Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinflammatory cytokines, including gamma-interferon (IFN-gamma), have been implicated in the destruction of beta-cells in autoimmune diabetes. IFN-gamma signaling is transient in some cell types, but there is indirect evidence that it may be prolonged in beta-cells. In this study, we have shown that IFN-gamma signaling, measured by signal transducer and activator of transcription-1 (STAT1) activation and the expression of IFN-gamma-responsive genes, is persistent in beta-cells for as long as the cytokine is present. Because members of the suppressor of cytokine signaling (SOCS) family may regulate the duration of IFN-gamma signaling, their expression was investigated in beta-cells. We found that cytokine-inducible SH2-containing protein, SOCS-1, and SOCS-2 are expressed in primary islets and NIT-1 insulinoma cells, both at the mRNA and protein levels, after treatment with IFN-gamma and other proinflammatory cytokines. Transfected SOCS-1 was found to inhibit responses to IFN-gamma in NIT-1 insulinoma cells, including STAT1 activation, class I major histocompatibility complex upregulation, and IFN-gamma-induced cell death, but only when expressed at levels higher than those found in untransfected cells. Consistent with this, IFN-gamma signaling was not affected in SOCS-1-deficient beta-cells. Therefore, persistent IFN-gamma signaling in beta-cells is associated with SOCS-1 expression that is not sufficient to terminate signaling. Because overexpression of SOCS-1 can suppress responses to IFN-gamma, this may be a useful strategy for protecting beta-cells from cytotoxicity mediated by IFN-gamma and possibly other proinflammatory cytokines.
Diabetes 2001 Dec
PMID:gamma-Interferon signaling in pancreatic beta-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1. 1172 57

Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of the Jak-STAT (signal transducer and activator of transcription cytokine) signaling pathway but may also regulate other pathways. At least in vitro, SOCS-1 inhibits the action of multiple cytokines. By studying the effects of SOCS-1 deficiency, we investigated whether SOCS-1 is involved in preventing cytokine-induced death of pancreatic islet cells, a potential mechanism of insulin deficiency in autoimmune diabetes. Tumor necrosis factor (TNF) + interferon-gamma (IFNgamma) was more potent at inducing cell death in SOCS-1-/- islets than in wild type. Individually, these cytokines did not induce cell death. The titration of the two cytokines suggested that this increased cell death was because of hypersensitivity to TNF. Interleukin-1 + IFNgamma induced the same level of cell death in SOCS-1-/- and wild-type islets, suggesting that the sensitivity of islets to IFNgamma or interleukin-1-mediated cytotoxicity is not affected by SOCS-1 deficiency. Additionally, SOCS-1-/- beta cells were responsive to lower concentrations of TNF measured by class I major histocompatibility complex up-regulation. The TNF + IFNgamma damage of islets was mediated by inducible nitric-oxide synthase (iNOS), and increased iNOS expression and nitric oxide production were found in SOCS-1-/- islets following cytokine treatment. A further analysis revealed that SOCS-1 deficiency results in augmented TNF signaling via the p38 mitogen-activated protein kinase pathway but not NFkappaB or c-Jun N-terminal kinase pathways. Increased p38 signaling may be responsible for the increased iNOS expression in SOCS-1-/- islets. Therefore, these findings provide evidence that physiological levels of SOCS-1 negatively regulate TNF signaling.
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PMID:Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. 1203 39

Pancreatic beta-cell antiviral defense plays a critical role in protection from coxsackievirus B4 (CVB4)-induced diabetes. In the present study, we tested the hypothesis that interferon (IFN)-induced antiviral defense determines beta-cell survival after infection by the human pathogen CVB3, cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). We demonstrated that mice harboring beta-cells that do not respond to IFN because of the expression of the suppressor of cytokine signaling-1 (SOCS-1) succumb to an acute form of type 1 diabetes after infection with CVB3. Interestingly, the tropism of the virus was altered in SOCS-1 transgenic (Tg) mice, and CVB3 was detected in islet cells of SOCS-1-Tg mice before beta-cell loss and the onset of diabetes. Furthermore, insulitis was increased in SOCS-1-Tg mice after infection with murine CMV, and a minority of the mice developed overt diabetes. However, infection with LCMV failed to cause beta-cell destruction in SOCS-1 Tg mice. These findings suggest that CVB3 can cause diabetes in a host lacking adequate beta-cell antiviral defense, and that incomplete target cell antiviral defense may enhance susceptibility to diabetes triggered by CMV. In conclusion, suppressed beta-cell antiviral defense reveals the diabetogenic potential of two pathogens previously linked to the onset of type 1 diabetes in humans.
Diabetes 2003 Aug
PMID:Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells. 1288 19

Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of beta-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in beta-cell death. We investigated whether beta-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring beta-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) littermates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing beta-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target beta-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by beta-cells can represent a promising strategy to prevent type 1 diabetes.
Diabetes 2003 Nov
PMID:Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. 1457 88

