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

The non-obese diabetic mouse (NOD mouse) is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta cells mediated by T cells and culminating in insulin-dependent diabetes mellitus. Here, we report that the NOD mouse also develops Coombs'-positive hemolytic anemia, a B cell-mediated autoimmune disease. Aged NOD mice were found to have splenomegaly and jaundice predominantly due to raised unconjugated serum bilirubin. Their hematocrits were markedly lowered, and there was a reciprocal increase in the reticulocyte count. Red blood cells (RBC) from anemic mice showed a normal lytic response to hypotonicity. RBC from non-anemic mice had normal half lives in non-anemic, non-diabetic NOD mice by 51Cr labeling but, dramatically shortened half lives in anemic mice. Similar results were obtained with RBC from anemic mice. Hemolysis could be transferred with serum from anemic mice resulting in reticulocytosis. The antibody-mediated nature of the anemia was confirmed with the direct Coombs' test. Anemia was found only in mice aged greater than 200 days and was more common in diabetic (4/8) than non-diabetic (1/16) mice at 300 days. However, by 550 days, 14/17 non-diabetic mice were affected.
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PMID:Hemolytic anemia in non-obese diabetic mice. 188 56

Experimental studies in vitro suggest that cytokines are important mediators in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). However, there is little evidence for the role of cytokines in vivo, either in humans or in the spontaneous animal models of IDDM such as the NOD mouse or BB rat. To address this question, we used the model of cyclophosphamide (CYP)-induced autoimmune diabetes in the NOD/Wehi mouse to examine for (a) the production of IFN-gamma and IL-6 from isolated islets, and (b) the effect of anti IFN-gamma or anti IL-6 monoclonal antibodies on the development of diabetes. After cyclophosphamide, the majority of these mice develop of mononuclear cell infiltrate (insulitis) which by 10-14 d is associated with beta cell destruction. IFN-gamma activity at low levels (2.7 +/- 0.3 U/ml) could be detected only in culture supernatants from islets isolated at day 7 post-cyclophosphamide. In contrast, IL-6 activity progressively increased from 457 +/- 44 U/ml at day 0 to 6,020 +/- 777 U/ml at day 10. Culture of islets with anti-CD3 monoclonal antibody resulted in a significant increase in IFN-gamma activity from 41 +/- 7 U/ml at day 0 to 812 +/- 156 U/ml at day 10. Mice given either anti-IFN-gamma or anti-IL-6 antibody had a significantly reduced (P less than 0.001) incidence of diabetes and especially with IFN-gamma, decreased severity of insulitis. We conclude that IFN-gamma and IL-6 have essential roles in the pathogenesis of pancreatic islet beta cell destruction in this model.
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PMID:Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. 189 31

The NOD mouse is studied as an animal model of human insulin-dependent diabetes mellitus (IDDM). To evaluate the role of IFN gamma in the pathogenesis of the disease, we have studied the effect of anti-IFN gamma mAb on the expression of insulitis and clinical diabetes. Treatment of mice with anti-IFN gamma mAb prevented the induction of early IDDM by cyclophosphamide as well as the adoptive transfer of diabetes by spleen cells from diabetic NOD mice. The protection against induction of diabetes by cyclophosphamide was observed in animals treated with the anti-IFN gamma mAb within 24 h following the first cyclophosphamide injection but not in animals in which mAb treatment was started 7 days later. Transfer of disease was prevented both in adult irradiated and in newborn recipients. The absence of clinical signs in these mice was corroborated by a significant reduction of both the extent and severity of insulitis. Over-expression of Ia antigen on endothelial cells lining the islets was also considerably reduced in mice treated with mAb. These data strongly suggest a role for IFN gamma during the autoimmune process leading to beta cell destruction in diabetes and prompt further investigation of the use of such antibodies in the immunoprevention of IDDM.
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PMID:Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. 190 35

