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

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1 beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1 beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1 beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells. 132 36

Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
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PMID:Molecular pathology of type 1 diabetes. 223 44

The in vitro production of interferon-alpha was studied in cultures of peripheral blood mononuclear cells from children with insulin-dependent diabetes. Significantly lower levels (p less than 0.01) of interferon (median 64 IU/ml) were found in mumps antigen stimulated cultures of IDDM patients compared to control children (median 256 IU/ml) whereas no differences between groups were found in the amount of interferon induced by Coxsackie B pool antigen or live Sendai virus.
Diabetes Res 1989 Oct
PMID:Low levels of mumps virus antigen induced interferon-alpha production in insulin-dependent diabetes. 256 52

Persistent condylomata acuminata in a 21-year-old patient with diabetes mellitus were treated with highly purified interferon-alpha (IFN-alpha) obtained by recombinant DNA technology. Daily dose was 1.5 X 10(6) IU, given subcutaneously. Already during treatment the condylomata regressed. Two weeks after the end of therapy, i.e. after a total dose of 10.5 X 10(6) IU IFN-alpha, all condylomata had completely receded. Blood glucose levels remained constant with concomitant insulin therapy. Toxic side-effects or antibodies to IFN-alpha were not observed.
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PMID:[Alpha interferon in condylomata acuminata and juvenile diabetes mellitus]. 374 47

To elucidate the role played by interferon-alpha (IFN alpha) in the pathogenesis of autoimmune endocrine disease, we determined the autoantibody status, thyroid function test results, hemoglobin-A1c levels, and clinical symptoms of 58 patients who received IFN alpha for treatment of chronic active type C hepatitis. Each patient was treated for 6 months with a total dose of 391 +/- 140 x 10(6) U (mean +/- SD). Thyroid microsomal and/or thyroglobulin antibodies newly appeared or were increased in titer in 6 patients, 2 of whom developed hypothyroidism during IFN alpha therapy. Neither islet cell antibodies nor insulin-dependent diabetes mellitus developed during IFN alpha therapy, although hemoglobin-A1c levels were increased in 2 patients. One patient became positive for antimitochondrial antibodies, and another patient with preexisting antimitochondrial antibodies also manifested deterioration in liver function test results. Parietal cell antibodies and smooth muscle cell antibodies were the most frequent newly developed antibodies in 7 patients. Adrenal medullary cell antibodies and nuclear antibodies newly developed in 2 and 1 patients, respectively. At least 1 of 8 autoantibodies newly appeared in 19 patients (32.8%) and hypothyroidism developed in 2 patients (3.4%) during IFN alpha therapy. On the other hand, in 19 age- and sex-matched patients who did not receive IFN alpha, no autoantibody appeared, and no autoimmune disease developed during a follow-up period of 3 months. These findings suggest that IFN alpha acts as an immunomodulatory agent, inducing autoantibody production and the development of autoimmune disease in susceptible patients. Special attention should be paid to the development of hypothyroidism during IFN alpha therapy.
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PMID:Autoimmune endocrine disease induced by recombinant interferon-alpha therapy for chronic active type C hepatitis. 788 51

The mechanism(s) leading to beta cell dysfunction in type I diabetes has not been defined. We have investigated whether islet expression of IFN alpha could be a cause of the lesions that are hallmarks of type I diabetes. Streptozotocin induces the expression of interferon-alpha by pancreatic islets prior to the diabetes induced by streptozotocin. Increased IFN alpha, induced by poly I/C or expressed from a transgene will exacerbate the diabetogenic effects of streptozotocin. In another rodent model of type I diabetes (the BB rat), islet expression of IFN alpha precedes lymphocytic infiltration and diabetes. As in the streptozotocin model, in the BB rats poly I/C will induce islet expression of IFN alpha and accelerate the onset of diabetes. These results are consistent with the hypothesis that islet expression of IFN alpha participates in causing type I diabetes.
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PMID:Islet expression of interferon-alpha precedes diabetes in both the BB rat and streptozotocin-treated mice. 789 58

