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首页> 外文期刊>Cellular Signalling >High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1B and suppressor of cytokine signalling-1 in mouse pancreatic beta cells
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High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1B and suppressor of cytokine signalling-1 in mouse pancreatic beta cells

机译：高糖通过上调小鼠胰腺β细胞中内源性IL-1B和细胞因子Signaling-1的表达来抑制胰岛素信号传导和细胞凋亡

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摘要

Chronic hyperglycemia and inflammatory cytokines disrupt and/or attenuate signal transduction pathways that promote normal β-cell survival, leading to the destruction of endocrine pancreas in type 2 diabetes. There is convincing evidence that autocrine insulin signalling exerts protective anti-apoptotic effects on beta cells. Suppressors of cytokine signalling (SOCS) were induced by several cytokines and inhibit insulininitiated signal transduction. The aim of this study was to investigate whether high glucose can influence endogenous interleukin-1β (IL-1β) and SOCS expression thus affecting insulin signalling and survival in insulin-producing mouse pancreatic beta cells (βTC-6). Results showed that prolonged exposure of βTC-6 cells to increased glucose concentrations resulted in significant inhibition of insulin-induced tyrosine phosphorylation of the insulin receptor (IR), and insulin receptor substrate-2 (IRS-2) as well as PI3-kinase activation. These changes were accompanied by impaired activation of the anti-apoptotic signalling protein Akt and annulment of Akt-mediated suppression of the Forkhead family of transcription factors (FoxO) activation. Glucose-induced attenuation of IRS-2/Akt-mediated signalling was associated with increased IL- 1β expression. Enhanced endogenous IL-1β specifically induced mRNA and protein expression of SOCS-1 in βTC-6 cells. Inhibition of SOCS-1 expression by SOCS-1-specific small interfering RNA restored IRS-2/PI3Kmediated Akt phosphorylation suppressed by high glucose. The upregulation of endogenous cytokine signalling and FoxO activation were accompanied by enhanced caspase-3 activation and increased susceptibility of cells to apoptosis. These results indicated that glucose-induced endogenous IL-1β expression increased βTC-6 cells apoptosis by inhibiting, at least in part, IRS-2/Akt-mediated signalling through SOCS-1 upregulation.
机译：慢性高血糖症和炎性细胞因子破坏和/或减弱促进正常β细胞存活的信号转导途径，从而导致2型糖尿病内分泌胰腺的破坏。有令人信服的证据表明自分泌胰岛素信号传导对β细胞具有保护性抗凋亡作用。细胞因子信号转导（SOCS）的抑制因子被几种细胞因子诱导，并抑制胰岛素引发的信号转导。这项研究的目的是研究高血糖是否可以影响内源性白介素-1β（IL-1β）和SOCS表达，从而影响胰岛素产生的小鼠胰腺β细胞（βTC-6）的胰岛素信号传导和存活。结果表明，βTC-6细胞长时间暴露于升高的葡萄糖浓度会显着抑制胰岛素诱导的胰岛素受体（IR）和胰岛素受体底物2（IRS-2）的酪氨酸磷酸化以及PI3激酶激活。这些变化伴随着抗凋亡信号蛋白Akt的激活受损以及Akt介导的Forkhead转录因子家族（FoxO）激活抑制的废止。葡萄糖诱导的IRS-2 / Akt介导的信号传导减弱与IL-1β表达增加有关。增强的内源性IL-1β特异性诱导βTC-6细胞中SOCS-1的mRNA和蛋白表达。 SOCS-1特异的小干扰RNA抑制SOCS-1表达可恢复高糖抑制的IRS-2 / PI3K介导的Akt磷酸化。内源性细胞因子信号转导和FoxO激活的上调伴随caspase-3激活增强和细胞对凋亡的敏感性增加。这些结果表明葡萄糖诱导的内源性IL-1β表达通过至少部分抑制通过SOCS-1上调的IRS-2 / Akt介导的信号传导而增加了βTC-6细胞的凋亡。

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