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

Inhibition of endosomal acidification disturbs insulin signaling in both liver and adipose cells. In this study we used MIN6 beta cells to determine whether bafilomycin, a potent inhibitor of the proton-translocating vacuolar ATPase, disrupts insulin signaling in islet beta cells. Pretreatment of MIN6 cells with varying concentrations of bafilomycin according to a time course revealed concentration and time-dependent changes in phosphorylation of insulin receptor signaling components. Increased phosphorylation of insulin receptor (IR), IRS2 and Akt was prolonged at low bafilomycin concentrations (10 and 50 nmol/L), whereas at high concentrations (100 and 200 nmol/L) phosphorylation rapidly returned to basal levels or below. Akt activation was demonstrated by transient increases in phosphorylation of BAD, cytoplasmic retention of FoxO1 and increased preproinsulin mRNA. Bcl2 expression was also transiently increased but reduced after 30 min exposure to bafilomycin, and this coincided with reduced cell viability. Thus, in beta cells inhibition of endosomal acidification by low concentrations of bafilomycin transiently increases insulin signaling, whereas high concentrations promote cell death. Bafilomycin and other agents that interfere with insulin signaling may contribute to diabetes development through disturbing homeostatic control of beta cell growth.
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PMID:The plecomacrolide vacuolar-ATPase inhibitor bafilomycin, alters insulin signaling in MIN6 beta-cells. 1655

Analysis of amino acid sequences of insulinotropic polypeptides revealed a common short fragment consisting of four amino acid residues. We synthesized KEDWa tetrapeptide, analog of this fragment protected from the effects of gastrointestinal proteinases. This tetrapeptide partially restored insulin synthesis in rats with alloxan-induced diabetes. The slope of the sugar curve in this case was similar to that in normal animals. Presumably, this tetrapeptide activates the preproinsulin gene promotor site via complementary interactions with the ggcagg and cctgcc nucleotide sequences of the leading strand of double-stranded DNA.
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PMID:Effect of tetrapeptide on insulin biosynthesis in rats with alloxan-induced diabetes. 1667 79

DNA vaccination of autoimmune diabetes-prone NOD mice with unmodified target islet antigens, i.e., preproinsulin (PPIns) or glutamic acid decarboxylase 65 (GAD65), is poorly protective. However, in this study, we demonstrate protection against disease by covaccination with a mutant B7-1 molecule (B7-1wa) that binds the negative T cell regulator CTLA-4 (CD152), but not CD28. Codelivery of plasmids encoding a PPIns-GAD65 fusion construct and B7-1wa protected against both insulitis and diabetes. In vitro, the T cells of covaccinated mice had negative responses to both insulin and GAD65, and this was restored by adding blocking antibodies to transforming growth factor beta1 (TGF-beta1), suggesting a role for this cytokine. Adoptive transfer experiments revealed that DNA vaccination generated protective CD4(+) regulatory T cells (Tr) of either CD25(+) or CD25(-) phenotype. Furthermore, vaccinated mice had increased numbers of T cells with Tr-associated markers, such as CTLA-4, Foxp3, and membrane-bound TGF-beta1. Tr cells inhibited the responses of diabetogenic T cells to islet antigens, and depletion of T cells expressing membrane-bound TGF-beta1 abolished the suppressive effect. Thus, selective engagement of CTLA-4 during islet-antigen DNA vaccination induces Tr cells that protect against this autoimmune disease.
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PMID:Protective regulatory T cell generation in autoimmune diabetes by DNA covaccination with islet antigens and a selective CTLA-4 ligand. 1679 Mar 65

