TY - JOUR
T1 - Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and β-Cells
AU - Lai, Keng Po
AU - Wan, Hin Ting
AU - Ng, Alice Hoi Man
AU - Li, Jing Woei
AU - Chan, Ting Fung
AU - Wong, Chris Kong Chu
N1 - Funding information:
This work was supported by the Partner State Key Laboratory of Environmental and Biological Analysis (SKLP-16-17-P01, HKBU) and Department of Biology (Strategy Development Fund, 40-49-038, HKBU) to C.K.C.W (Hong Kong Baptist University).
Publisher copyright:
© 2017 American Chemical Society
PY - 2017/10/3
Y1 - 2017/10/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85030710180&partnerID=8YFLogxK
U2 - 10.1021/acs.est.7b02830
DO - 10.1021/acs.est.7b02830
M3 - Journal article
C2 - 28880546
AN - SCOPUS:85030710180
SN - 0013-936X
VL - 51
SP - 11390
EP - 11400
JO - Environmental Science and Technology
JF - Environmental Science and Technology
IS - 19
ER -