Insulin is a key anabolic hormone that plays a crucial role in growth, differentiation and metabolism. Insulin action is initiated by the binding of the hormone to its tyrosine kinase cell surface receptor, leading to the multisite autophosphorylation of the receptor. This results in the activation of the receptor kinase and subsequent tyrosine phosphorylation of insulin receptor substrates, most of which are docking proteins for signaling molecules. For the last several years, our laboratory has been interested in the mechanisms that lead to the modulation of insulin signal transduction, and hence might be involved in insulin resistance found in obesity and type II diabetes. For this review, we have focused on three 'modulators' of insulin action: hyperinsulinemia, suppressor of cytokine signaling proteins and advanced glycation end products.
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PMID:Modulators of insulin action and their role in insulin resistance. 1470 48

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.
Diabetes 2004 Feb
PMID:Leptin impairs insulin signaling in rat adipocytes. 1474 84

In type 1 diabetes, cytokine action on beta cells potentially contributes to beta cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block beta cell responsiveness to multiple cytokines, we overexpressed suppressor of cytokine signaling-1 (SOCS-1). This completely prevented progression to diabetes in CD8(+) TCR transgenic nonobese diabetic (NOD) 8.3 mice without affecting pancreas infiltration and partially prevented diabetes in nontransgenic NOD mice. SOCS-1 appeared to protect at least in part by inhibiting TNF- and IFN-gamma-induced Fas expression on beta cells. Fas expression was up-regulated on beta cells in vivo in prediabetic NOD8.3 mice, and this was inhibited by SOCS-1. Additionally, IFN-gamma-induced class I MHC up-regulation and TNF- and IFN-gamma-induced IL-15 expression by beta cells were inhibited by SOCS-1, which correlated with suppressed 8.3 T cell proliferation in vitro. Despite this, 8.3 T cell priming in vivo appeared unaffected. Therefore, blocking beta cell responses to cytokines impairs recognition by CD8(+) T cells and blocks multiple mechanisms of beta cell destruction, but does not prevent T cell priming and recruitment to the islets. Our findings suggest that increasing SOCS-1 expression may be useful as a strategy to block CD8(+) T cell-mediated type 1 diabetes as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.
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PMID:Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction. 1510 Mar 17

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival.
Diabetes 2004 Dec
PMID:The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. 1556 30

Insulin resistance, obesity, diabetes, dyslipidemia and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism of the development of this syndrome is poorly understood. In this study, we show that expression of suppressor of cytokine signaling SOCS-1 and SOCS-3 is increased in livers of obese insulin-resistant animals, and that adenoviral-mediated overexpression of SOCS-1 or SOCS-3 in liver causes insulin resistance through down-regulation of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Moreover, the increased SOCS-1 and SOCS-3 also cause a prominent up-regulation of the key regulator of fatty acid synthesis in liver, sterol regulatory element binding protein (SREBP)-1. Conversely, inhibition of SOCS-1 and SOCS-3 in livers of obese diabetic db/db mice by antisense treatment modestly improves insulin sensitivity, but completely normalizes the increased expression of SREBP-1. The latter leads to dramatic amelioration of hepatic steatosis and hypertriglyceridemia. Promoter activity analysis reveals that expression of SOCS-1 or SOCS-3 with SOCS-3 being more potent enhances SREBP-1c expression, while it is inhibited by expression of STAT3. This STAT3-mediated inhibition of SREBP-1c expression is antagonized by co-expression of SOCS proteins. Moreover, db/db mice display decreased STAT3 phosphorylation in liver that is normalized by antisense treatment of SOCS proteins. These data suggest that obese subjects in the persistent inflammatory states, such as elevated circulating tumor necrosis factor-alpha, may have down-regulated STAT3-mediated signaling by increased SOCS proteins, leading to up-regulation of SREBP-1c expression and increased fatty acid synthesis in liver. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating cytokine signaling and insulin signaling.
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PMID:Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome. 1622 15

Leptin inhibits insulin secretion and preproinsulin gene expression in pancreatic beta-cells, but signal transduction pathways and molecular mechanisms underlying this effect are poorly characterized. In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic beta-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator of transcription (STAT)3 and STAT5b in INS-1 beta-cells. Leptin also induced mRNA expression of the JAK-STAT inhibitor suppressor of cytokine signaling (SOCS)3 in INS-1 beta-cells and human pancreatic islets in vitro and in pancreatic islets of ob/ob mice in vivo. Transcriptional activation of the rat SOCS3 promoter by leptin was observed with concomitant leptin-induced STAT3 and STAT5b DNA binding to specific promoter regions. Unexpectedly, SOCS3 inhibited both basal and STAT3/5b-dependent rat preproinsulin 1 gene promoter activity in INS-1 cells. These results suggest that SOCS3 represents a transcriptional inhibitor of preproinsulin gene expression, which is induced by leptin through JAK-STAT3/5b signaling in pancreatic beta-cells. In conclusion, although SOCS3 is believed to be a negative feedback regulator of JAK-STAT signaling, our findings suggest involvement of SOCS3 in a direct gene regulatory pathway downstream of leptin-activated JAK-STAT signaling in pancreatic beta-cells.
Diabetes 2005 Dec
PMID:Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. 1630 56


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