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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus is characterized by progressive autoimmune destruction of pancreatic Beta cells mediated by ill-defined effector mechanisms. Experimental data suggest that cytokines, e.g. interleukin 1 and tumor necrosis factor, could play a fundamental role. The aim of this study was to analyze the effect of recombinant IL-1 beta (rIL-1 beta) on both islet functional capacity and morphology, using long-term cultures and various glucose concentrations. Islet cultured with 1 g/l (5.5 mmol/l) glucose maintained normal insulin- secretion and morphology for more than two months. In contrast, islets cultured with 2 g/l (11 mmol/l) glucose showed an altered insulin secretion and a shorter survival (40 days). At 11 g/l (60 mmol/l) glucose, islets died by 2 weeks of culture. rIL-1 beta exerted a cytotoxic effect on islet cells only when added to cultures containing supraphysiological glucose concentrations. But, in the presence of 1 g/l glucose, the addition of rIL-1 beta (40 ng/ml) for prolonged periods (14 days), did not alter islet function. Our results suggest that in auto-immune type I diabetes, IL-1 beta represents an aggravating factor in lesion formation more than a primary pathogenic mechanism.
Eur Cytokine Netw
PMID:The effects of interleukin-1 on pancreatic beta cell function in vitro depend on the glucose concentration. 147 95

In insulin dependent diabetes mellitis (IDDM) beta cell destruction is associated with infiltration of the pancreatic islets by T lymphocytes and macrophages. Cytokine products from the infiltrating immunocytes not only have powerful immunoregulatory actions but also are capable of impairing islet cell functions and have thus been postulated to assume a central role in mediating anti-beta cell immunity and beta cell destruction. In an effort to explore further the role of cytokines in the pathogenesis of IDDM, we examined clinical, metabolic and pathological features of NOD/Wehi mice injected intraperitoneally with multiple doses of IFN-gamma and/or TNF-alpha. Blood glucose profiles were not significantly altered by injection of cytokines alone or in combination. Except for a hypoglycaemic rebound in mice injected with TNF-alpha, arginine stimulation tests revealed no disturbances in islet secretory function in cytokine injected mice. Compared with vehicle and cytokines alone, injection of IFN-gamma + TNF-alpha was associated with a variety of clinical and pathological changes including abdominal distention, piloerection, ascites, oedema, thymic atrophy, splenic enlargement and pancreatic distention. Histological examination of the pancreas in these mice revealed moderate to severe pancreatitis which included focal haemorrhagic necrosis, oedema and polymorphonuclear and mononuclear cell infiltration. The islets in these mice appeared normal morphologically and when stained for insulin. The injection of IFN-gamma + TNF-alpha, and to a lesser extent TNF-alpha alone, was associated with a significant reduction in the severity of insulitis. Examination of pancreatic MHC-class I and class II molecule expression revealed in mice given IFN-gamma + TNF-alpha, as compared with controls, significant and uniform induction of both these molecules on ductal and acinar cells; low level MHC-class II expression was also detectable on beta cells in these mice. MHC-class I molecules which were expressed at high levels by beta cells in control mice did not appear to change following administration of the cytokines alone or in combination. We conclude that despite their immunostimulatory actions in vitro and in other models in vivo, systemic administration of the cytokines IFN-gamma and/or TNF-alpha to NOD/Wehi mice does not activate or enhance, and may actually suppress, anti-beta cell immunity in this model.
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PMID:Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. 190 36

Insulin-dependent diabetes mellitus (IDDM) is characterized by a progressive autoimmune destruction of pancreatic beta cells. Many data suggest that interleukin 1 (IL-1) plays a fundamental role in the pathogenesis of the disease. In the nonobese diabetic (NOD) mouse, a spontaneous model of IDDM, it was put forward that the disease is linked to a susceptibility locus, called idd5, which contains the IL-1 receptor (IL-1R) gene. The polymerase chain reaction (PCR) was used to characterize the IL-1R gene in our NOD mouse colony and in two mouse strains taken as controls. Using primers to amplify the IL-1R gene between bp-106 and +378, a 580 bp fragment was obtained from C57BL/6 DNA but not from DBA/2 and NOD DNA. However, amplification of the IL-1R gene region between bp +1 and +378 in the three strains yielded amplicons 480 bp long. The specificity of the amplification was confirmed by restriction analysis. Our results suggest, depending on the strain, the presence of one or two introns: one (480 bp) in the 5'-untranslated region and the other (100 bp) in the region coding for amino acids between 69 and 126, and an exon-intron organization of the mouse IL-1R gene different than that described in the human genome.
Eur Cytokine Netw
PMID:PCR analysis of interleukin-1 receptor gene in the nonobese diabetic mouse. 757 87

