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- Reinhard, H, et al.
(författare)
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Endothelial progenitor cells in long-standing asymptomatic type 1 diabetic patients with or without diabetic nephropathy
- 2011
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Ingår i: Nephron. Clinical practice. - : S. Karger AG. - 1660-2110. ; 118:3, s. C309-C314
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Tidskriftsartikel (refereegranskat)abstract
- A decrease in the number and dysfunction of endothelial progenitor cells (EPC) may increase the risk for progression of cardiovascular disease (CVD) in type 1 diabetic patients with diabetic nephropathy (DN). Our aim was to evaluate EPC numbers in asymptomatic CVD type 1 diabetic patients with or without DN and to study the effect of CVD and medication on EPC numbers. <i>Methods:</i> We examined EPC numbers in 37 type 1 diabetic patients with DN and 35 type 1 diabetic patients with long-standing normoalbuminuria. Patients were without symptoms of CVD and the prevalence of CVD was previously shown to be very low. EPC number was assessed in in vitro cultures by fluorescent staining of attached cells. <i>Results:</i> There was no difference in EPC numbers between patients with DN (mean ± SD 120 ± 49 cells/field) and normoalbuminuria (108 ± 41 cells/field; p = 0.25). Furthermore, EPC number was not associated with CVD (p > 0.05). Conventional risk factors were significantly higher in patients with DN and they received more CVD-preventive treatment. All patients receiving simvastatin or calcium-channel blockers had higher numbers of EPC compared to patients not treated with these drugs. <i>Conclusions:</i> Asymptomatic patients with DN had EPC numbers similar to normoalbuminuric patients, which was related to aggressive CVD intervention therapy. This may have contributed to the low prevalence of CVD.
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| 9. |
- Börjesson, Andreas, et al.
(författare)
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beta-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotocin induced type 1 diabetes in mice
- 2011
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Ingår i: Immunology Letters. - : Elsevier BV. - 0165-2478 .- 1879-0542. ; 136:1, s. 74-79
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the impact of beta-cell specific overexpression of suppressor of cytokine signalling-3 (SOCS-3) on the development of multiple low dose streptozotocin (MLDSTZ) induced Type 1 diabetes and the possible mechanisms involved. MLDSTZ treatment was administered to RIP-SOCS-3 transgenic and wild-type (wt) mice and progression of hyperglycemia monitored. Isolated islets from both strains were exposed to human IL-1 beta (25 U/ml) or a combination of human IL-1 beta (25 U/ml) and murine IFN-gamma (1000 U/ml) for 24h or 48h and we investigated the expression of IL-1 receptor antagonist (IL-1Ra) mRNA in islet cells and secretion of IL-1Ra into culture medium. MLDSTZ treatment caused gradual hyperglycemia both in the wt mice and in the transgenic mice with the latter tending to be more sensitive. In vitro experiments on wt and transgenic islets did not reveal any differences in sensitivity to damaging effects of STZ. Exposure of wt islets to 1L-1 beta or IL-1 beta + IFN-gamma seemed to lead to a failing IL-1Ra response from SOCS-3 transgenic islets. It could be that an increased expression of a possible protective molecule against beta-cell destruction may lead to a dampered response of another putative protective molecule. This may have counteracted a protective effect against MLDSTZ in SOCS-3 transgenic mice.
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- Frobose, H, et al.
(författare)
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Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex
- 2006
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Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 20:7, s. 1587-1596
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Tidskriftsartikel (refereegranskat)abstract
- IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor κ B (NFκB) and MAPKs. Although a great deal is known about the mechanism of activation of NFκB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFκB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFκB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFβ-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.
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- Gylvin, T., et al.
(författare)
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Functional SOCS1 polymorphisms are associated with variation in obesity in whites
- 2009
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 11:3, s. 196-203
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Tidskriftsartikel (refereegranskat)abstract
- The suppressor of cytokine signalling 1 (SOCS1) is a natural inhibitor of cytokine and insulin signalling pathways and may also play a role in obesity. In addition, SOCS1 is considered a candidate gene in the pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective was to perform mutation analysis of SOCS1 and to test the identified variations for association to T2D-related quantitative traits, T2D or T1D. Mutation scanning was performed by direct sequencing in 27 white Danish subjects. Genotyping was carried out by TaqMan allelic discrimination. A total of more than 8100 individuals were genotyped. Eight variations were identified in the 5' untranslated region (UTR) region. Two of these had allele frequencies below 1% and were not further examined. The six other variants were analysed in groups of T1D families (n = 1461 subjects) and T2D patients (n = 1430), glucose tolerant first-degree relatives of T2D patients (n = 212) and normal glucose tolerant (NGT) subjects. The rs33977706 polymorphism (-820G > T) was associated with a lower body mass index (BMI) (p = 0.004). In a second study (n = 4625 NGT subjects), significant associations of both the rs33977706 and the rs243330 (-1656G > A) variants to obesity were found (p = 0.047 and p = 0.015) respectively. The rs33977706 affected both binding of a nuclear protein to and the transcriptional activity of the SOCS1 promoter, indicating a relationship between this polymorphism and gene regulation. This study demonstrates that functional variations in the SOCS1 promoter may associate with alterations in BMI in the general white population.
