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

CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment.
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PMID:In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. 776 40

Over the last several years, there has been a considerable and rapid expansion in our understanding of the cytokines. Insights into cytokine functions gained from basic biological studies are currently being applied to the study of autoimmune diabetes. It has become clear that cytokines are critical regulating elements involved in the processes of initiating, promoting, and effecting beta-cell destruction. It is also evident that cytokine functions in IDDM are determined by timing of appearance and local synthesis, as well as the prevailing cytokine and cellular milieu. Elucidating individual cytokine responses in IDDM may offer new insights into mechanisms of disease pathogenesis and may lead to novel cytokine-based therapies for the treatment of IDDM. It may also be possible that the intensity or character of a patient's cytokine response to islet injury or to the metabolic changes inherent to diabetes may influence the ultimate expression of IDDM or its complications. Clearly, this rapidly expanding field of study should have a major impact on our understanding of diabetogenesis, our ability to intervene in our understanding of diabetogenesis, our ability to intervene in the disease process itself, and ultimately our capacity to care for individuals with IDDM.
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PMID:Cytokines as mediators of autoimmune diabetes and diabetic complications. 778 92

Renal hypertrophy is an early feature of diabetes, and it may predispose the kidney to the eventual development of parenchymal dysfunction. Since we have previously demonstrated that short-term culture in high glucose concentration stimulates production of transforming growth factor-beta 1 (TGF-beta 1) in proximal tubular and glomerular mesangial cells, we postulated that this cytokine, which has potent regulatory effects on cellular growth and extracellular matrix production, is important in mediating diabetic renal disease. In this study we evaluated the gene and protein expression of TGF-beta 1 in the kidney of two rodent models of spontaneous insulin-dependent diabetes mellitus [the biobreeding (BB) rat and the nonobese diabetic (NOD) mouse]. In association with the appearance in both models of significant renal hypertrophy, TGF-beta 1 mRNA levels were increased threefold in the kidney of the diabetic BB rat after 3 days of diabetes and also threefold after 7-9 days in the NOD mouse. There was no increase in TGF-beta 1 transcripts in the livers of the diabetic animals, suggesting that this response is tissue specific. Immunohistochemical studies revealed that TGF-beta 1 protein is concordantly elevated in the cortical tubular cells of the diabetic kidney in both models. These results suggest that the stimulated expression of renal TGF-beta is an early manifestation of the involvement of the kidney by diabetes. Whether increased TGF-beta production in the diabetic kidney is a key promoter of diabetic renal manifestations (e.g., hypertrophy) deserves additional studies.
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PMID:Renal hypertrophy is associated with upregulation of TGF-beta 1 gene expression in diabetic BB rat and NOD mouse. 781 Jun 96

A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2- and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.
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PMID:On the pathogenesis of IDDM. 782 44

T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas-infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases.
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PMID:Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. 783 34

Evidence has accumulated suggesting the existence in humans of polarized T helper (Th) cell subsets, coded as Th1 and Th2, with defined cytokine secretion profiles. Immune responses to intracellular bacteria and viruses result in the preferential development of the Th1 cell subset. Th1 cells express cytolytic activity against antigen-presenting cells and provide helper function for IgM, IgG and IgA synthesis only at low T/B cell ratios. In contrast, Th2 cells develop in response to allergens or helminth antigens, provide help for all immunoglobulin classes, including IgE, and lack cytolytic potential. The cytokine milieu in the microenvironment plays a fundamental role in determining the functional phenotype of the subsequent antigen-specific Th1 or Th2 responses. In recent years it has become clear that Th1 and Th2 cells play different roles not only in protection against exogenous offending agents, but also immunopathology. Th2 cells are involved in immunopathology induced by helminths and are responsible for the initiation and maintenance of allergic disorders. Th1 cells seem to be involved in contact dermatitis, acute allograft rejection and organ-specific autoimmunity, such as thyroid autoimmune disorders, diabetes mellitus or multiple sclerosis, whereas less polarized patterns of Th cells are detectable in target organs of patients with rheumatoid arthritis. Sjogren's syndrome or systemic lupus erythematosus.
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PMID:Human Th1 and Th2 cells: functional properties, regulation of development and role in autoimmunity. 785 16

