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 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.
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PMID:DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice. 1610 64

CD40 ligand interaction with its receptor (CD40) not only mediates lymphocyte communication, but also associates with chronic inflammation and atherothrombosis. High soluble CD40L (sCD40L) levels were reported in dyslipidemia, diabetes mellitus, and coronary disease. So far, there are no data about sCD40L levels in hypertension. We investigated sCD40L and high sensitive C reactive protein (hsCRP) levels in 30 nonobese young hypertensive men and 30 matched controls. sCD40L and hsCRP levels were not different, and there were no correlations between blood pressure and sCD40L or hsCRP levels. These results might indicate lack of any inflammatory state in new onset hypertension.
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PMID:Soluble CD40 ligand levels in patients with hypertension. 1630 39

The aim of the study was to determine whether the levels of soluble P-selectin (sP-selectin) and soluble CD40L (sCD40L) are elevated in Asian Indian subjects with impaired glucose tolerance (IGT), diabetes, and metabolic syndrome (MS). Study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing population-based study on a representative population of Chennai city in southern India, and were grouped as follows: group 1, normal glucose tolerance (NGT) (n = 60); group 2, IGT (n = 60); and group 3, type 2 diabetes mellitus (n = 60). Normal glucose tolerance, IGT, and diabetes were defined using World Health Organization consulting group criteria. The inclusion criteria were nonsmokers; normal resting 12-lead electrocardiogram; absence of angina, myocardial infarction, or history of any known vascular, infectious, or inflammatory diseases; and subjects not on statins or aspirin. Insulin resistance was calculated using the homeostasis assessment model using the formula: fasting insulin (microIU/mL) x fasting glucose (mmol/L)/22.5. Soluble P-selectin and sCD40L were estimated by enzyme-linked immunosorbent assay. Metabolic syndrome was defined using Adult Treatment Panel III guidelines. Subjects with diabetes and IGT were older (diabetes: 53 +/- 9 years, P < .01; IGT: 51 +/- 10 years, P < .05) compared with the NGT group (48 +/- 10 years). Subjects with diabetes and IGT had higher levels of sP-selectin (diabetes: 162 +/- 79 ng/mL, P < .001; IGT: 102 +/- 37 ng/mL, P < .001) compared with the NGT group (55 +/- 48 ng/mL). Soluble CD40L levels were also higher in those with diabetes and IGT (diabetes: 3.2 +/- 2.0 ng/mL, P < .001; IGT: 2.0 +/- 1.3 ng/mL, P < .001) compared with the NGT group (1.1 +/- 0.9 ng/mL). Subjects with MS had significantly higher levels of sP-selectin (with MS, 118 +/- 76 ng/mL; without MS, 95 +/- 66 ng/mL; P = .028) and sCD40L (with MS, 2.4 +/- 1.8 ng/mL; without MS, 1.9 +/- 1.5 ng/mL; P = .036) compared with subjects without MS. Among subjects with NGT and IGT, the mean levels of sP-selectin (tertile I, 65.0 ng/mL; tertile II, 80.0 ng/mL; tertile III, 91.0 ng/mL) and sCD40L levels (tertile I, 1.2 ng/mL; tertile II, 1.7 ng/mL; tertile III, 1.8 ng/mL) increased with increase in tertiles of homeostasis assessment model-insulin resistance, and the difference reached statistical significance in the last tertile compared with the first tertile (P < .05). This study demonstrates that increased levels of sP-selectin and sCD40L are seen in Asian Indian subjects with IGT, type 2 diabetes mellitus, MS, and insulin resistance.
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PMID:Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome--the Chennai Urban Rural Epidemiology Study. 1642 32

Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.
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PMID:Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. 1649 Oct 83

Type 1 diabetes is associated with increased vascular complications, and monocytes are pivotal cells in atherogenesis. However, there are few data on monocyte function and inflammation in type 1 diabetes. The aim of this study was to compare monocyte function and biomarkers of inflammation in type 1 diabetic subjects without macrovascular disease with that in matched control subjects (n = 52 per group). Fasting blood was obtained for biomarkers of inflammation (C-reactive protein [CRP], plasma-soluble cell adhesion molecules [CAMs], monocyte chemoattractant protein 1, nitrotyrosine, CD40 ligand [CD40L], and monocyte function). High-sensitive CRP, soluble intracellular adhesion molecule (sICAM), sCD40L, and nitrotyrosine levels were significantly elevated in type 1 diabetic subjects compared with in control subjects (P < 0.05). Monocyte superoxide anion release was significantly increased in the resting (37%; P < 0.05) and activated state (26%; P < 0.005) in type 1 diabetic compared with in control subjects. Monocyte interleukin (IL)-6 levels were significantly elevated in type 1 diabetic subjects compared with in control subjects in the resting state (51%; P < 0.05) and after lipopolysaccharide activation (31%; P < 0.01). Monocyte IL-1beta levels were increased in the activated monocytes in type 1 diabetic compared with in control subjects. There were no significant differences in monocyte tumor necrosis factor levels or adhesion between the two groups. Thus type 1 diabetes is a proinflammatory state, as evidenced by increased levels of monocyte IL-6, superoxide anion, and plasma CRP, sICAM, sCD40L, and nitrotyrosine levels. These results have a major implication on our understanding of the role of inflammation in vasculopathies in type 1 diabetes.
Diabetes 2006 Mar
PMID:Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. 1650 42

