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

Microencapsulated rat islets of Langerhans (alginatepolylysine microcapsules) were implanted into the peritoneal cavity of diabetic mice (500 rat islets per mouse) in order 1) to evaluate the ability of this xenograft in correcting hyperglycemia in different models of diabetes and 2) to examine the implanted material recovered from the recipients after several weeks. 1) In the high-dose streptozotocin model in Balb/c mice (n = 14), 6 had a sustained (over one month) decrease in plasma glucose concentration from 401 +/- 7 to 171 +/- 7 mg/dl, with no effect in the other. 2) In the low dose streptozotocin model in C57BL/6J mice (n = 17), plasma glucose levels decreased in 9 mice, from 439 +/- 27 to 180 +/- 30 mg/dl, and remained below 250 mg/dl up to 60 days. In 8 mice, only a transient effect was observed. Empty capsule transplantation had no effect. Plasma insulin in successfully transplanted mice was higher in fed than in fasted state. 3) Microencapsulated rat islets had no effect on plasma glucose in male NOD mice made diabetic by cyclophosphamide treatment (n = 10). Thus, microencapsulated rat islets can improve the diabetic state in some, but not all diabetic mice. In this study, microcapsules were consistently surrounded by an inflammatory reaction, which remains a major concern.
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PMID:Comparative study of microencapsulated rat islets implanted in different diabetic models in mice. 208 71

In insulin-dependent diabetes mellitus in humans, the BB rat and the NOD mouse, serum has been reported to contain autoantibodies that precipitate a 64,000 Mr protein from (32S) methionine labeled histoincompatible non-autoimmune rat or mouse islet cell proteins. Because experimental data reported recently have brought into question the role of the 64,000 Mr protein in targeting autoantibodies and hence initiate beta-cell destruction, we report differently designed experiments to clarify the apparent 64,000 Mr autoantigen enigma. Using an in vitro model of NOD mouse origin mimicking diabetic insulitis we found that target beta-cells induced a 6-fold increase in proliferative response of splenic L3T4+, Thy-1,2+ T cells. The magnitude of the proliferative response was not affected when target beta-cells were pretreated with 50% (vol/vol) partially purified immunoglobulins ((NH4)2SO4 precipitation at 33% saturation) from sera from newly diagnosed (less than 4d after onset) diabetic NOD mice. Cytofluorimetric analysis of beta-cells pretreated with partially purified immunoglobulins plus FITC-conjugated goat antimouse IgG as a second-step antibody were negative and thus gave no indication of an autoantigen-autoantibody complex formed on the surface of the beta-cells. We conclude from the experimental data that it remains still in question whether an autoantigen is targeted by an islet cell surface specific autoantibody and plays a role as a triggering event in the pathogenesis of diabetes in NOD mice.
Diabetes Res 1990 Jan
PMID:Autoantibodies in the sera from newly diagnosed diabetic nod mice: evidence against cross-reactivity with a putative beta-cell surface autoantigen. 209 91

Type I, insulin-dependent diabetes (IDD) in man and the NOD (non-obese diabetic) mouse is believed to result from an autoimmune destruction of pancreatic beta (beta) cells. In both species the pathologic correlate of this destruction is a peri- and intra-islet immune cell infiltrate, referred to as insulitis, easily recognized histologically. Although histologic studies of insulitis have established the autoimmune nature of IDD, controversy remains concerning the phenotypes and especially function of the islet-infiltrating immune cells. In the present study, we reveal a new protocol which permits enumeration of islet-infiltrating leukocytes using flow cytometry (FACS). Using this technique, we have analyzed systematically the changes in major leukocyte phenotypes during the development of the insulitis lesion. Results indicate that: 1) the first islet-infiltrating leukocytes are class II+, Ig- monocytes and CD8+ T lymphocytes, 2) after a slight decrease in the CD8+ cell population, an influx of CD4+ T lymphocytes occurs, accompanied by increasing numbers of CD8+ T cells, as well as IgM+ and IgG+ B lymphocytes, 3) whereas all the IgM+ B cells appear to be CD5+, between 70-95% of IgG+ B cells express CD5, and 4) throughout the response, the class II+, IgG-cell population remains relatively constant. These data, together with our previous work showing that autoantibody binds to pancreatic beta cells prior to leukocytic infiltration, permit construction of a working model for the natural history of insulitis in the NOD mouse. Briefly, the initial cellular response against the beta cell, which begins between 5-7 weeks of life, appears to be a local inflammation in which class II-positive macrophages and CD8-positive cells (possibly with antibody-dependent cell-mediated cytotoxic potential) infiltrate the islet. Finally, T helper cells are activated, traffic briefly through the islet, and elicit a B lymphocyte and T killer cell invasion of the islet that ultimately leads to beta cell necrosis.
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PMID:Flow cytometric enumeration of mononuclear cell populations infiltrating the islets of Langerhans in prediabetic NOD mice: development of a model of autoimmune insulitis for type I diabetes. 213 56