Immune tolerance to self-antigens is established during lymphocyte differentiation in the thymus, but a simple means to induce antigen-specific tolerance in the thymus is still elusive. We show here that intrathymic injection of a lentiviral vector expressing the hemagglutinin antigen (HA) in TCR-HA transgenic mice resulted in negative selection of HA-specific effector T cells and sustained positive selection of HA-specific regulatory T cells (Tregs). This positive selection increased the number of HA-specific Tregs 10-fold and was comparable with the one observed in TCR-HA transgenic mice crossed with transgenic mice expressing HA under the control of the insulin promoter (Ins-HA). HA expression by radioresistant thymic epithelial cells was sufficient to drive Treg generation. Intrathymic injection of the lentiviral vector also resulted in an enrichment of HA-specific Tregs in peripheral lymphoid organs, which prevented diabetes induced in Ins-HA mice by transfer of HA-specific effector T cells. In this model, HA-specific Tregs inhibited effector T-cell division in pancreatic lymph nodes. Finally, we show that intrathymic injection of a lentiviral vector expressing preproinsulin-2 could reduce the occurrence of spontaneous diabetes in nonobese diabetic mice. Intrathymic gene transfer using lentiviral vectors thus offers new means to manipulate antigen-specific tolerance.
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PMID:Induction of antigen-specific tolerance by intrathymic injection of lentiviral vectors. 1680 18

The purpose of current experiment is the generation of insulin-producing human mesenchymal stem cells as therapeutic source for the cure of type 1 diabetes. Type 1 diabetes is generally caused by insulin deficiency accompanied by the destruction of islet beta-cells. In various trials for the treatment of type 1 diabetes, cell-based gene therapy using stem cells is considered as one of the most useful candidate for the treatment. In this experiment, human mesenchymal stem cells were transduced with AAV which is containing furin-cleavable human preproinsulin gene to generate insulin-producing cells as surrogate beta-cells for the type 1 diabetes therapy. In the rAAV production procedure, rAAV was generated by transfection of AD293 cells. Human mesenchymal stems cells were transduced using rAAV with a various multiplicity of infection. Transduction of recombinant AAV was also tested using beta-galactosidse expression. Cell viability was determined by using MTT assay to evaluate the toxicity of the transduction procedure. Expression and production of Insulin were tested using reverse transcriptase-polymerase chain reaction and immunocytochemistry. Secretion of human insulin and C-peptide from the cells was assayed using enzyme-linked immunosorbent assay. Production of insulin and C-peptide from the test group represented a higher increase compared to the control group. In this study, we examined generation of insulin-producing cells from mesenchymal stem cells by genetic engineering for diabetes therapy. This work might be valuable to the field of tissue engineering for diabetes treatment.
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PMID:Generation of insulin-producing human mesenchymal stem cells using recombinant adeno-associated virus. 1732 53

Despite the understanding that type 1 diabetes pathogenesis is mediated by T-cells, detection of these rare lymphocytes remains largely elusive. Suitable T-cell assays are highly needed, since they could offer preclinical diagnoses and immune surrogate end points for clinical trials. Although CD4+ T-cell assays have met with limited success, CD8+ T-cells are increasingly recognized as key actors in the diabetes of the NOD mouse. CD8+ T-cells are likely to play a role also in humans and may provide new markers of beta-cell autoimmunity. Taking advantage of a panel of HLA-A2-restricted beta-cell epitopes derived from preproinsulin, GAD, and islet glucose-6-phosphatase catalytic subunit-related protein (IGRP), we have implemented an islet-specific CD8+ T-cell interferon-gamma enzyme-linked immunospot (ISL8Spot) assay. The ISL8Spot assay is capable of detecting and quantifying beta-cell-reactive CD8+ T-cells directly ex vivo, without any preliminary expansion, using either fresh or frozen samples. Positive ISL8Spot responses separate new-onset diabetic and healthy samples with high accuracy (86% sensitivity, 91% specificity), using as few as five immunodominant epitopes. Moreover, sensitivity reaches 100% when the ISL8Spot assay is complemented by antibody determinations. Combination of CD8+ T-cell measurements with immune intervention strategies may open new avenues toward type 1 diabetes prediction and prevention.
Diabetes 2007 Mar
PMID:CD8+ T-cell responses identify beta-cell autoimmunity in human type 1 diabetes. 1732 28

