Upregulation of PTEN by peroxynitrite contributes to cytokine-induced apoptosis in pancreatic β-cells

Hou, Rongrong; Zhang, Jing; Yin, Tao; Cao, Hongwei; Zhang, Nanyan; Li, Xiaomiao; Wang, Li; Xing, Ying; Li, Deqiang; Ji, Qiuhe

doi:10.1007/s10495-010-0510-z

Cited by 17 publications

(12 citation statements)

References 45 publications

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“…The oxidative stress pathway genes regulated by IL-22 have the capability to decrease intracellular concentrations of O 2 − , H 2 O 2 , NO, OH and ONOO − , plausibly explaining how IL-22 prevents ER stress. Downregulation of iNOS will limit production of NO, a mediator of the beta cell response to cytokines, NEFAs and high glucose and a trigger for apoptosis 10 40 and beta cell apoptosis 41 . Prdx5 highly efficiently reduces peroxynitrite 42 .…”

Section: Discussionmentioning

confidence: 99%

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Hasnain

Borg

Harcourt

et al. 2014

Nat Med

223

261

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In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.

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Section: Discussionmentioning

confidence: 99%

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Hasnain

Borg

Harcourt

et al. 2014

Nat Med

223

261

View full text Add to dashboard Cite

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“…Therefore, the relative concentrations of LPS and metformin in different experimental conditions may determine the final effect of metformin on inflammation. In addition to their interaction in inflammatory signaling, a previous report has shown that LPS upregulates PTEN expression [31] , and PTEN is important for the negative regulation of PI3K activity, an upstream signaling component of PKB [32,33] . We assessed PTEN abundance and found that LPS clearly increased its expression in both skeletal muscle and the liver, while metformin reduced its expression.…”

Section: Discussionmentioning

confidence: 99%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

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Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

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“…PTEN was initially identified as a tumor suppressor, and its loss or mutation is reported to be associated with the development of various cancers (16,17). PTEN may exert this regulatory role by altering its own expression and activity in response to external stimuli such as inflammatory mediators or cytokines (18,19). In addition, some studies have revealed decreases in PTEN expression by TNF (20) or cigarette smoking (21).…”

mentioning

confidence: 99%

Protein Kinase CK2/PTEN Pathway Plays a Key Role in Platelet-Activating Factor-Mediated Murine Anaphylactic Shock

Kang

Yoon

Kim

et al. 2011

The Journal of Immunology

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Platelet-activating factor (PAF) is a major mediator in the induction of fatal hypovolemic shock in murine anaphylaxis. This PAF-mediated effect has been reported to be associated with PI3K/Akt-dependent eNOS-derived NO. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is phosphatidylinositol phosphate phosphatase, which negatively controls PI3K by dephosphorylating the signaling lipid, phosphatidylinositol 3,4,5-triphosphate. In this study, we examined the possible involvement of PTEN in PAF-mediated anaphylactic shock. Induction of anaphylaxis or PAF injection resulted in a rapid decrease in PTEN activity, followed by increases in PI3K activity and phosphorylation of Akt and eNOS. Systemic administration of adenoviruses carrying PTEN cDNA (adenoviral PTEN), but not the control AdLacZ, not only attenuated anaphylactic symptoms, but also reversed anaphylaxis- or PAF-induced changes in PTEN and PI3K activities, as well as phosphorylation of Akt and eNOS. We found that the decreased PTEN activity was associated with PTEN phosphorylation, the latter effect being prevented by the protein kinase CK2 inhibitor, DMAT. DMAT also inhibited anaphylactic symptoms as well as the anaphylaxis- or PAF-mediated PTEN/PI3K/Akt/eNOS signaling cascade. CK2 activity was increased by PAF. The present data provide, as the key mechanism underlying anaphylactic shock, PAF triggers the upstream pathway CK2/PTEN, which ultimately leads to the activation of PI3K/Akt/eNOS. Therefore, CK2/PTEN may be a potent target in the control of anaphylaxis and other many PAF-mediated pathologic conditions.

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Upregulation of PTEN by peroxynitrite contributes to cytokine-induced apoptosis in pancreatic β-cells

Cited by 17 publications

References 45 publications

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Protein Kinase CK2/PTEN Pathway Plays a Key Role in Platelet-Activating Factor-Mediated Murine Anaphylactic Shock

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