The mechanisms contributing to the development of autoimmune insulin-dependent diabetes mellitus have been analyzed in allophenic mouse chimeras of the NOD in equilibrium with C57BL/6 strain combination (where NOD is nonobese diabetic). Occurrence of lymphoid cell infiltration (insulitis) in pancreatic islets was observed in the majority of such chimeras. The development of insulitis was found to correlate with major histocompatibility complex chimerism in lymphoid cells and in thymus cortical regions. Chimeras with more than 50% of C57BL/6 lymphoid cells rarely developed insulitis. Our data suggest that the correlation with the thymic cortical region is absolute. Thus, all individuals displaying NOD or NOD/C57BL/6 thymic cortical regions developed insulitis, whereas we have not observed insulitis in chimeras with only C57BL/6 thymic cortical regions. Thus the positive selection of T cells appears to play a crucial role in the development of insulin-dependent diabetes mellitus.
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PMID:The phenotype of lymphoid cells and thymic epithelium correlates with development of autoimmune insulitis in NOD in equilibrium with C57BL/6 allophenic chimeras. 192 97

We investigated whether the development of spontaneous T-cell-mediated type I diabetes in NOD mice is influenced by B cells and immunoglobulin (Ig). During the first 4 weeks of life, B-cell development was suppressed by repeated administration of rabbit anti-mouse IgM (RaIgM), while controls received polyclonal rabbit Ig (NRIg). A reduction in the incidence of diabetes, as well as in development of insulitis, was observed after either of these treatments. However, the effect on insulitis was more pronounced in mice treated with RaIgM compared with those treated with NRIg. Furthermore, while the optimal effect of NRIg was obtained after a single injection at birth, the additional effect of RaIgM on development of insulitis was observed only after continued treatment for the first 4 weeks of life. Taken together these data suggest a possible role of Ig/B cells in the development of autoimmunity in the NOD mouse. The additional effect observed after continued suppression of the neonatal B-cell development suggests that this population may contribute significantly to the establishment of an auto-aggressive lymphocyte repertoire in the NOD mouse.
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PMID:Immunoglobulin-mediated prevention of autoimmune diabetes in the non-obese diabetic (NOD) mouse. 192 9

Transplantation of the islets of Langerhans could be the most promising approach to the clinical treatment of insulin-dependent (type I) diabetes mellitus. In this study, we report on a modified encapsulation technique that produces small alginate-polylysine capsules (0.25-0.35 mm diam). In an in vitro study, both encapsulated and unencapsulated islets showed comparable responses to glucose challenge in terms of insulin secretion. With the new capsules, 16 spontaneously diabetic NOD mice received transplants of 800 encapsulated rat islets/animal. Nonfasting blood glucose concentration decreased from 24.4 +/- 1.4 to 4.0 +/- 1.3 mM. At 4 and 5 mo posttransplantation, the capsules were removed from 2 recipients. Both animals regressed to a hyperglycemic state after capsule removal. However, after another islet transplantation, normoglycemia was again restored in these 2 animals. In control mice, which received unencapsulated islets, the xenografts remained functional for less than 10 days. A high mortality rate was observed among these animals within 2 mo of the recurrence of the hyperglycemic state. Our results clearly indicate that encapsulation of pancreatic islets in the improved capsules can effectively prolong xenograft survival without immunosuppression in an animal model that mimics human type I diabetes mellitus.
Diabetes 1991 Nov
PMID:Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets. 193 9

The incidence of destructive pancreatic infiltrates and overt diabetes in animal models of insulin-dependent (type I) diabetes mellitus can be greatly reduced by inactivating or eliminating most T lymphocytes early in life. Because of theoretical and practical concerns about inducing long-term pan-T-lymphocyte inactivation for prevention or treatment of type I diabetes in humans, we hoped that more selective suppression of only the diabetogenic T lymphocyte population might be possible. To this end, two groups suggested that diabetogenic subpopulations of T lymphocytes in NOD mice could be identified by the protein sequence of their T-lymphocyte receptors. This assertion was based on experimental elimination of candidate T-lymphocyte subpopulations in two different short-term models of diabetes induction in NOD mice. For these experiments, identification and elimination of T-lymphocyte subsets were accomplished with monoclonal antibodies that bind specifically to the variable region of the beta-chain (V beta) of the T-lymphocyte antigen receptor and divide the T-lymphocyte pool of the NOD mouse into approximately 20 V beta subsets. To test the relationship between the two T-lymphocyte V beta subsets implicated in these studies and pancreatic beta-cell destruction in unmanipulated animals, both T-lymphocyte subpopulations identified were genetically eliminated from NOD-derived mice by introduction of a mutant T-lymphocyte receptor V beta gene, from which these sequences are genomically deleted. Histological evidence of severe beta-cell destruction and overt diabetes was found in mice homozygous for the deleted V beta gene, indicating that neither V beta gene segment identified in previous studies is required for diabetogenesis in unmanipulated diabetes-prone mice.
Diabetes 1991 Nov
PMID:Diabetes in NOD mice does not require T lymphocytes expressing V beta 8 or V beta 5. 193 13

