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)

Type I (insulin-dependent) diabetes mellitus (IDDM) is an autoimmune disease that results from the destruction of insulin-secreting pancreatic islet beta-cells by autoreactive cells and their mediators. Although its exact cause is not completely understood, it is well established that IDDM is associated with dysregulated humoral and cellular immunity, exemplified by altered production of and response to macrophage- and T cell-derived cytokines and a shift in T helper (Th) cell differentiation in favor of a pathogenic Th1 pathway. Th1 cytokines, including interleukin-2 and interferon-gamma, induced islet beta-cell destruction directly by accelerating activation-induced cell death (apoptosis) and by up-regulating the expression of select adhesion molecules, Th1 cytokines facilitated the pancreatic homing of autoreactive leukocytes, hence enhancing beta-cell destruction. More recently, a role for Th2 cytokines in IDDM pathogenesis was described. Accordingly, local production of Th2 cytokines, in particular interleukin-10, accelerated beta-cell destruction by enhancing autoreactive cell infiltration of the pancreas (insulitis) through modulation of the release of other cytokines and by modulating the microvasculature. Whereas both Th1 and Th2 cytokines are present in peripheral T cells and in the pancreas in IDDM, the mechanism of action and the kinetics of a cell damage induced by Th1 and Th2 cytokines appeared to be distinct. Collectively, this supports the idea that IDDM is not an exclusive Th1-mediated disorder as was suggested, and that both Th1 and Th2 cells and their respective mediators participate and cooperate in inducing and sustaining pancreatic islet beta-cell destruction in IDDM.
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PMID:Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type I (insulin-dependent) diabetes. 1032 67

Mucosal delivery of soluble antigen induces systemic tolerance and has been applied to the prevention of autoimmune diseases. We have studied mucosal tolerance in autoimmune diabetes using the non-obese diabetic mouse model. Treatment of prediabetic mice with the pancreatic islet autoantigen insulin, by aerosol or intranasal delivery, reduces the incidence of diabetes and is associated with induction of CD8 (alpha alpha) gamma delta T cells, small numbers of which prevent adoptive transfer of diabetes. We examine the evidence for gamma delta T cells in mucosal tolerance and discuss possible mechanisms underlying the induction and action of insulin-induced CD8 gamma delta regulatory T cells. CD8 gamma delta cells constitute the most abundant subpopulation of intraepithelial lymphocytes (IELs), the major lymphoid cell compartment and first line of cellular immune defence in the mucosa. Induction of regulatory CD8 gamma delta T cells requires conformationally intact but not biologically active insulin. In contrast, intranasal (pro)insulin peptide, or oral insulin which is degraded in the gut, induces CD4 regulatory cells. Regulatory gamma delta T cells secrete interleukin-10 in pancreatic lymph nodes, which could account for the antidiabetic and bystander suppressor effect of naso-respiratory insulin. The physiological role of gamma delta IELs in maintaining peripheral self-tolerance deserves further study.
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PMID:Gamma delta T cells as mediators of mucosal tolerance: the autoimmune diabetes model. 1071 72

Studies of two post-mortem pancreata of children at the onset of type I diabetes have suggested activation and expansion of islet infiltrating T cells by a superantigen. We present the first reported case of a superantigen mediated disease, toxic shock syndrome (TSS), occurring at the diagnosis of type I diabetes. A 12-year-old girl presented with TSS and newly diagnosed diabetes with ketoacidosis. At presentation she was unconscious, febrile and hypotensive, with a desquamating erythematous rash and Kussmaul breathing. During resuscitation, her renal impairment, diarrhoea, thrombocytopaenia and ketoacidosis resolved. Vaginal discharge and blood cultures grew Staphylococcus aureus. T cell studies at 2 weeks after diagnosis detected a high level of spontaneous and islet antigen-specific proliferation with associated interleukin-10 production compared to human leucocyte antigen DR matched controls.
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PMID:Toxic shock syndrome associated with newly diagnosed type I diabetes. 1084 34