Tumor necrosis factor-alpha (TNF alpha) is a cytokine implicated in the development of septic shock, cachexia, and other pathological states. Recent studies indicated a direct role for adipose expression of TNF alpha in obesity-linked insulin resistance and diabetes. Pioglitazone, CP-86,325 (CP), AD-5075, CS-045, ciglitazone, and englitazone are members of a new class of insulin-sensitizing thiazolidinedione derivatives with in vivo antidiabetic activities. To test whether these agents antagonize the effect of TNF alpha, 3T3-L1 cells were induced to differentiate in the presence of TNF alpha with or without thiazolidinedione derivatives. Incubation of 3T3-L1 cells with TNF alpha alone completely inhibited adipocyte conversion and expression of fatty acid-binding protein messenger RNA (mRNA). However, coincubation of TNF alpha-treated cells with CP (1 microM), AD-5075 (1 microM), pioglitazone (10 microM), or CS-045 (10 microM) blocked these effects. Long term incubation of 3T3-L1 adipocytes with a low dose of TNF alpha (50 pM) significantly decreased the levels of the adipocyte/muscle-specific glucose transporter (GLUT4) and the CCAAT enhancer-binding protein mRNAs, but did not affect expression of the ubiquitously expressed glucose transporter (GLUT1) or lipoprotein lipase mRNAs. Incubation of 3T3-L1 adipocytes with TNF alpha also inhibited insulin-stimulated 2-deoxyglucose uptake as well as expression of GLUT4 protein. Furthermore, in 3T3-L1 adipocytes, incubation with TNF alpha attenuated the expression of fatty acid-binding protein mRNA in a time- and dose-dependent manner. These inhibitory effects were partially or completely blocked by coincubation of the cells with CP. These results implicate that the insulin-sensitizing agents may exert their antidiabetic activities by antagonizing the inhibitory effects of TNF alpha.
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PMID:Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. 789 57

Two main hypotheses support the contention that type I diabetes is an autoimmune disease, namely "the cytokine hypothesis" and "the T-lymphocyte hypothesis". Various strategies can be used at diagnosis with a view to stopping beta-cell destruction or at least attenuating the process. This review discusses the use of antioxidants based on the idea that free oxygen radicals are important mediators. Experimental animal models have indicated that several antioxidants may prevent diabetes, although in humans only nicotinamide has been shown to have some effect on preventing the disease in high-risk individuals and to produce a slight effect on residual insulin secretion in newly diagnosed patients. Bearing in mind these considerations, we tried a cocktail of several antioxidants at high dosage. As the code of this randomized double-blind study is not broken, results cannot be given, but preliminary observation indicates that there has been no dramatic increase of complete remission. Based on the hypothesis that type I diabetes is a T-lymphocyte-mediated disease, lymphocyte photopheresis may be useful. Photopheresis, comprising the treatment of lymphocytes by a combination of the light-activated drug methoxypsoralen and UVA irradiation, has been shown to be effective in the treatment of some other autoimmune disease. One hypothesis regarding its efficacy holds that the method causes changes in the antigenicity of the treated lymphocyte clones which cause a vaccination-like effect when these cell lines are retransfused at repeated intervals into the patient. Nothing to date is known about its effect in diabetes, although a double-blind randomized placebo-controlled study has been commenced.
Diabetes Metab Rev 1993 Dec
PMID:Intervention at diagnosis of type I diabetes using either antioxidants or photopheresis. 792 31

Recent observations have suggested a role for interleukin 1 (IL-1), a macrophage-derived cytokine, in the autoimmune beta-cell destruction, that is associated with type 1 diabetes. In this study, we investigated the effects of human recombinant IL-1 beta on pancreatic beta-cells from NOD and NON mice (diabetes-resistant NOD-related strain), focussing upon the appearance of intracisternal type A virus (IAP) and retrovirus type C. NOD mice pancreatic islets were incubated with or without IL-1 (0.1, 1, 10, 100 U/ml) for 10 days. Thereafter, the islets were examined using an electron microscope. When the islets of NOD mice were incubated with the IL-1 (10, 100 U/ml) under condition of high glucose, IAP and endogenous retrovirus type C frequently appeared in the beta-cells. Retrovirus type C was present as a cluster. In contrast, IAP and retrovirus type C were rarely found in beta-cells from the control group. When the islets of NON mice were incubated with or without IL-1 (10 U/ml) in the presence of high glucose, IAP was rarely found in beta-cells and retrovirus type C was undetectable in beta-cells. This study indicated that IL-1 is an important effector that leads to insulitis or aggravates insulitis in NOD mice.
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PMID:IL-1 induces intracisternal type A virus and retrovirus type C in pancreatic beta-cells of NOD mice. 794 65

Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. 794 48


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