Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and β‑Cells

• Published in: Environmental science & technology 2017-10, Vol.51 (19), p.11390-11400
• Main Authors: Lai, Keng Po, Wan, Hin Ting, Ng, Alice Hoi-Man, Li, Jing Woei, Chan, Ting Fung, Wong, Chris Kong-Chu
• Format: Article
• Language: English
• Subjects: Animals; Dioxins - toxicity; Environmental Pollutants - toxicity; Glucose; Insulin; Insulin-Secreting Cells - drug effects; Islets of Langerhans; Mice; Polychlorinated Dibenzodioxins - toxicity
• ISSN: 0013-936X; 1520-5851
• DOI: 10.1021/acs.est.7b02830

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.