Beta cell destruction has been shown to occur when rodent or human islets are exposed in vitro to inflammatory cytokines, such as interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Other cytokines such as interleukin-4 (IL-4) or interleukin-10 (IL-10), when given to NOD mice, prevent insulin-dependent diabetes mellitus (IDDM). In this study, we have employed immunofluorescence histochemistry to study the expression of IFN-gamma and IL-4 in the pancreas of female NOD mice at various time-points (days 0, 4, 7, 11 and at onset of diabetes) following disease acceleration with cyclophosphamide (Cy). Dual-label confocal and light microscopy were employed to determine the precise cellular sources of the two cytokines. IL-4 immunolabelling was observed in a few immune cells at days 0, 4, and 7 within the pancreatic islets but in larger numbers at day 11 and at onset of diabetes. The cytokine was co-localized predominantly in CD4 cells, while only a small minority of CD8 cells and macrophages also expressed IL-4. At days 0, 4, 7 and 11, weak to moderate immunolabelling for IL-4 was also observed in beta cells. In contrast, immunolabelling for IFN-gamma within the islets was not observed until day 11 and this labelling persisted at onset of diabetes. It was immunolocalized in macrophages and to a lesser extent in CD4 cells. Only a few CD8 cells were immunopositive for IFN-gamma. At day 11, a proportion of beta cells showed weak immunolabelling for IFN-gamma. During the study period, immunolabelling for IFN-gamma was also observed in a proportion of endothelial cells located in the intra-islet and exocrine regions of Cy and diluent-treated mice. From day 11 onwards, both the cytokines were observed in some of the peri-vascular regions. Our results demonstrate that during Cy-induced diabetes, there is increasing expression of both IL-4 and IFN-gamma in specific immune cells within the inflamed islets in the late prediabetic stage and at onset of diabetes. Further studies are required to correlate our protein immunohistochemical findings with in situ cytokine gene expression and to determine whether there is a clear Th1 cytokine protein bias at clinical onset of diabetes and immediately preceding it.
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PMID:Dual-label immunohistochemical study of interleukin-4-and interferon-gamma-expressing cells within the pancreas of the NOD mouse during disease acceleration with cyclophosphamide. 1109 98

Type I Diabetes mellitus (DM1) is the effect of T cell dependent autoimmune destruction of insulin producing beta cells in the pancreas islet. T cells are activated in response to islet dominant autoantigens, the result being the development of DM1. Insulin is one of the islet autoantigens responsible for activation of T lymphocyte functions, inflammatory cytokine production and development of DM1. The experiments reported in this study have shown the spontaneous increase of CD95 molecule expression on lymphocytes of the first-degree relatives of DM1 patients. The autoantigen insulin is responsible for stimulation in vitro of potentially hazardous 'memory' lymphocytes to produce interleukin-6 (IL-6) and interleukin-10 (IL-10) interleukins. Insulin induced stimulation of lymphocytes in vitro was observed in patients at high risk of developing diabetes mellitus (prediabetics). Phytohaemagglutinin (PHA) stimulates lymphocytes of all groups in the same way. Stimulated lymphocytes in second cultures undergo apoptosis induced with anti-Fas specific antibodies. The deletion in vitro of resting peripheral lymphocytes is nonfunctional. Insulin activated T lymphocytes, which undergo apoptosis were not observed in peripheral blood of healthy people and in patients with DM1. This observation suggests that insulin is involved as autoantigen in DM1 progression in patients with high risk of diabetes type I. The autoreactive T lymphocytes may persist in peripheral blood of patients with high risk DM1. Defective elimination of autoreactive T cells may result in autodestructive damage of islets beta cells in the prediabetic stage and disease progression to DM1.
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PMID:Activated T lymphocytes from patients with high risk of type I diabetes mellitus have different ability to produce interferon-gamma, interleukin-6 and interleukin-10 and undergo anti-CD95 induced apoptosis after insulin stimulation. 1116 80

The ability to transfer immunoregulatory, cytoprotective, or antiapoptotic genes into pancreatic islet cells may allow enhanced posttransplantation survival of islet allografts and inhibition of recurrent autoimmune destruction of these cells in type 1 diabetes. However, transient transgene expression and the tendency to induce host inflammatory responses have limited previous gene delivery studies using viral transfer vectors. We demonstrate here that recombinant adeno-associated virus (rAAV) serotype 2, a vector that can overcome these limitations, effectively transduces both human and murine pancreatic islet cells with reporter genes as well as potentially important immunoregulatory cytokine genes (interleukin-4, interleukin-10), although a very high multiplicity of infection (10,000 infectious units/islet equivalent) was required. This requirement was alleviated by switching to rAAV serotype 5, which efficiently transduced islets at a multiplicity of infection of 100. Although adenovirus (Ad) coinfection was required for efficient ex vivo expression at early time points, islets transduced without Ad expressed efficiently when they were transplanted under the renal capsule and allowed to survive in vivo. The rAAV-delivered transgenes did not interfere with islet cell insulin production and were expressed in both beta- and non-beta-cells. We believe rAAV will provide a useful tool to deliver therapeutic genes for modulating immune responses against islet cells and markedly enhance longterm graft survival.
Diabetes 2001 Mar
PMID:Efficient ex vivo transduction of pancreatic islet cells with recombinant adeno-associated virus vectors. 1124 70

