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

Insulin has been used to modify T-cell autoimmunity in experimental models of type 1 diabetes. In a large clinical trial, the effect of insulin to prevent type 1 diabetes is currently investigated. We here show that insulin can adversely trigger autoimmune diabetes in two mouse models of type 1 diabetes, using intramuscular DNA vaccination for antigen administration. In female nonobese diabetic (NOD) mice, diabetes development was enhanced after preproinsulin (ppIns) DNA treatment, and natural diabetes resistance in male NOD mice was diminished by ppIns DNA vaccination. In contrast, GAD65 DNA conferred partial diabetes protection, and empty DNA plasmid was without effect. In RIP-B7.1 C57BL/6 mice (expressing the T-cell costimulatory molecule B7.1 in pancreatic beta-cells), autoimmune diabetes occurred in 70% of animals after ppIns vaccination, whereas diabetes did not develop spontaneously in RIP-B7.1 mice or after GAD65 or control DNA treatment. Diabetes was characterized by diffuse CD4(+)CD8(+) T-cell infiltration of pancreatic islets and severe insulin deficiency, and ppIns, proinsulin, and insulin DNA were equally effective for disease induction. Our work provides a new model of experimental autoimmune diabetes suitable to study mechanisms and outcomes of insulin-specific T-cell reactivity. In antigen-based prevention of type 1 diabetes, diabetes acceleration should be considered as a potential adverse result.
Diabetes 2002 Nov
PMID:Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice. 1240 15

Molecular mimicry is one of the mechanisms by which enterovirus infections have been postulated to have a role in the pathogenesis of type 1 diabetes. Immunogenic epitopes in enterovirus capsid protein VP1 and procapsid protein VP0 have sequence similarities with diabetes-associated epitopes in tyrosine phosphatase IA-2/IAR and heat shock protein 60. In the present study, documented enterovirus infection was shown to induce humoral responses, that in 7% and 1% of patients cross-reacted with the known diabetes-associated epitopes in tyrosine phosphatase IAR and heat shock protein 60, respectively. In contrast, none of the children vaccinated against poliomyelitis had antibodies to the diabetes-associated epitope of tyrosine phosphatases IA-2/IAR. The antibody response studied in serum samples from six patients with coxsackievirus A9 infection was mainly targeted to capsid protein VP1. Coxsackievirus A9 infection induced antibodies cross-reacted with one epitope in heat shock protein 60, but not with epitopes derived from other autoantigens. Most diabetic children had high levels of antibodies to both coxsackievirus and poliovirus derived VP1 peptides but the pattern of reactivity did not differ from that seen in healthy children. The reactivity of linear epitopes derived from autoantigens was low in general and associated with the presence of multiple autoantibodies in the patients. Some linear auto-epitopes derived from tyrosine phosphatase IA-2, glutamic acid decarboxylase 65, preproinsulin, and heat shock protein 60 were recognized by sera from diabetic patients, but not by sera from healthy children. In conclusion, enteroviruses may induce immune responses that react with islet cell autoantigens, which is a concern when a putative inactivated enterovirus vaccine is considered.
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PMID:Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. 1252 55

Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the non-obese diabetic mice, an animal model for human autoimmune insulin-dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization-activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune response to virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta-cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA-2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4-dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non-obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non-obese diabetic mice.
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PMID:Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice. 1260 59

T cell responses toward pancreatic beta cell autoantigens arise spontaneously or on immunization in many mouse strains, yet sustained islet infiltration and progressive diabetes rarely ensues. Most mouse diabetes models overcome the innocuous coexistence of anti-islet specific T cells and endogenous islets via incompletely understood mechanisms (e.g. the spontaneous disease onset of the non-obese diabetic mouse) or depend on overwhelming numbers of peripheral islet-specific T cells. We report that insulin promoter murine CD80 (RIP-CD80) transgenic mice are extraordinarily susceptible to autoantigen-induced diabetes, while spontaneous disease is rare. Autoimmunity to the pancreatic beta cell-expressed glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) was elicited by a single injection of syngeneic fibroblastoid cell lines (FCL) loaded with the immunodominant LCMV-GP peptide, gp33. While both RIP-GP(+)and RIP-CD80(+)GP(+)mice mounted moderate CD4-independent CTL responses, only CD80(+)GP(+)mice developed severe insulitis and diabetes due to islet-infiltration of activated, gp33-specific, CD8(+)T cells. Strikingly, DNA immunization using plasmids encoding LCMV-GP or murine preproinsulin also efficiently induced Ag-specific RIP-CD80-dependent diabetes. We conclude that aberrant CD80-expression in a peripheral tissue disrupts that tissue's natural resistance to CD8 T cell-mediated autoimmune destruction. This rodent model thus represents a novel approach to identify beta cell-derived autoantigenic determinants involved in the pathogenesis of autoimmune diabetes, and may also serve as a prototype approach to uncover relevant autoantigens leading to a variety of organ-specific autoimmune disorders.
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PMID:Beta cell-specific CD80 (B7-1) expression disrupts tissue protection from autoantigen-specific CTL-mediated diabetes. 1260 8