A number of observations indicate an essential role of macrophage activity in the development of hyperglycemia in animal models of Type I diabetes. Administration of macrophage-toxic silica particles prevents spontaneous diabetes development in BB rats or NOD mice. The same result was noted in the low-dose streptozotocin-induced diabetes model in mice. Macrophages appear to be the first immune cells infiltrating islets during early insulitis. Macrophages in inflamed islets of BB rats bear the ED1 marker, whereas resident islet macrophages are ED2-positive. In vitro, ED1-positive macrophages were found to lyse pancreatic islet cells to a similar degree to various tumor cells but not normal thyrocytes. Macrophage-mediated lysis of islet cells was inhibited in the presence of 10-100 mM nicotinamide.
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PMID:Essential contribution of macrophages to islet cell destruction in vivo and in vitro. 214 Feb 61

The MSZ diabetic male mouse represents one of the most useful tools available to researchers interested in analyzing the consequences of insulin dependent diabetes in male mice. In contrast to the high mortality induced by single high doses of SZ, protracted administration of smaller SZ dosages yields a more stable diabetic condition. Moreover, in insulitis prone strains such as BKs, the model allows "synchronization" of beta cell destruction such that the inflammatory events occur on a predictable timescale. The MSZ-diabetic mouse represents a diabetic condition in which the primary etiopathologic effect is produced by an environmental toxin, and not by a genetically programmed loss of tolerance to beta cell specific antigens. In this regard, etiopathogenesis in the MSZ model is quite distinct from that underlying autoimmune type I diabetes in humans, NOD mice, and BB rats, and it is probably not appropriate to refer to pathogenesis in the MSZ model as one of "autoimmune insulitis" as has sometimes been done. The fact that insulitis in the MSZ model may not be "autoimmune," but may actually be a normal response to either tissue damage or to beta cells that have been structurally modified by a chemical, makes the model of special interest. Clearly, there is no single cause of insulin dependent diabetes, with disease induction representing a genetic susceptibility interacting with environmental triggers, such as toxins in the diet (including nitrosamines and fungal metabolites) as well as pathogenic viruses. The MSZ model will continue to be actively investigated because of insights it will afford regarding the genetic bases for susceptibility and resistance to diabetogenic environmental toxins. The model will be of further value by contributing to knowledge of the complicated interactions between pancreatic islet cells, other endocrine cells, and leukocytes in maintenance of glucose homeostasis.
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PMID:Streptozotocin interactions with pancreatic beta cells and the induction of insulin-dependent diabetes. 214 32

Normal mouse islet cells express low levels of MHC class I molecules and undetectable or extremely low levels of MHC class II molecules. Class I expression was dose-dependently augmented by incubation with interferon-gamma (IFN-gamma) or tumor necrosis factor (TNF). Although neither IFN-gamma nor TNF alone induce class II molecules on islet cells, synergistic interaction of IFN-gamma (200 U/ml) and TNF (200 U/ml) may induce class II expression on approximately 50% of islet cells. Niacinamide and 3-aminobenzamide, both inhibitors of ADP ribosylation and scavengers of free radicals, attenuated the class II expression induced by IFN-gamma and TNF. Twenty millimolar niacinamide and 10 mM 3-aminobenzamide reduced the rates of class II antigen-positive cells to mean +/- SD 3.6 +/- 0.3 and 6.1 +/- 1.9%, respectively. The agents did not affect the cytokine-induced augmentation of class I antigens. The inhibition of class II molecule expression may at least partly account for the preventive effect of niacinamide on autoimmune-associated beta-cell damage in NOD mice.
Diabetes 1990 Sep
PMID:Inhibition of cytokine-induced MHC class II but not class I molecule expression on mouse islet cells by niacinamide and 3-aminobenzamide. 214 88

In NOD mice. 50-70% of females and 10-20% of males develop diabetes, although almost all the animals show insulitis. To see if environmental insults could induce diabetes in subjects with pre-clinical anti-Beta cell autoimmunity, non-diabetic NOD mice were selected and injected with a sub-diabetogenic dose of streptozotocin at 6 or 20 weeks of age. The streptozotocin failed to induce diabetes in 16 male and 16 female NOD mice within 4 weeks when they were injected at the age of 6 weeks. In contrast, 6 of 16 male and 10 of 16 female NOD mice developed diabetes within 4 weeks when they were injected at the age of 20 weeks. In untreated age-matched control NOD mice, none of the male and only 2 of 16 female mice became diabetic during the same 4 week period. On histologic examination, the degree of insulitis in streptozotocin-treated NOD mice (at the age of 24 weeks) was not significantly different from that of untreated control NOD mice. However, the streptozotocin-treated animals showed significantly lower pancreatic insulin content than the control mice. These results show that an anti-Beta cell autoimmune process in NOD mice has a predisposing effect on the induction of diabetes by a sub-diabetogenic dose of streptozotocin, and suggest that the precipitation of clinical diabetes by some environmental insults in subjects with pre-existing pre-clinical autoimmune Beta-cell destruction may be one mechanism of disease presentation in human Type 1 (insulin-dependent) diabetes.
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PMID:Predisposing effect of anti-beta cell autoimmune process in NOD mice on the induction of diabetes by environmental insults. 215 51