It has been suggested that the metabolic syndrome and type 2 diabetes are manifestations of the inflammatory host response. This host response is orchestrated by the production of pro- and anti-inflammatory cytokines that are under genetic control. We therefore hypothesized that a low production capacity of interleukin-10 (IL-10), a centrally operating cytokine with strong anti-inflammatory properties, associates with the metabolic syndrome and type 2 diabetes in old age. In the current study, 599 inhabitants of the city of Leiden, age 85 years, were visited at their place of residence. The production capacity of the anti-inflammatory cytokine IL-10 was assessed in a whole-blood assay in which lipopolysaccharide was used as a stimulus. Serum concentrations of lipids, lipoproteins, glucose, and HbA(1c) were determined, and a history of type 2 diabetes was obtained. Serum concentrations of total cholesterol, LDL cholesterol, triglycerides, glucose, and HbA(1c) gradually decreased over strata representing higher IL-10 production capacity, whereas the concentration of HDL cholesterol gradually increased (all P < 0.01). The odds ratio for type 2 diabetes was 2.7 (95% confidence interval 1.5-4.9) when subjects with the lowest IL-10 production capacity were compared with those with the highest IL-10 production capacity. These findings showed that low IL-10 production capacity (i.e., a pro-inflammatory response) is associated with the metabolic syndrome and type 2 diabetes.
Diabetes 2002 Apr
PMID:Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. 1191 30

Diabetes-prone Bio Breeding (DP-BB) rats spontaneously develop diabetes between 60 and 120 days of age. Diabetes-resistant (DR)-BB rats can be induced to develop diabetes by poly(I:C) and anti-RT6. Here, we studied the effect of pentoxifylline, a potent anti-inflammatory agent, on diabetes development in both BB rat models of insulin-dependent diabetes mellitus and investigated whether these effects were related to differential modulation of tumour necrosis factor (TNF)-alpha and interleukin-10. When DP-BB rats received pentoxifylline from day 60 onwards, diabetes development was delayed and reduced. The other treatment protocols had no effect. In DR-BB rats, pentoxifylline treatment resulted only in a delay of diabetes development. In both BB rat models, in vivo pentoxifylline treatment potently suppressed TNF-alpha, but only moderately affected interleukin-10 production in vitro. These results show that timing of pentoxifylline treatment determines its protective effect on diabetes development in DP-BB rats. The observed pentoxifylline-induced increase of the interleukin-10/TNF-alpha ratio might be a mechanism for protection or delay of the diabetes development.
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PMID:Timing of pentoxifylline treatment determines its protective effect on diabetes development in the Bio Breeding rat. 1206 4

The combined administration of interleukin-4 (IL-4) and interleukin-10 (IL-10) expression plasmids has demonstrated synergistic effects on the prevention of autoimmune diabetes. To this end, we constructed a co-expression 'chimeric' plasmid, pCMV-IL4-IL10, in which the expression of IL-4 and IL-10 was driven by two separate CMV immediate early promoters by using the biodegradable polymer, poly[alpha-(4-aminobutyl)-L-glycolic acid] (PAGA) as a gene carrier to optimize gene delivery. In vitro transfection assays of the chimeric plasmid in 293T cells showed higher expression levels as well as dose dependence than the single gene expression plasmids. To evaluate the in vivo efficacy of the chimeric plasmid, the pCMV-IL4-IL10/PAGA complex was intravenously injected into 4-week-old non-obese diabetic (NOD) mice and compared to the co-administration group. While both groups had persistent gene expression longer than 5 weeks, the IL-4 and IL-10 serum levels of the chimeric group were higher than those in the co-administration group. Furthermore, the degree of insulitis in the chimeric group was improved over both the co-administration and non-injected control groups. These results suggest that the chimeric IL-4 and IL-10 expression plasmid can effectively reduce the incidence of autoimmune insulitis.
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PMID:Prevention of autoimmune insulitis by delivery of a chimeric plasmid encoding interleukin-4 and interleukin-10. 1262 39

From earlier studies it appears that weaning associated changes in the animal's physiology and that of the pancreas in particular, render diabetes-prone Bio-Breeding (DP-BB) rats susceptible to the induction and development of insulin-dependent diabetes mellitus (IDDM). In this study we tested whether a short-term dietary adjustment at weaning would influence the development of diabetes later in life. For this purpose a diet in which the protein source was replaced with hydrolyzed casein (HC) was given to the rats from weaning to 60 days of age and from weaning to 130 days of age. The control group received the cereal-based standard diet throughout the experiment. The short-term dietary adjustment resulted in a significant delay of diabetes development. The rats fed the HC diet from weaning to 130 days of age showed a lower incidence of diabetes at 130 days of age. No differences were seen in the histological insulitis scores between the rats of the different treatment groups. Interestingly, when testing (mucosal) immune functions of short-term HC-fed rats, their mesenteric lymph node cells (MLNC) showed increased interferon-gamma (IFN-gamma) and reduced interleukin-10 (IL-10) production after in vitro stimulation. These results demonstrate that short-term dietary adjustments at a young age can influence the course of diabetes later in life. The shift in cytokine profile of MLNC of the HC-fed rats suggests that mechanisms involved can be at the level of both the (mucosal) immune system and the beta cell.
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PMID:Short-term dietary adjustment with a hydrolyzed casein-based diet postpones diabetes development in the diabetes-prone BB rat. 1264 72


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