Cell-based therapies for treating insulin-dependent diabetes (IDD) can provide a more physiologic regulation of blood glucose levels in a less invasive fashion than daily insulin injections. Promising cells include non-beta cells genetically engineered to secrete insulin in response to physiologic cues; responsiveness can be introduced at the transcriptional level to regulate preproinsulin (PPI) mRNA biosynthesis. However, these cells exhibit sluggish secretion dynamics, which is not appropriate for achieving euglycemia in higher animals and, eventually, humans. In this work, we have engineered the PPI mRNA so as to destabilize it through nonsense-mediated mRNA decay (NMD). When expressed under transcriptional regulation in HepG2 hepatomas, the engineered PPI mRNA level and of the insulin secretion rate declined faster upon switching off transcription, compared to the one-copy non-engineered control. Our work provides a simple and straightforward method to improve the dynamics of transcriptionally regulated insulin secretion, which can be a useful tool in developing cell-based therapies for IDD.
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PMID:Preproinsulin mRNA engineering and its application to the regulation of insulin secretion from human hepatomas. 1260 56

Neonatal female rat pups that were raised artificially on a high-carbohydrate (HC) milk formula during their suckling period developed hyperinsulinemia immediately, maintained chronic hyperinsulinemia in the postweaning period on laboratory diet, and developed obesity in adulthood. Pups (second-generation HC [2-HC]) born to such female rats (first-generation HC [1-HC]) spontaneously developed chronic hyperinsulinemia and adult-onset obesity (HC phenotype) without the requirement for any dietary intervention in their suckling period. Leftward shift in the insulin secretory response to a glucose stimulus, increase in hexokinase activity, and increased preproinsulin gene transcription were observed in islets from 28-day-old 2-HC rats, and these adaptations are similar to those reported for islets from 12-day-old and 100-day-old 1-HC rats. Unlike 1-HC islets, the ability to secrete moderate amounts of insulin in the absence of glucose and calcium and the incretin input for augmentation of insulin secretion were not observed in 2-HC islets. These results show that a dietary modification in the early postnatal life of the 1-HC female rat sets up a vicious cycle of spontaneous transfer of the HC phenotype to its progeny, implicating a new component to the growing list of factors that contribute to the fetal origins of adult-onset diseases.
Diabetes 2003 Apr
PMID:Programming of islet functions in the progeny of hyperinsulinemic/obese rats. 1266 70

Glutathione (GSH) participates in deoxidization and elimination of hydrogen peroxide and other reactive oxygen species, and plays an important part in the antioxidant system. To investigate the effect of GSH content on insulin gene expression, we utilized a stable transfectant, designated as ribo-MIN6 cells, which were stably transfected with the ribozyme of gamma-glutamylcysteine synthetase (gamma-GCS), exhibiting approximately 50% reduction of intracellular GSH content. We transiently transfected a luciferase expression vector driven by human preproinsulin gene promoter spanning from -1998 to +237 (pINS-1998/luc) and several deletion constructs into ribo-MIN6. Furthermore, transient transfection with ribozyme vector and pINS-1998/luc into wild-type MIN6 cells was also carried out. Luciferase activity was about 9-fold higher in ribo-MIN6 cells as compared to wild-type MIN6 cells. In the transient transfection of pINS-1998/luc with gamma-GCS ribozyme vector into wild-type MIN6 cells, the luciferase activity was increased in proportion to the added amounts of ribozyme vector. In transfection with deletion constructs, two major sites were found to be critical for insulin promoter activity. For the wild-type MIN6 cells, regions important for the promoter activity were also located at regions similar to those of ribo-MIN6 cells. Our results suggest that the suppression of intracellular GSH level might, in part, regulate the insulin gene expression.
Diabetes Nutr Metab 2003 Apr
PMID:Enhanced insulin gene expression by reduced intracellular glutathione level in insulin secreting cells MIN6. 1284 46

It has been reported that an insulin 2 gene knockout, when bred onto nonobese diabetic (NOD) mice, accelerates diabetes. We produced insulin 1 gene knockout congenic NOD mice. In contrast to insulin 2, diabetes and insulitis were markedly reduced in insulin 1 knockout mice, with decreased and delayed diabetes in heterozygous females and no insulitis and diabetes in most homozygous female mice. Lack of insulitis was found for insulin 1 female homozygous knockout mice at 8, 12, and 37 weeks of age. Despite a lack of insulitis, insulin 1 homozygous knockout mice spontaneously expressed insulin autoantibodies. Administration of insulin peptide B:9-23 of both insulin 1 and 2 to NOD mice induced insulin autoantibodies. Insulin 1 is not the only lymphocytic target of NOD mice. Insulin 1 homozygous knockout islets, when transplanted into recently diabetic wild-type NOD mice, became infiltrated with lymphocytes and only transiently reversed diabetes. These observations indicate that loss of either insulin gene can influence progression to diabetes of NOD mice and suggest that the preproinsulin 1 gene is crucial for the spontaneous development of NOD insulitis and diabetes.
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PMID:Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. 1292 30

Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in beta cells develop diabetes. To determine the role of IFNbeta in diabetes, we studied transgenic mice expressing human IFNbeta in the beta cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of beta(2)-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNbeta, thus suggesting that the disease is caused by a local effect of IFNbeta, strong enough to break the peripheral tolerance to beta cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNbeta breaks peripheral tolerance to beta cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.
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PMID:IFN beta accelerates autoimmune type 1 diabetes in nonobese diabetic mice and breaks the tolerance to beta cells in nondiabetes-prone mice. 1555 58

There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.
Diabetes 2004 Dec
PMID:Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. 1556 61


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