Nicotinamide, a vitamin B group substance, has previously been shown to prevent diabetes and suppress insulitis in the NOD mouse. In order to further understand its mode of action, we have administered the vitamin orally to female NOD mice from weaning and have examined its effect cross-sectionally (days 40, 106 and 250) on the severity of insulitis, changes in T cell subpopulations, levels of islet cell antibodies (ICA) and insulin autoantibodies (IAA) and diabetes development. At day 40, the incidence and severity of insulitis were much lower in the nicotinamide group (n = 22) than in the control mice (n = 21; 23.8% versus 57.1%, 2.9 +/- 1.4% versus 9.6 +/- 2.6%, respectively). At day 106, the incidence of insulitis increased to 82% in the nicotinamide group (n = 11) and remained similar at day 250 (n = 14). At these two age groups all control mice developed insulitis. The insulitis score increased to about 20% at day 106 in the nicotinamide mice and remained the same at day 250. In the control animals, this score increased from 9.6 +/- 2.6% at day 40 to about 33% and 60% at days 106 and 250, respectively. Diabetes was not detected in the 14 animals maintained on nicotinamide while 4/14 control mice developed the disease with severe insulitis. Most of the immune cells infiltrating the islets were T cells, with higher numbers of L3T4 than Lyt2 cells. At days 40 and 106, the L3T4:Lyt2 cell ratios remained unchanged in both the nicotinamide and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1990 Oct
PMID:Early nicotinamide treatment in the NOD mouse: effects on diabetes and insulitis suppression and autoantibody levels. 215 92

Ly-6C is a differentiation antigen that distinguishes T-lymphocyte subsets. In concordance with previous results, splenocytes from NOD mice do not express the epitope recognized by anti-Ly-6C monoclonal antibodies (MoAbs), including MoAb HK1.4 in this study, and cannot be stimulated to proliferate in response to HK1.4. However, when splenocytes from NOD mice were stimulated in vitro with the anti-CD3 MoAb 145-2C11, T lymphocytes expressing Ly-6C were detected after 48 h of stimulation, with as many as 25% of lymphocytes expressing this antigen with prolonged passage in culture. Most of the cells expressing Ly-6C were Thy-1.2+, CD4+, and CD8- and proliferated after stimulation with HK1.4. To further understand the failure of NOD splenocytes to express Ly-6C, freshly isolated cells were stimulated with alpha/beta-interferon (IFN-alpha/beta) and IFN-gamma. Although these lymphokines induced expression of Ly-6A and Ly-6C in splenocytes from C57BL/6J mice and Ly-6A in NOD cells, Ly-6C was not induced on NOD cells. Because Ly-6C expression on splenocytes was a marker of activation via the CD3 T-lymphocyte receptor complex, we also examined expression of Ly-6C on T lymphocytes within islets showing insulitis in vivo. Lymphocytes that were Ly-6C+ were identified within islets on histological sections of pancreas, whereas Ly-6C+ cells in the spleen from the same mouse could not be detected. Our findings imply functional abnormality in expression of Ly-6C in NOD mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Jul
PMID:Expression of Ly-6C by T lymphocytes of NOD mice after CD3-complex stimulation. Identification of activated cells during insulitis of prediabetic mice. 216 2

The murine alloantigen, Ly-6C, is found on 45% of bone marrow cells, 25% of splenocytes and 15% of lymph node cells in all inbred strains of mice tested, with the exception of NOD, NZB and ST. In these three strains, Ly-6C expression can be detected on only 5% of bone marrow cells and not at all on cells from spleen or lymph node. NOD and NZB, which are models for the autoimmune diseases, diabetes and lupus, respectively, also exhibit a depressed syngeneic mixed lymphocyte reaction. Southern blot analysis reveals a restriction fragment length polymorphism involving the Ly-6C gene which is unique to these three strains. Cloning of the affected genomic segment from the NOD mouse indicates the presence of an interruption in the flanking region of the Ly-6C gene at a point 475 bp upstream of the transcription initiation site and the consequent separation of distal 5' sequences from the body of the gene by at least 10 kb. Inspection of the recombination borders reveals a set of inverted copies of a mouse repetitive R element. Transfection of the Ly-6C genes from NOD and BALB/c into a murine carcinoma line indicates relative functional impairment of the NOD gene, thus paralleling performance in vivo.
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PMID:A recombination event in the 5' flanking region of the Ly-6C gene correlates with impaired expression in the NOD, NZB and ST strains of mice. 216 72


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