Insulin-dependent diabetes is an autoimmune disease specifically targeting the pancreatic beta cells and several observations, both experimental and clinical, suggest that the interaction of the immune system with the beta cells is in part determined by the functional state of the target cells, increased beta cell activity resulting in augmented immunologic mechanisms and vice versa for suppressed beta cell activity and decreased immune attack. In this study we investigated whether cytokine induced islet cell cytotoxicity in vitro was in part dependent on the functional state of the beta cells. Cytotoxicity of cultured rat islets was induced by IL-1 (100 pg/ml) and TNF (62.5 ng/ml) individually and in combination and beta cell activity was modulated by culturing the islets in media containing 3.3, 5.5, 11, and 20 mmol/liter glucose. Both IL-1 and TNF were cytotoxic when administered individually and the combination of IL-1 and TNF was more cytotoxic than either cytokine alone. Maximum cytotoxicity was observed at 11 mmol/liter glucose with cytotoxicity being reduced at 5.5 mmol/liter glucose and further reduced at 3.3 mmol/liter glucose. Interestingly, the degree of cytotoxicity was lower in 20 mmol/liter glucose compared to 11 mmol/liter. These results firmly establish that islet cytotoxicity of IL-1 and TNF is highly dependent on the functional state of the beta cells. This suggests that during the IDDM disease process as some beta cells are destroyed, the compensatory increased activity of the remaining beta cells may increase their susceptibility to cytokine attack. Furthermore, our observations provide rational support for the use of beta cell rest as intervention therapy for IDDM.
Lymphokine Cytokine Res 1993 Aug
PMID:The functional state of the beta cell modulates IL-1 and TNF-induced cytotoxicity. 821 98

We have identified two PstI polymorphisms of the interleukin 1 receptor type I gene (IL1RI). One of these (RFLP-A) showed significant association to IDDM (P = 0.027), whereas no difference between patients and control subjects was found for RFLP-B (p = 0.42). RFLP-A was physically mapped to the 5'UTR of the gene. We sequenced and analysed a 411 bp region of a putative promotor region (P2) around RFLP-A. RFLP-A was due to a C to T transition in exon 1B of the IL1RI gene. This single-base mutation did not affect any known transcription factor recognition sequence or the predicted secondary mRNA structure. In addition, we found two other single-base substitutions in more than one individual. Neither of these showed specific disease association or absolute linkage with the RFLP-A.
Cytokine 1995 Oct
PMID:Characterization of polymorphisms of an interleukin 1 receptor type 1 gene (IL1RI) promotor region (P2) and their relation to insulin-dependent diabetes mellitus (IDDM). The Danish Study Group of Diabetes in Childhood. 858 Mar 83

T cells from NOD mice display an age-dependent, TCR-inducible proliferative hyporesponsiveness that may be causal to IDDM. Exogenous IL-4 completely restores this hyporesponsiveness in vitro and prevents IDDM in vivo when administered to NOD mice. We therefore tested the hypothesis that stimulation of a Th2 response by either IL-4 or CD28 costimulation may block progression to IDDM. Low-dose IL-4 treatment beginning at 2 weeks of age (pre-insulitis) protects NOD mice from insulitis, sialitis, and thyroiditis, indicating that IL-4 modulates T cell migration to these inflammatory sites. Cytokine secretion profiles of stimulated T cells and assays of intrapancreatic cytokine concentrations revealed that IL-4 treatment prevents IDDM by stabilizing a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Whereas treatment of NOD mice with an anti-CD28 mAb between 2 to 4 weeks of age inhibits destructive insulitis and protects against IDDM by enhancing IL-4 production by T cells, anti-CD28 treatment between 5 to 7 weeks of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the protective effect conferred by anti-CD28 treatment. Our data demonstrate that stimulation of a Th2-cell-enriched environment in the pancreas during the inductive phase of disease development blocks progression to IDDM in NOD mice.
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PMID:Cytokine- and costimulation-mediated therapy of IDDM. 941 41

