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

Diabetes-prone (DP) BB rats spontaneously develop a hyperglycaemic condition which closely resembles human insulin-dependent diabetes mellitus (IDDM), both in terms of clinical and histological features. The incidence of IDDM was significantly reduced when these animals were treated with 2 or 4 mg fusidic acid (FA)/day i.m. from day 30 to day 120 of age. In addition, the mean insulitis score was significantly diminished in the animals treated with FA compared to both vehicle-treated and untreated controls. Finally, 2 mg/day of FA i.m. prevented cell proliferation and interferon-gamma secretion from peripheral blood mononuclear cells upon ex vivo stimulation with concanavalin A. The capacity of FA to substantially reduce the incidence of autoimmune diabetes in a well-known animal model of human IDDM supports previous observations regarding the immunosuppressive properties of FA and its potential use in the treatment of human autoimmune diabetes.
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PMID:Reduction of spontaneous autoimmune diabetes in diabetes-prone BB rats with the novel immunosuppressant fusidic acid. Effect on T-cell proliferation and production of interferon-gamma. 815 81

The autoimmune response that leads to destruction of pancreatic islet beta-cells and insulin-dependent diabetes mellitus (IDDM) has a genetic basis; however, environmental factors can exert profound modulating effects on the genetic predisposition to this autoimmune response. Recent studies in animal models for human IDDM, the genetically diabetes-prone NOD mouse and BB rat, have revealed that microbial agents--including certain viruses and extracts of bacteria, fungi, and mycobacteria--often have a protective action against diabetes development. Many of these microbial preparations are immune adjuvants, which are agents that stimulate the immune system. The protective effects of these agents against diabetes appear to involve perturbations in the production of cytokines, which are polypeptides produced by and acting on cells of the immune system. Thus, recent studies in NOD mice suggest that the islet beta-cell-directed autoimmune response may be mediated by a T-helper 1 (Th1) subset of T-cells producing the cytokines interleukin-2 (IL-2) and interferon-gamma. These studies also suggest that the diabetes-protective effects of administering microbial agents, adjuvants, and a beta-cell autoantigen (GAD65 [glutamic acid decarboxylase]) may result from activation of a Th2 subset of T-cells that produce the cytokines IL-4 and IL-10 and consequently downregulate the Th1-cell-mediated autoimmune response. The clinical implication of these findings is that the autoimmune response leading to islet beta-cell destruction and IDDM may be amenable to prevention or suppression by therapeutic interventions aimed at stimulating the host's own immunoregulatory mechanisms.
Diabetes 1994 May
PMID:Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? 778 55

There is evidence that cytokines, in particular interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) might mediate beta cell destruction in type 1 diabetes. Therefore the secretion of these cytokines by peripheral blood lymphomononuclear cells (PBMNC) was investigated in basal conditions and 48 h after stimulation with T-cell mitogen phytohaemagglutinin (PHA) in 33 diabetic patients and in 10 normal controls. The patients were divided in 4 groups (Group 1, 10 controls; Group 2, 13 newly diagnosed type 1 diabetics, the onset had occurred from 5 days to 3 months before the study; Group 3, 10 Long Standing (LS) type 1 diabetics with duration of the disease between 2 years and 10 years; and Group 4, 10 type 2 diabetics). No difference was found among the 4 groups considered in IL-1 beta secretion by unstimulated cultures, although the percentage of TAC+ cells was significantly higher in type 1 newly diagnosed diabetic patients with respect to the LS, the type 2 diabetics and the controls. After PHA stimulation a significant increase of IL-1 beta was found in newly diagnosed type 1 diabetic patients in comparison with the control subjects, the LS and type 2 diabetic patients (P < 0.001). The supernatants of newly diagnosed type 1 diabetics also showed a significant reduction in IFN-gamma production both in basal (P < 0.01) and in stimulated conditions (P < 0.001) in comparison with the controls, the LS (P < 0.002 in basal, and P < 0.001 in stimulated conditions) and the type 2 diabetic patients (P < 0.001 both in basal and stimulated conditions).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res Clin Pract
PMID:In vitro secretion of interleukin-1 beta and interferon-gamma by peripheral blood lymphomononuclear cells in diabetic patients. 826 23