Rodent immune-mediated diabetes model studies have advanced understanding of beta cell-specific T cell responses, and the testing of therapeutic approaches. We have used an inducible diabetes model based on rat insulin promotor (RIP)-driven expression of CD80 (B7-1) on pancreatic beta cells. Using these mice, we have established that immunizing with a single autoantigen can promote progressive islet inflammation and eventually T cell-mediated diabetes. We now describe a potent immunization protocol using peptide-pulsed mature dendritic cells (DCs) to examine peptide epitopes derived from endogenous (preproinsulin) and transgenically expressed beta cell antigens, namely lymphocytic choriomeningitis virus glycoprotein (LCMV-GP). LCMV-GP epitopes efficiently promote beta cell destruction, and the autoantigenic peptide concentration used to load the DCs correlates directly with diabetes onset. The system allowed us to assess cytotoxic T cell (CTL) fine specificity by immunizing with DCs presenting altered peptide ligands (APLs) of the dominant LCMV-GP epitope, gp33. Finally, using an adoptive transfer system, we tested alternative in vitro T cell activation conditions, including APLs and mitogens, for their impact on T cell effector function and diabetes onset. Our studies revealed a marked discrepancy between (inflammatory) effector functions and diabetes progression, thus emphasizing the importance of structural identity between sensitizing and target epitope and the context of initial T cell activation.
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PMID:Cytotoxic T cell-mediated diabetes in RIP-CD80 transgenic mice: autoantigen peptide sensitivity and fine specificity. 1737 36

Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and beta-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes.
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PMID:Glucose responsive insulin production from human embryonic germ (EG) cell derivatives. 1738 13

Rodents have two functional preproinsulin genes named insulin 1 and insulin 2 on different chromosome and have two amino acid differences in insulin B chain. We have established insulin 1 or insulin 2 knockout (KO) non-obese diabetic (NOD) colonies in the animal institute of Kobe University and evaluated anti-insulin autoimmunity. Similar to the previous report, insulin 1-KO provides strong protection from insulitis (islet-infiltration of mononuclear cells) and diabetes, whereas the insulin 2-KO markedly accelerated insulitis and development of diabetes even at further backcross breeding with NOD/Shi/Kbe mice (P<0.0001). Expression of serum anti-insulin autoantibodies (IAA) was enhanced in insulin 2-KO mice at a time between 10 and 15 weeks of age (P<0.005) while the expression of insulin 1-KO NOD mice was rather reduced. Furthermore, T cell reactivity in splenocytes of insulin 2-KO NOD mice to insulin 1 B:9-23 peptide was increased (P<0.05), suggesting that expanding insulin-reactive T cells may contribute to the acceleration of diabetes in insulin 2-KO mice. Based on those observations, we hypothesize that insulin 1 is a crucial T cell antigen in murine autoimmune diabetes and modification of anti-insulin autoimmunity can be applicable to antigen-based therapy for human type 1 diabetic patients.
Diabetes Res Clin Pract 2007 Sep
PMID:Insulin as a T cell antigen in type 1 diabetes supported by the evidence from the insulin knockout NOD mice. 1745 8

NOD mice with knockout of both native insulin genes and a mutated proinsulin transgene, alanine at position B16 in preproinsulin (B16:A-dKO mice), do not develop diabetes. Transplantation of NOD islets, but not bone marrow, expressing native insulin sequences (tyrosine at position B16) into B16:A-dKO mice rapidly restored development of insulin autoantibodies (IAAs) and insulitis, despite the recipients' pancreatic islets lacking native insulin sequences. Splenocytes from B16:A-dKO mice that received native insulin-positive islets induced diabetes when transferred into wild-type NOD/SCID or B16:A-dKO NOD/SCID mice. Splenocytes from mice immunized with native insulin B chain amino acids 9-23 (insulin B:9-23) peptide in CFA induced rapid diabetes upon transfer only in recipients expressing the native insulin B:9-23 sequence in their pancreata. Additionally, CD4(+) T cells from B16:A-dKO mice immunized with native insulin B:9-23 peptide promoted IAAs in NOD/SCID mice. These results indicate that the provision of native insulin B:9-23 sequences is sufficient to prime anti-insulin autoimmunity and that subsequent transfer of diabetes following peptide immunization requires native insulin B:9-23 expression in islets. Our findings demonstrate dependence on B16 alanine versus tyrosine of insulin B:9-23 for both the initial priming and the effector phase of NOD anti-islet autoimmunity.
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PMID:Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity. 1760 59


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