and 0.100, respectively). Immunohistochemical analysis of diabetic day 5 uterine sections revealed that most of the TNF-alpha synthesis occurs in the epithelium lining the uterine lumen. Finally, the growth of day-5 embryos in culture medium conditioned with day-5 diabetic uterine cells was significantly reduced when compared with that of embryos in medium conditioned with control cells. Embryonic development was markedly improved when anti-TNF-alpha antibodies were added to the diabetic-cell conditioned medium. Our data support the hypothesis that TNF-alpha may be implicated in the developmental deficiencies observed in preimplantation embryos from pregnant diabetic rats.
Diabetes 1995 May
PMID:Possible role for TNF-alpha in early embryopathy associated with maternal diabetes in the rat. 772 11

Tumor necrosis factor-alpha (TNF) is a multifunctional protein hormone that contributes to host defense and perinatal immunologic development. Dysregulated TNF production, however, occurs during the pathogenesis of autoimmune diseases and may be inherent to their development. In animal models of autoimmunity, dysregulated TNF synthesis has resulted from mutations in TNF gene regulatory sequences, specifically those sequences involved in translational control of TNF gene expression. In this study, we have determined whether mutations in the TNF translational control sequences are present in pediatric patients with type I diabetes mellitus and connective tissue diseases. Blood samples were collected from 48 patients with connective tissue diseases, 32 patients with diabetes, and 29 controls. A 250-bp fragment of the translational control sequences present in the TNF 3'-untranslated region was amplified by the polymerase chain reaction, sequenced, and analyzed relative to the published TNF sequence. In this study, all patients and controls exhibited the normal sequence, with no insertions or deletions in the translational control motifs. We conclude that polymorphisms in the TNF 3'-untranslated region occur infrequently, if at all, in patients with diseases examined here.
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PMID:Sequence analysis of the tumor necrosis factor gene in pediatric patients with autoimmunity. 773 52

Tumor necrosis factor-alpha (TNF alpha) is a cytokine implicated in the development of septic shock, cachexia, and other pathological states. Recent studies indicated a direct role for adipose expression of TNF alpha in obesity-linked insulin resistance and diabetes. Pioglitazone, CP-86,325 (CP), AD-5075, CS-045, ciglitazone, and englitazone are members of a new class of insulin-sensitizing thiazolidinedione derivatives with in vivo antidiabetic activities. To test whether these agents antagonize the effect of TNF alpha, 3T3-L1 cells were induced to differentiate in the presence of TNF alpha with or without thiazolidinedione derivatives. Incubation of 3T3-L1 cells with TNF alpha alone completely inhibited adipocyte conversion and expression of fatty acid-binding protein messenger RNA (mRNA). However, coincubation of TNF alpha-treated cells with CP (1 microM), AD-5075 (1 microM), pioglitazone (10 microM), or CS-045 (10 microM) blocked these effects. Long term incubation of 3T3-L1 adipocytes with a low dose of TNF alpha (50 pM) significantly decreased the levels of the adipocyte/muscle-specific glucose transporter (GLUT4) and the CCAAT enhancer-binding protein mRNAs, but did not affect expression of the ubiquitously expressed glucose transporter (GLUT1) or lipoprotein lipase mRNAs. Incubation of 3T3-L1 adipocytes with TNF alpha also inhibited insulin-stimulated 2-deoxyglucose uptake as well as expression of GLUT4 protein. Furthermore, in 3T3-L1 adipocytes, incubation with TNF alpha attenuated the expression of fatty acid-binding protein mRNA in a time- and dose-dependent manner. These inhibitory effects were partially or completely blocked by coincubation of the cells with CP. These results implicate that the insulin-sensitizing agents may exert their antidiabetic activities by antagonizing the inhibitory effects of TNF alpha.
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PMID:Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. 789 57

Tumor necrosis factor (TNF) is implicated in wasting syndromes and insulin resistance in chronic infection and obese-linked diabetes. TNF (10 ng/ml) inhibited adipocyte differentiation of 3T3-L1 cells, and in these TNF treated cells little insulin-stimulated glucose uptake was observed. Treatment of 3T3-L1 cells with troglitazone (1-10 microM) partially prevented this inhibitory effect of TNF on adipogenesis, and enhanced expression of C/EBP alpha and GLUT4, even in the presence of TNF. Troglitazone also prevented the inhibitory effects of interleukin-1, interleukin-6, and leukemia inhibitory factor, but not of transforming growth factor beta on adipocyte differentiation of 3T3-L1 cells. These effects might contribute to the antidiabetic effect of troglitazone in obese diabetic animals.
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PMID:Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3-L1 cells. 795 51

Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells.
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PMID:Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. 806 45


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