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

Many clinical and experimental data are in favour of a participation of leukocytes in vascular disease. Diabetes, a risk factor, is associated with a dysfunction of neutrophils. If chemotaxis and phagocytosis are deficient, it is not clearly established whether superoxide generation is conserved in these patients. We have measured this function in 35 noninsulin dependent diabetic patients, compared with a control population. We have assessed, in parallel, a profile of the cytokines involved in vascular phenomenons including TNF alpha, IL-1 beta et IL-6. Our results indicate that the generation of free radicals is normal in diabetics, with a significant elevation of TNF alpha. These results suggest a possible participation of this cytokine in the modulation of granulocyte reactivity.
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PMID:[Respiratory burst of neutrophils and cytokine profile in the non-insulin-dependent diabetic]. 765 Apr 34

Syngeneic pancreatic islet grafts in nonobese diabetic (NOD) mice elicit a cell-mediated autoimmune response that destroys the insulin-producing beta cells in the islet graft. IL-4 and IL-10 are cytokines that inhibit cell-mediated immunity. In this study, we evaluated the effects of IL-4 and IL-10 on the survival of syngeneic pancreatic islets transplanted into diabetic NOD mice. Islet grafts survived beyond 18 days and normoglycemia was maintained in 67% (10 of 15) of mice treated with IL-4 plus IL-10, but in none (0 of 20) of vehicle-injected (control) mice. Also, 40% (6 of 15) of the mice treated with IL-4 plus IL-10 were normoglycemic at 30 days after transplantation, compared with 14% (1 of 7) of the mice treated with IL-4 alone, 8% (1 of 13) of the mice treated with IL-10 alone, and none (0 of 20) of the control mice. Histological examination of grafts at 10 days after transplantation revealed peri-islet accumulations of mononuclear leukocytes and intact islet beta cells in grafts from IL-4 plus IL-10-treated mice, whereas islets were infiltrated by leukocytes and the beta cell mass was greatly reduced in grafts from control mice. Polymerase chain reaction (PCR) analysis of cytokine mRNA expression in the grafts revealed higher levels of IL-2, IFN gamma, and IL-10 mRNA in grafts of diabetic compared with normoglycemic control mice, whereas IFN gamma and TNF alpha mRNA levels were significantly decreased in grafts of IL-4 plus IL-10-treated mice compared with either normoglycemic or diabetic control mice. These results suggest that T helper (Th)1 cells and their cytokine products (IL-2, IFN gamma, and TNF alpha) may promote islet beta cell destructive insulitis and autoimmune diabetes recurrence in syngeneic islet-transplanted NOD mice, and that administration of IL-4 plus IL-10 may inhibit diabetes recurrence by suppressing Th1 cytokine production in the islet grafts.
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PMID:Combined therapy with interleukin-4 and interleukin-10 inhibits autoimmune diabetes recurrence in syngeneic islet-transplanted nonobese diabetic mice. Analysis of cytokine mRNA expression in the graft. 765 67

Previously we reported that the administration of human (h) lymphotoxin (h-LT) markedly protected NOD mice from insulin-dependent diabetes mellitus (IDDM) partly by affecting the generation phase of anti-islet effector cells, probably in the thymus. In this study, we investigated the effect of h-LT on the signal transduction of the mouse thymocytes by observing c-Fos expression in the thymocytes by using a flow cytometer. The intensity of c-Fos expression in whole thymocytes was significantly lower in the female NOD with a high incidence of diabetes than that in the male NOD mice with a low incidence of diabetes and than that in normal mice (P < 0.0001). The low c-Fos expression in the female NOD thymocytes was most prominent in CD3low thymocytes. c-Jun expression of the CD3low thymocytes was also lower in the female NOD mice. Administrations of h-LT, h-TNF, and h-IL-2, which has been reported to prevent IDDM in NOD mice by systemic administration, significantly up-regulated c-Fos expression in CD3low thymocytes. From these results, it is assumed that a relationship may exist between the high diabetes incidence and the defective c-Fos expression in female NOD mice and between the prevention of IDDM and the amelioration of the defective c-Fos expression with h-LT in female NOD mice.
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PMID:Reduced expression of c-Fos in female NOD mouse thymocytes and up-regulation with human lymphotoxin. 765 36

To understand the role of TNF in the regulation of inflammation and the development of autoimmune diseases such as insulin-dependent diabetes mellitus, we produced transgenic mice in which the synthesis of murine TNF-alpha was directed by the rat insulin II promoter. The expression of the TNF-alpha transgene was restricted to the pancreas, in contrast to TNF-beta expression from the same promoter, in which the transgene was expressed in the pancreas, kidney, and skin. The expression of TNF-alpha in the pancreas of transgenic mice resulted in an overwhelming insulitis, composed of CD4+ and CD8+ T cells and B220+ B cells, considerably greater than that of TNF-beta transgenics. Moreover, in contrast to the predominant peri-insulitis observed in TNF-beta transgenic mice, the majority of the infiltrate in the TNF-alpha transgenic mice was within the islet itself. These unique patterns of infiltration were observed in the F1 progeny of crosses with C57BL/6 as well as NOD. Both TNF-alpha and TNF-beta transgenic mice show elevated expression of leukocyte adhesion molecules VCAM-1 and ICAM-1 in islet endothelia and increased expression of MHC class I on islet cells. This inflammation did not result in reduced insulin content of the islets, nor did it lead to diabetes. These data suggest that additional stimuli are necessary to initiate the process of islet destruction.
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PMID:Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. 768 90

