Suppressive effects of glucagon-like peptide-1 on interferon-γ-induced nitric oxide production in insulinproducing cells is mediated by inhibition of tumor necrosis factor-α production

Hahm, Eunsil; Lee, Y. S.; Jun, Hee-Sook

doi:10.1007/bf03346367

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…This finding conforms to the previous study that GLP-1 exerted antiinflammatory effect. GLP-1 inhibits IFN-γ-induced NO production by suppression of TNF-α production in MIN6N8a mouse β cells (Hahm et al 2008). Exendin-4 suppresses LPS-induced mRNA expression of TNF-α, MCP1, and NFκB translocation to the nucleus in macrophage (Arakawa et al 2010).…”

Section: Discussionmentioning

confidence: 97%

DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

Chen

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. Both DPP4 inhibitors and GLP-1 analog have been approved for antihyperglycemic agents. In addition to the insulinotropic effect, GLP-1 signaling was reported to modulate cardiac function. DPP4 inhibition was shown to improve survival rate after myocardial infarction in mice, but the precise mechanism remains unknown. We aimed to compare the cardiovascular responses of ischemia/reperfusion (I/R) between wild-type and DPP4-deficient rats and investigate the underlying mechanism. Rats were subjected to 45 min of coronary artery occlusion, followed by reperfusion for 2 h. Cardiac function was characterized by analyzing pressure-volume loops. As compared to wild-type rats, after I/R, DPP4-deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers (LDH, ANP, and BNP), which could be attenuated by exendin-(9-39), a GLP-1 receptor antagonist. Exendin-(9-39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3β as well as the higher expression of GLUT4 in post-infarcted DPP4-deficient rats. However, exendin-(9-39) could not completely abrogate the less infarct size in DPP4-deficient rats as compared with that in wild-type rats, implicating the involvement of GLP-1 receptor-independent pathway. In summary, this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in DPP4-deficient rats, which is mediated through both GLP-1 receptor-dependent and receptor-independent mechanisms.

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Section: Discussionmentioning

confidence: 97%

DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

Chen

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…These findings suggest that the suppressive effect of cAMP-increasing agents on iNOS protein expression may be exerted via non-proteasomal mechanisms. Moreover, GLP-1 inhibited IFN-g-induced NO production via suppression of TNF-a production in MIN6N8a cells (Hahm et al 2008). Therefore, to clarify the mechanism of EX-4 inhibition of IL-1b-induced iNOS protein expression, further studies including both proteasomal and non-proteasomal pathways will be required.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 inhibits interleukin-1β-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F β-cells

Kang¹,

Chang²,

Jang³

et al. 2009

Journal of Endocrinology

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Cytokines such as interleukin-1b (IL-1b) stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction leading to b-cell damage. Meanwhile, glucagon-like peptide-1 (GLP-1) and its potent analog exendin-4 (EX-4) were well known for b-cell proliferation. However, the protective mechanisms of GLP-1 in b-cells exposed to cytokines were not fully elucidated. Therefore, the effects of EX-4 on the IL-1b-induced iNOS gene expression were investigated employing RINm5F b-cells. EX-4 inhibited IL-1b-induced iNOS protein expression and nitrite production. However, northern blot and promoter analyses showed that EX-4 failed to inhibit IL-1b-induced iNOS mRNA expression and iNOS promoter activity. By electrophoretic mobility shift assay (EMSA), EX-4 did not alter the binding activity of NF-kB to the iNOS promoter. Consistent with the EMSA result, EX-4 did not inhibit nuclear translocation of p65. We also tested the effect of EX-4 on iNOS mRNA stability. Actinomycin D chase experiments showed that EX-4 did not affect the decay rate of iNOS mRNA and the promoter assay using the construct containing 3 0 -untranslated region of iNOS showed that EX-4 did not alter the stability of iNOS mRNA. Meanwhile, forskolin significantly inhibited IL-1b-induced iNOS protein, which was reversed by H-89, a protein kinase A (PKA) inhibitor. Moreover, EX-4 pretreatment restored IL-1b-induced decrease in cAMP toward control level. Additionally, the cycloheximide chase study demonstrated that EX-4 significantly accelerated iNOS protein degradation. We therefore concluded that EX-4 inhibited IL-1b-induced iNOS protein and nitrite production via cAMP/PKA system irrespective of both transcriptional and posttranscriptional mechanisms of iNOS gene, and this inhibitory effect of EX-4 appears to be regulated at posttranslational level.

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“…Furthermore, suppression of iNOS activity has been shown to reduce hyperglycemia and insulitis in NOD mice and in the STZdiabetes model, respectively [157,158]. Interference with iNOS expression has also been suggested to contribute to the protective effect of GLP-1 against cytokine-mediated beta-cell death [159,160].…”

Section: Strategies Targeting Ros or Rns Formation In Beta-cells Cumentioning

confidence: 96%

Oxidative stress and beta-cell dysfunction

Drews

Koehler

Düfer

2010

Pflugers Arch - Eur J Physiol

257

208

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Diabetes mellitus type 1 and 2 (T1DM and T2DM) are complex multifactorial diseases. Loss of beta-cell function caused by reduced secretory capacity and enhanced apoptosis is a key event in the pathogenesis of both diabetes types. Oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during the development of diabetes. Because of their low antioxidant capacity, beta-cells are extremely sensitive towards oxidative stress. In beta-cells, important targets for an oxidant insult are cell metabolism and K(ATP) channels. The oxidant-evoked alterations of K(ATP) channel activity seem to be critical for oxidant-induced dysfunction because genetic ablation of K(ATP) channels attenuates the effects of oxidative stress on beta-cell function. Besides the effects on metabolism, interference of oxidants with mitochondria induces key events in apoptosis. Consequently, increasing antioxidant defence is a promising strategy to delay beta cell failure in (pre)-diabetic patients or during islet transplantation. Knock-out of K(ATP) channels has beneficial effects on oxidant-induced inhibition of insulin secretion and cell death. Interestingly, these effects can be mimicked by sulfonylureas that have been used in the treatment of T2DM for many years. Loss of functional K(ATP) channels leads to up-regulation of antioxidant enzymes, a process that depends on cytosolic Ca(2+). These observations are of great importance for clinical intervention because they show a possibility to protect beta-cells at an early stage before dramatic changes of the secretory capacity and loss of cell mass become manifest and lead to glucose intolerance or even overt diabetes.

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Suppressive effects of glucagon-like peptide-1 on interferon-γ-induced nitric oxide production in insulinproducing cells is mediated by inhibition of tumor necrosis factor-α production

Cited by 5 publications

References 25 publications

DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

Exendin-4 inhibits interleukin-1β-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F β-cells

Oxidative stress and beta-cell dysfunction

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