Nitric oxide (NO) may contribute to pancreatic beta cell damage during the development of type 1 diabetes. Its formation can be triggered by cytokines which induce the expression of the inducible form of nitric oxide synthase (iNOS) in pancreatic islets. In the iNOS-catalyzed reaction, arginine is converted into citrulline and NO. Cellular NO formation may be regulated by the availability of arginine. Arginine can be provided extracellularly, entering the cell mainly through the cationic amino acid transporter system y+CAT, and intracellularly, by protein degradation or synthesis from citrulline (the citrulline-NO cycle). This study demonstrates for the first time that the citrulline-NO cycle is induced in FACS-purified rat beta cells exposed to interleukin-1beta(IL-1beta) and that extracellular arginine or citrulline is required for NO production by beta cells. Moreover, the accumulation of arginine was higher in IL-1beta-treated beta cells than in control cells.beta cells expressed mRNAs for the two y+CAT transporters CAT-2A and CAT-2B with no change in transporter expression after exposure to IL-1beta. It is concluded that the activation of the citrulline-NO cycle and an increase in arginine accumulation may be adaptive responses in cytokine-exposed beta-cells to assure an adequate arginine supply for continuous NO production in the presence of low extracellular arginine levels which may prevail during insulitis.
Cytokine 1999 Jun
PMID:Interleukin 1beta increases arginine accumulation and activates the citrulline-NO cycle in rat pancreatic beta cells. 1034 79

Infiltration of immunocytes into pancreatic islets precedes loss of beta cells in type 1 diabetes. It is conceivable that local release of cytokines affects the function of beta cells before their apoptosis. This study examines whether the elevated proinsulin levels that have been described in prediabetes can result from exposure of beta cells to cytokines. Human beta-cell preparations were cultured for 48 or 72 hours with or without IL-1beta, TNF-alpha, or IFN-gamma, alone or in combination. None of these conditions were cytotoxic, nor did they reduce insulin biosynthetic activity. Single cytokines did not alter medium or cellular content in insulin or proinsulin. Cytokine combinations, in particular IL-1beta plus IFN-gamma, disproportionately elevated medium proinsulin levels. This effect expresses an altered functional state of the beta cells characterized by preserved proinsulin synthesis, a slower hormone conversion, and an increased ratio of cellular proinsulin over insulin content. The delay in proinsulin conversion can be attributed to lower expression of PC1 and PC2 convertases. It is concluded that disproportionately elevated proinsulin levels in pre-type 1 diabetic patients might result from exposure of their beta cells to cytokines released from infiltrating immunocytes. This hormonal alteration expresses an altered functional state of the beta cells that can occur independently of beta-cell death.
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PMID:Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release. 1039

We have analysed the frequency of cytokine-producing T cells in different dialysis groups (haemodialysis; HD and peritoneal dialysis; PD) over time. Although we saw no difference in type 1 cytokine production (IL-2 and IFN-gamma) in either dialysis group, there was a clear increase in the percentage of T cells spontaneously producing the type 02 cytokines in the PD group (IL-4, r = 0.558, P < 0.05; IL-10, r = 0.527, p < 0.05). Our patient group was carefully selected to include patients with an ongoing autoimmune disease, insulin dependent diabetes mellitus (IDDM) (DN group) and chronic glomerulonephritis (GN), which are common reasons of end stage renal failure. As expected there was no increase in the spontaneous production of either IL-4 or IL-10 in either disease group with patients undergoing HD treatment. However, there was a clear correlation with the frequency of T cells producing IL-4 (r = 0.755, P < 0.05) and IL-10 (r = 0.725, P < 0.05) and time on dialysis in the PD patients with DN, but not those with GN. Much work has suggested that the pathogenesis of IDDM is associated with a Th1 dominated response. We show here that this response is skewed towards a Th2 response after long term treatment with PD. This work demonstrates that the immunological effects of different dialysis modalities on patients with different diseases vary. This may go some way to explain why certain patient groups have more complications with different dialysis modalities.
Eur Cytokine Netw 1999 Jun
PMID:The frequency of Th2 type cells increases with time on peritoneal dialysis in patients with diabetic nephropathy. 1040 Aug 28

Insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetes (NOD) mouse model is thought to be an autoimmune CD4 Th1-like cell-mediated disease. We tested the efficacy of oral use of interferon-alpha (IFN-alpha) therapy on IDDM in NOD mice. Using urine and blood sugar levels as indicators of IDDM, oral administration of murine IFN-alpha (100 IU/body) to NOD mice significantly delayed the onset of symptomatic diabetes. However, oral use of IFN-alpha did not prevent diabetic NOD mice from losing weight once NOD mice were symptomatic, suggesting that orally administered IFN-alpha is a prophylactic rather than therapeutic approach to the management of IDDM.
J Interferon Cytokine Res 1999 Aug
PMID:Oral use of interferon-alpha delays the onset of insulin-dependent diabetes mellitus in nonobese diabetes mice. 1047 32


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