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

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

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 +/- 40 vs. 530 +/- 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 +/- 0.22 vs. 4.72 +/- 0.24 micrograms/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Oct
PMID:Monokine antagonism is reduced in patients with IDDM. 792 95

Because the etiology of insulin-dependent diabetes mellitus (IDDM) is thought to be autoimmune, several clinical trials have utilized immunosuppression to treat newly diagnosed diabetic patients. In the University of Miami trial, cyclosporine A (CyA) was used to treat one group (n = 10), while the other received placebo (n = 13). During the 1-year study, islet beta-cell function was better preserved in the CyA group compared to the placebo group, based on the response (C-peptide production) to a physiologic stimulus (meal challenge). Specifically, when measured by regression analysis, the slope defining the rate of decline of beta-cell function was significantly lower for the CyA-treated group (p < 0.05). Cytokine levels were analyzed retrospectively from frozen (-70 degrees C) stored sera from both groups. At time 0, tumor necrosis factor alpha (TNF alpha) levels were similar in the CyA (40.1 +/- 14.2 pg/mL) and placebo group (38.5 +/- 12.1 pg/mL) of IDDM subjects (normal 32.0 +/- 5.0 pg/mL). At 1 month, the level of TNF alpha in the CyA group was significantly lower than that observed in the placebo group (22.3 +/- 7.2 versus 53.3 +/- 8.9 pg/mL (P < .05). TNF alpha levels subsequently fell in the placebo group and were not significantly different between placebo and CyA groups. Soluble interleukin 2 receptor (IL-2R) levels in IDDM patients were significantly higher than in normal subjects at diagnosis of IDDM. For the next 6 months, these levels fell consistently in both the CyA and placebo groups.(ABSTRACT TRUNCATED AT 250 WORDS)
J Diabetes Complications
PMID:Effect of cyclosporine A on serum tumor necrosis factor alpha in new-onset type I (insulin-dependent) diabetes mellitus. 816 86

Upon stimulation with lipopolysaccharide (LPS), peritoneal macrophages from diabetes-prone Bio-Breeding (BB) rats secrete more tumour necrosis factor-alpha (TNF-alpha) than macrophages from diabetes-resistant BB or normal Wistar rats. Enhanced transcription was demonstrated by Northern blot analysis and at the single cell level by mRNA: RNA hybridization. Cytofluorometry analysis showed 2-4 times more plasma membrane and total cell-associated TNF-alpha in macrophages of diabetes-prone BB rats. The analysis of fluorescence intensity showed a single peak, and TNF-alpha mRNA was found in > 90% of macrophages. These findings exclude TNF hypersecretion as being due to an abnormal subfraction of cells. TNF-alpha gene hyperexpression in diabetes-prone BB rats was not due to mutations in the regulatory regions of the promoter, which could be shown by cloning and sequencing of the TNF-alpha promoter in the three rat strains. When searching for other regulatory defects we found the production of prostaglandin E2 (PGE2) in response to LPS to be up to 10 times lower in macrophages from diabetes-prone BB rats than from Wistar rats. Furthermore, BB rats macrophages required significantly higher concentrations of PGE2 for suppression of TNF-alpha secretion. We conclude that abnormal TNF-alpha production in macrophages from diabetes-prone BB rats is due to enhanced gene transcription and translation and that this is associated with defective PGE2 feedback inhibition.
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PMID:Abnormal TNF-alpha production in diabetes-prone BB rats: enhanced TNF-alpha expression and defective PGE2 feedback inhibition. 820 14

Insulin-dependent diabetes is an autoimmune disease specifically targeting the pancreatic beta cells and several observations, both experimental and clinical, suggest that the interaction of the immune system with the beta cells is in part determined by the functional state of the target cells, increased beta cell activity resulting in augmented immunologic mechanisms and vice versa for suppressed beta cell activity and decreased immune attack. In this study we investigated whether cytokine induced islet cell cytotoxicity in vitro was in part dependent on the functional state of the beta cells. Cytotoxicity of cultured rat islets was induced by IL-1 (100 pg/ml) and TNF (62.5 ng/ml) individually and in combination and beta cell activity was modulated by culturing the islets in media containing 3.3, 5.5, 11, and 20 mmol/liter glucose. Both IL-1 and TNF were cytotoxic when administered individually and the combination of IL-1 and TNF was more cytotoxic than either cytokine alone. Maximum cytotoxicity was observed at 11 mmol/liter glucose with cytotoxicity being reduced at 5.5 mmol/liter glucose and further reduced at 3.3 mmol/liter glucose. Interestingly, the degree of cytotoxicity was lower in 20 mmol/liter glucose compared to 11 mmol/liter. These results firmly establish that islet cytotoxicity of IL-1 and TNF is highly dependent on the functional state of the beta cells. This suggests that during the IDDM disease process as some beta cells are destroyed, the compensatory increased activity of the remaining beta cells may increase their susceptibility to cytokine attack. Furthermore, our observations provide rational support for the use of beta cell rest as intervention therapy for IDDM.
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PMID:The functional state of the beta cell modulates IL-1 and TNF-induced cytotoxicity. 821 98


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