Type I diabetes is an autoimmune disease involving an interaction between an epigenetic event (possibly a viral infection), the pancreatic beta cells, and the immune system in a genetically susceptible host. The possibility that the type I interferons could mediate this interaction was tested with transgenic mice in which the insulin-producing beta cells expressed an interferon-alpha. These mice developed a hypoinsulinemic diabetes associated with a mixed inflammation centered on the islets. The inflammation and the diabetes were prevented with a neutralizing antibody to the interferon-alpha. Thus, the expression of interferon-alpha by the beta cells could be causal in the development of type I diabetes, which suggests a therapeutic approach to this disease.
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PMID:Induction of type I diabetes by interferon-alpha in transgenic mice. 810 Mar 67

To evaluate the clinical efficacy of interferon-alpha in hepatocellular carcinoma, 71 adult Chinese patients with histologically proven inoperable hepatocellular carcinoma were randomized to receive recombinant interferon-alpha 2a (50 x 10(6) IU/m2) intramuscularly three times a week (n = 35) or no antitumor therapy (n = 36). The survival of interferon-alpha-treated patients was significantly better than that of patients who received no antitumor therapy (p = 0.0471); median lengths of survival were 14.5 and 7.5 wk, respectively. Objective tumor regression greater than 50% was observed in 31.4% (11 of 35) of patients receiving interferon-alpha. Interferon-alpha induced tumor regression greater than 50% in 11 (31.4%) patients. Compared with the group receiving no antitumor therapy, the interferon-alpha therapy group had more tumor regression (p < 0.0001) and less tumor progression (p = 0.001). This high-dose interferon-alpha therapy was relatively well tolerated; only 34.3% of patients required reduction of dosage by one third or one half because of persistent fatigue. Two patients with diabetes mellitus (one also had tabes dorsalis) exhibited mental deterioration that might have been partially attributable to interferon-alpha therapy. We conclude that interferon-alpha is useful in a proportion of Chinese patients with inoperable hepatocellular carcinoma, both in prolonging survival and in inducing tumor regression.
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PMID:Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. 838 88

Type 1 diabetes is an organ-specific autoimmune disease in which the insulin-secreting B cell is destroyed. Both genetic factors (linked to class II MHC genes) and environmental agents (viruses, diet) appear to be involved in the aetiology. Study of autopsy pancreases of children who die at presentation of their disease has proved elucidating. In such pancreases islets before, during and after B cell destruction, are all visible. The earliest defined immunological event in the disease process appears to be expression of interferon-alpha by insulin-containing B cells. Secretion of this cytokine is associated with hyperexpression of class I MHC by all the endocrine cells within insulin-containing islets. Another immunological phenomenon which is unique to type I diabetes is the presence of aberrant class II MHC molecule expression by B cells. This may induce autoimmunity by allowing antigen presentation of B cell specific antigens. If the onset of the disease process is marked by interferon-alpha expression by B cells then a search for the presence of a continuing viral infection in these cells may prove profitable, although no viruses have been found in them to date.
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PMID:The pathology of the endocrine pancreas in type 1 (insulin-dependent) diabetes mellitus. 861 Nov 88

Development of type 1 insulin-dependent diabetes mellitus has been recently reported in patients who underwent interferon-alpha (IFN-alpha) therapy because of chronic viral hepatitis. Furthermore IFN-alpha seems to be involved in the immunological events that lead to beta-cell destruction and development of type 1 diabetes. To evaluate whether IFN-alpha treatment could elicit an autoimmune response against beta-cell antigens, we determined the occurrence of islet cell antibodies and insulin autoantibodies in the sera of 60 patients with HCV- or HBV-related chronic hepatitis who had been treated with IFN-alpha for 6 or 12 months. The presence of antibodies against thyroglobulin, thyroid microsomal antigen, gastric parietal cells, and non-organ-specific antigens was also investigated. Insulin autoantibody positivity was observed in 2/60 (3.3%), 8/60 (13.3%), and 4/30 (13.3%) patients, before IFN-alpha treatment, and after 6 months and 12 months of therapy, respectively. None of the studied patients developed islet cell antibodies or type 1 diabetes. Before IFN-alpha therapy four patients showed thyroid autoantibodies and four others developed antibodies against thyroglobulin and/or thyroid microsomal antigen during the treatment. Coexistence of insulin autoantibodies and thyroid autoantibodies was observed in only two patients. Our results showed that IFN-alpha therapy in patients with chronic viral hepatitis is capable of inducing development of autoantibodies against insulin. This event seems to be not related to other autoimmune disorders.
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PMID:Interferon-alpha therapy may induce insulin autoantibody development in patients with chronic viral hepatitis. 876


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