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.
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PMID:Costimulation and autoimmune diabetes in BB rats. 1661 20

Peroxisome proliferator-activated receptor gamma (PPARgamma) is an important transcription factor for lipid and glucose metabolism. Currently, the PPARgamma ligands rosiglitazone and pioglitazone are used for the treatment of type 2 diabetes mellitus because they are potent insulin sensitizers. Recently, PPARgamma has emerged as an important anti-inflammatory factor. Platelets, anucleate cells involved in hemostasis, have also been implicated as key contributors to inflammation, because they produce many pro-inflammatory and pro-atherogenic mediators when activated. Surprisingly, it was discovered recently that platelets contain PPARgamma and that PPARgamma ligands, both natural and synthetic, inhibit platelet activation and release of bioactive mediators. In particular, release of soluble CD40 ligand (sCD40L) and thromboxane (TXA(2)) was inhibited by PPARgamma ligands in thrombin-activated platelets. CD40L signaling induces pro-inflammatory processes in many cell types, and increased blood levels of sCD40L are closely associated with inflammation, diabetes, and cardiovascular disease. Targeting platelet PPARgamma will, therefore, be an important treatment strategy for the attenuation of chronic inflammatory processes and prevention of thrombus formation.
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PMID:Platelets as a novel target for PPARgamma ligands : implications for inflammation, diabetes, and cardiovascular disease. 1683 Oct 22

Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic beta-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets. Islet beta-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1beta, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1beta was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1beta expression in beta-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways in insulinoma NIT-1 cells, and inhibitors of either pathway suppress cytokine/chemokine production in islets. Moreover, ligation of CD40 receptor upregulates intercellular adhesion molecule-1, associated with inflammation, at both transcriptional and translational levels. Our results in vitro indicate that the CD40 receptor expressed by beta-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.
Diabetes 2006 Sep
PMID:CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets. 1693 91

Surprisingly, the effect of acute diabetes on immunity has not been examined in detail. We, herein, show for the first time that untreated acute diabetes causes rapid lymphopenia followed by homeostatic T-cell proliferation. The diabetes-induced lymphopenia was associated with an immunosuppressed state that could be sufficiently strong to allow engraftment of fully allogeneic beta-cells or block rejection of islet transplants. In contrast, homeostatic proliferation and recovery of T-cell numbers were associated with islet rejection. Thus, the timing of islet transplant challenge in relation to diabetes induction was critical in determining whether islets were accepted or rejected. In addition, we tested whether diabetes-related immunosuppression could result in an overestimation of the efficacy of a tolerance-inducing protocol. Consistent with this possibility, a protocol targeting CD40L and ICOS that we have shown induces tolerance in diabetic recipients was unable to induce tolerance in non-diabetic recipients. The data uncover a previously unrecognized suppressive effect of diabetes on adaptive immunity. Furthermore, they suggest that the standard methods of testing new tolerance-inducing protocols in islet transplantation require modification and that diabetes itself can contribute to homeostatic proliferation, a process associated with autoimmunity and a resistance to tolerance induction.
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PMID:Diabetes induces rapid suppression of adaptive immunity followed by homeostatic T-cell proliferation. 1721 63

Several publications describing the use of anti-CD40L monoclonal antibodies (anti-CD40L) for the treatment of type 1 diabetes in non-obese diabetic (NOD) mice have reported different treatment responses to similar protocols. The Entelos Type 1 Diabetes PhysioLab platform, a dynamic large-scale mathematical model of the pathogenesis of type 1 diabetes, was used to study the effects of anti-CD40L therapy in silico. An examination of the impact of pharmacokinetic variability and the heterogeneity of disease progression rate on therapeutic outcome provided insights that could reconcile the apparently conflicting data. Optimal treatment protocols were identified by exploring the dynamics of key pathophysiological pathways.
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PMID:Dosing and timing effects of anti-CD40L therapy: predictions from a mathematical model of type 1 diabetes. 1737 35


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