Insulin, carboxypeptidase-H (CP-H), and glutamate decarboxylase (GAD) have been identified as potential autoantigens in insulin-dependent diabetes mellitus (IDDM). Previous studies have described immunoreactive insulin as a surface molecule on the plasma membrane of rat islet cells and suggested that cell-surface insulin was derived during exocytosis by the fusion of insulin secretory granules with the beta-cell plasma membrane. These findings predict that insulin and other secretory granule-derived proteins such as the putative autoantigen CP-H may be colocalized with insulin at specific sites of exocytosis on the beta-cell surface. In studies to test this hypothesis, cell-surface staining of dispersed rat islet cells occurred in a granule-like pattern with antibodies for CP-H and insulin. The specificity of the CP-H antiserum was confirmed by immunoblotting and indicated that the antiserum was essentially monospecific for CP-H. Confocal laser microscopy confirmed that immunoreactive staining for CP-H and insulin was confined to the beta-cell surface. Colocalization of CP-H and insulin on the cell surface of beta-cells was demonstrated by double staining with antibodies to CP-H and insulin, and the percentage of beta-cells positive for both of these autoantigens increased twofold with increases in insulin secretion. In contrast, islet cells failed to reveal cell-surface staining for GAD65, another putative autoantigen in IDDM, under either basal or insulin stimulatory conditions or following exposure of islet cells to the cytokines interleukin-1 beta, tumor necrosis factor-alpha, and recombinant human interferon-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Mar
PMID:Potential autoantigens in IDDM. Expression of carboxypeptidase-H and insulin but not glutamate decarboxylase on the beta-cell surface. 831 14

Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.
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PMID:Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group. 832 1

Diabetic patients are highly susceptible to microbial and fungal infections. To better understand the immune mechanisms underlying the diabetic host-parasite relationship, we studied the course of systemic infection with Candida albicans in mice with low-dose streptozotocin-induced diabetes. For this purpose, we used a low-pathogenic strain of C. albicans, PCA-2, which causes a chronic infection in the intact host. Injection of PCA-2 cells into diabetic mice caused a lethal acute infection. The levels of interferon-gamma (IFN-gamma) determined in sera and splenocyte culture supernatants from diabetic mice were significantly higher than those in control mice. Moreover, splenic macrophages from diabetic mice were functionally activated relative to normal macrophages, as evaluated by significantly augmented C. albicans killing in vitro. However, when diabetic mice were infected with PCA-2, IFN-gamma levels dropped dramatically to undetectable levels during the first week of infection and there was a marked decrease in macrophage activation. These data suggest that the levels of IFN-gamma production early in infection might have a crucial role in generating the susceptibility of diabetic mice to infection.
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PMID:Low-dose streptozotocin-induced diabetes in mice. I. Course of Candida albicans infection. 834 67

The non-obese diabetic (NOD) mouse is a spontaneous model of human insulin-dependent diabetes mellitus. Both CD4+ and CD8+ T cells infiltrate the pancreatic islets of NOD mice prior to beta-cell destruction. T-cell lines isolated from the islets of NOD mice are tools for studying the pathogenesis of insulin-dependent diabetes mellitus. During attempts to generate such lines we isolated an autoreactive CD4+ T-cell line, designated C2, from the 'insulitis' lesion of a 20-week-old female non-diabetic NOD/WEHI mouse. Islet T cells were propagated by the addition of interleukin-2 and reexposure every 2 weeks to whole NOD islets and irradiated NOD spleen cells as antigen presenting cells. C2 cells proliferated up to 100-fold upon exposure to NOD antigen presenting cells but did not respond to whole NOD islets or antigen presenting cells from allogeneic mouse strains. Proliferation of C2 cells to NOD antigen presenting cells was blocked by a monoclonal antibody against the unique class II MHC molecule of NOD, I-Ag7. In response to NOD antigen presenting cells, C2 cells secreted interferon-gamma, tumour necrosis factor-alpha and interleukin-6 but no detectable interleukin-2, interleukin-4 or interleukin-10, a pattern of cytokine secretion more characteristic of Th1 CD4 cells. C2 cells displayed significant cytotoxicity in a redirected lysis assay. To explore a possible role for autoreactive T cells in the pathogenesis of autoimmune diabetes, C2 cells were injected i.v. into female NOD mice that had received cyclophosphamide to accelerate development of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppression of diabetes mellitus in the non-obese diabetic (NOD) mouse by an autoreactive (anti-I-Ag7) islet-derived CD4+ T-cell line. 840 38