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| 26. |
- Nielsen, Jens H, et al.
(författare)
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Regulation of the beta cell mass by hormones and growth factors
- 2001
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 50:Suppl . 1, s. 25-29
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Tidskriftsartikel (refereegranskat)abstract
- Substantial new information has accumulated on molecular mechanisms of pancreas development, regulation of beta-cell gene expression, and the role of growth factors in the differentiation, growth, and regeneration of beta-cells. The present review focuses on some recent studies on the mechanism of action of cytokines such as growth hormone (GH) and prolactin (PRL) in beta-cell proliferation and gene expression-in particular, the role of signal transducers and activators of transcription (STAT) proteins. The implication of the discovery of suppressors of cytokine signaling (SOCS) proteins for the interaction between stimulatory and inhibitory cytokines, including GH, PRL, leptin, and the proinflammatory cytokines interleukin-1 and interferon-gamma, in beta-cell survival is not yet clear. Recent studies indicate a role of cell adhesion molecules and the delta-like protein preadipocyte factor 1/fetal antigen 1 (Pref-1/FA-1) in cytokine-induced beta-cell growth and development. Surprisingly, glucagon-like peptide-1 (GLP-1) was recently found to stimulate not only insulin secretion but also beta-cell replication and differentiation, which may present a new perspective in treatment of type 2 diabetes. Together with the intriguing reports on positive effects of insulin on both beta-cell growth and function, a picture is emerging of an integrated network of signaling events acting in concert to control beta-cell mass adaptation to insulin demand.
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| 30. |
- Prause, M, et al.
(författare)
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JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1β-Induced Apoptosis Associated with Abrogated Myc Expression
- 2016
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Ingår i: Journal of diabetes research. - : Hindawi Limited. - 2314-6753 .- 2314-6745. ; 2016, s. 1312705-
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Tidskriftsartikel (refereegranskat)abstract
- The relative contributions of the JNK subtypes in inflammatoryβ-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1α1, JNK1α2, JNK1β1, JNK1β2, JNK2α1, JNK2α2, JNK3α1, and JNK3α2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1β-inducedβ-cell apoptosis. JNK1 knockdown prevented IL-1β-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1β-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1β-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1β-inducedβ-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatoryβ-cell failure and destruction.
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| 35. |
- Rønn, SG, et al.
(författare)
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Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:10, s. 1873-1882
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The pro-inflammatory cytokines IL-1 and IFN gamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. Methods Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. Results Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappa B and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. Conclusions/interpretation SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappa B and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.
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| 37. |
- Storling, J, et al.
(författare)
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Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:7, s. 3026-3036
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Tidskriftsartikel (refereegranskat)abstract
- The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1β-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic β-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1β activation of JNK in β-cells are largely unknown. In this study, we investigated whether Ca2+ plays a role for IL-1β-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca2+ channels suppressed IL-1β-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1β-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1β-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca2+ channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse βTC3 cells. Ca2+ influx, specifically via L-type but not T-type channels, contributed to IL-1β activation of JNK. Activation of p38 and ERK in response to IL-1β was also dependent on L-type Ca2+ influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca2+ ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca2+ ATPase, all caused an amplification of IL-1β-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca2+ [bis-(o-aminophenoxy)-N,N,N′,N′-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca2+/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1β-stimulated c-jun phosphorylation in INS-1 or βTC3 cells. Our data suggest that Ca2+ plays a permissive role in IL-1β activation of the JNK signaling pathway in insulin-secreting cells.
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| 39. |
- Tonnesen, MF, et al.
(författare)
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Inhibition of nuclear factor-kappaB or Bax prevents endoplasmic reticulum stress- but not nitric oxide-mediated apoptosis in INS-1E cells
- 2009
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 150:9, s. 4094-4103
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca2+ depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) contributes to β-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca2+ depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor κB (NFκB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFκB activation, as assessed by IκB degradation and NFκB DNA binding. Inhibition of NFκB or the Bcl-2 family member Bax pathways protected β-cells against TG- but not SNAP-induced β-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFκB and Bax.
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