The immune mechanisms directly responsible for beta-cell destruction in insulin-dependent diabetes are undefined. We studied the role of MHC class I-restricted T lymphocytes in the development of diabetes in cyclophosphamide (CY)-treated male and untreated female NOD mice (H-2Kd,Db). After administration of CY to 10-wk-old male NOD/Shi/Kbe mice, 37 of 64 (58%) phosphate-buffered saline-injected control mice and 13 of 22 (59%) anti-Kb and 12 of 27 (44%) anti-Db monoclonal antibody (MoAb)-injected mice became diabetic by 14 wk of age, whereas only 3 of 38 (8%) anti-Kd and 2 of 13 (15%) anti-Lyt-2 MoAb-injected mice did. In untreated female NOD/Shi/Kbe mice, 30 of 46 (65%) mice developed spontaneous diabetes by 30 wk of age, whereas none of 9 anti-Kd MoAb-injected mice became diabetic. Immunohistochemical studies showed that islet-infiltrating cells in CY-treated control mice were composed mainly of both L3T4+ and Lyt-2+ T lymphocytes, whereas many L3T4+ and very few Lyt-2+ lymphocytes infiltrated within the islets in anti-Kd MoAb-injected mice. Administration of anti-Lyt-2 MoAb induced the absence of Lyt-2+ T lymphocytes in the islet and spleen. However, anti-Kd MoAb did not change the number of spleen cells or the T-lymphocyte subset and response to concanavalin A. These results suggest that MHC class I Kd-restricted Lyt-2+ T lymphocytes play an important role as direct effector cells in destruction of beta-cells in NOD/Shi/Kbe mice.
Diabetes 1991 Sep
PMID:Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD/Shi/Kbe mice by anti-MHC class I Kd monoclonal antibody. 193 25

The dynamics of trace elements in various organs and eye tissues of NOD mouse and zinc deficiency rat were examined. Zinc content in eye tissues, especially the retina and choroid of NOD mouse with spontaneous diabetes mellitus and zinc deficiency rat were significantly decreased. Zinc uptake also was decreased in the retina and choroid, as compared with other organs. As a result, it was concluded that eye tissues, especially the retina and choroid were markedly reflected changes of the dynamics of trace elements.
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PMID:[The dynamics of trace elements in eye tissues]. 195 Aug 34

Current evidence supports an autoimmune etiopathogenesis for Type I, insulin-dependent diabetes mellitus (IDDM) in which the pancreatic beta (beta) cell is the specific target tissue. Recently, the NOD (non-obese diabetic) mouse has become an important model for IDDM, exhibiting many of the pathological features observed in man, including a progressive pancreatic islet leukocytic inflammation referred to as insulitis. The present study was carried out to determine the efficacy of the bacterial-derived bio-product, pertussigen, to retard the progression of insulitis and thereby prevent overt diabetes. Results revealed that (1) the rapid onset of IDDM in female NOD mice is absent if the mothers are treated with pertussigen prior to mating, (2) treatment of young prediabetic NOD mice with repeated injections of pertussigen results in the retardation of onset of IDDM when compared to untreated control NOD mice, and (3) the severity of insulitis in pertussigen-treated NOD mice not developing IDDM was noticeably less severe than age and sex-matched untreated control mice. Since earlier work had shown that pertussis vaccine, which contains pertussigen, could prevent development of IDDM in mice treated with streptozotocin, the present results may indicate basic differences in the inflammatory responses in the genetically-predisposed NOD mice and IDDM-nonsusceptible mice with streptozotocin-induced diabetes.
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PMID:Pertussigen treatment retards, but fails to prevent, the development of type I, insulin-dependent diabetes mellitus (IDDM) in NOD mice. 195 11


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