Ten out of 20 (50%) 17-week-old female NOD/WEHI mice developed an acute form of autoimmune diabetes when injected with two large doses of cyclophosphamide (CY), given at 14-day intervals. If these mice were treated under a prophylactic regimen with 2.5 mg/kg body weight per day of the novel immunosuppressant deoxyspergualin (DSP) the onset of diabetes was completely prevented. Moreover, DSP-treated animals showed reduced signs of pancreatic insulitis, had lower percentages of splenic lymphoid cells (SLC) expressing IL-2 receptors and Ly-6C antigens on their surfaces, and these cells released lower amounts of interferon-gamma (IFN) when stimulated in vitro. These data, providing evidence for the capacity of DSP to protect NOD/WEHI mice from experimental autoimmune diabetes and to modulate histo-immunological pathogenic pathways, indicate DSP as a drug of potential interest in the treatment of human insulin-dependent diabetes mellitus.
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PMID:Prevention of cyclophosphamide-induced diabetes in the NOD/WEHI mouse with deoxyspergualin. 842 90

The human fetal beta-cell is different from the adult beta-cell not only in that it is unable to release significant amounts of insulin during an acute glucose challenge, but also in that it is resistant to the toxic effects of a bolus of streptozotocin (STZ) and chronic exposure to cytokines tumour necrosis factor-alpha and interferon-gamma. To examine further the differences between the immature and mature beta-cell, these cells were exposed to multiple low doses of STZ (MLS) both in vivo and in vitro, the regimen used being classically toxic to rodent adult beta-cells. The in vivo experiments were conducted after the tissue had been grafted into the athymic mouse. There was no adverse effect of MLS on the insulin content of engrafted human fetal pancreatic explants, either 1, 4, or 15 weeks after the injection of 70 mg/kg/i.p. STZ daily for 5 days. Diabetes, induced in the mice by MLS or a bolus of STZ, was reversed in five of seven MLS-treated mice at 59 +/- 8 days and four of seven STZ-treated animals at 75 +/- 10 days (no significant difference). The growth rate of the implanted tissues also was not adversely affected by the MLS, nor was the percentage of beta-cells 2 weeks after completion of the MLS. In contrast, mouse fetal beta-cells transplanted into the athymic mouse were adversely affected, their insulin content 2 weeks after MLS being only 0.7% that of controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Resistance of the human fetal beta-cell to the toxic effect of multiple low-dose streptozotocin. 848 71

Nitric oxide has been implicated as one possible mediator of interleukin-1 beta (IL-1)-induced inhibition of insulin secretion and islet cell damage. The aim of this study was to define the effects of tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) on nitric oxide production, insulin secretion, and DNA damage in islets from unweaned rats. Treatment of islets with 0.5-500 U/ml of either TNF or IFN on their own inhibited glucose-stimulated insulin secretion in a dose-dependent manner (minimum effective dose 5 U/ml). In combination, the cytokines exerted a pronounced synergistic inhibitory effect on secretion and were equipotent at causing a significant and concentration-dependent increase in culture medium nitrite levels, islet cyclic GMP formation, and DNA damage. Used alone or in combination, TNF and IFN significantly enhanced the activity of inducible nitric oxide synthase as determined by measuring the conversion of 14C-labeled arginine to 14C-labeled citrulline and nitric oxide. Use of arginine-free medium, without or with NG-monomethyl-L-arginine, resulted in inhibition of nitrite formation by 5-1,000 U/ml IFN+TNF and partial restoration of the insulin secretory response to glucose. Treatment of rat islets with increasing doses of TNF+IFN (5, 50, and 500 U/ml) resulted in a progressive increase in DNA damage, as shown by the comet assay, which detects DNA strand breaks in individual islet cells. The DNA damage caused by an intermediate concentration (50 U/ml) of TNF+IFN was comparable to that generated by IL-1 when used at 20 U/ml. We conclude that TNF and IFN induce nitric oxide formation, which partially inhibits glucose-induced insulin secretion and causes significant DNA strand breakage, but that as cytokine concentrations increase, non-nitric-oxide-mediated events predominate.
Diabetes 1996 Feb
PMID:Tumor necrosis factor-alpha and interferon-gamma inhibit insulin secretion and cause DNA damage in unweaned-rat islets. Extent of nitric oxide involvement. 854 63


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