Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and β-Cells,Environmental Science & Technology

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Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and β-Cells
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2017-09-21 00:00:00 , DOI: 10.1021/acs.est.7b02830
Keng Po Lai ₁ , Hin Ting Wan ₂ , Alice Hoi-Man Ng ₂ , Jing Woei Li _{1,

3} , Ting Fung Chan ₃ , Chris Kong-Chu Wong ₂

Affiliation

In this study, transcriptomic and Ingenuity Pathway Analysis (IPA) underlined that an ex-vivo TCDD treatment (0.1 nM) stimulated insulin-release in mouse pancreatic islets via the effect on the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways. Functional studies using both ex-vivo islets and the mouse β-cell-line (Min-6) validated the stimulatory effects of TCDD (0.1 and 1 nM) on basal-insulin secretion. At 0.1 nM TCDD treatment on Min-6, Western blot analysis showed activation of ERK1/2 and decreased expression of pyruvate dehydrogenase kinase (PDK). A reduction of PDK expression is associated with an increase of pyruvate dehydrogenase flux. This observation was supported by the detection of significantly higher cellular ATP levels, an increase of glucose-stimulated-insulin-secretion (GSIS), and an inhibition of the AMPK pathway. At 1 nM TCDD treatment on Min-6, significant inhibitions of the Akt-mTOR pathway, cellular ATP production, and GSIS were evident. The experimental studies in Min-6 supported the IPA of transcriptomic data in pancreatic islets. Collectively, TCDD treatment caused an elevated basal-insulin release in both islets and β-cell cultures. Moreover, our data revealed that the modulation of the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways might be an important component of the mechanism for the TCDD-perturbing effects on ATP production in β-cells in affecting insulin secretion.

中文翻译：

二恶英对胰岛和β细胞胰岛素分泌的影响的转录组学和功能分析

在这项研究中，转录组学和独创性途径分析（IPA）强调了离体TCDD处理（0.1 nM）通过对Akt-mTOR-p70S6K，AMPK和ERK1 / 2途径的影响刺激了小鼠胰岛中的胰岛素释放。使用离体胰岛和小鼠β细胞系（Min-6）进行的功能研究验证了TCDD（0.1和1 nM）对基础胰岛素分泌的刺激作用。在Min-6上以0.1 nM TCDD处理后，Western印迹分析显示ERK1 / 2的激活和丙酮酸脱氢酶激酶（PDK）的表达降低。PDK表达的减少与丙酮酸脱氢酶通量的增加有关。观察到明显更高的细胞ATP水平，葡萄糖刺激的胰岛素分泌（GSIS）的增加以及AMPK途径的抑制，从而支持了这一观察结果。在Min-6上以1 nM TCDD处理后，Akt-mTOR途径，细胞ATP产生和GSIS的显着抑制作用是明显的。Min-6中的实验研究支持了胰岛中转录组数据的IPA。总体而言，TCDD处理导致胰岛和β细胞培养物中基础胰岛素的释放增加。此外，我们的数据显示，对Akt-mTOR-p70S6K，AMPK和ERK1 / 2途径的调节可能是TCDD干扰β细胞中ATP产生影响胰岛素分泌的机制的重要组成部分。TCDD处理导致胰岛和β细胞培养物中基础胰岛素的释放增加。此外，我们的数据显示，对Akt-mTOR-p70S6K，AMPK和ERK1 / 2途径的调节可能是TCDD干扰β细胞中ATP产生影响胰岛素分泌的机制的重要组成部分。TCDD处理导致胰岛和β细胞培养物中基础胰岛素的释放增加。此外，我们的数据显示，对Akt-mTOR-p70S6K，AMPK和ERK1 / 2途径的调节可能是TCDD干扰β细胞中ATP产生影响胰岛素分泌的机制的重要组成部分。

更新日期：2017-09-21

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