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A Murine Pancreatic Islet Cell-based Screening for Diabetogenic Environmental Chemicals
Published on: June 25, 2018
Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and β-Cells
Keng Po Lai1, Hin Ting Wan2, Alice Hoi-Man Ng2
1Department of Chemistry, City University of Hong Kong , Hong Kong SAR, China.
Abstract:
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.
Insights
Toxaphene (TCDD) exposure stimulates insulin release from pancreatic cells by affecting key signaling pathways like Akt-mTOR and ERK1/2. This toxicant impacts cellular energy production and glucose-stimulated insulin secretion (GSIS).
Area of Science:
- Endocrinology
- Toxicology
- Molecular Biology
Background:
- Toxaphene (TCDD) is an environmental toxicant with known endocrine-disrupting effects.
- Understanding TCDD's impact on pancreatic beta-cell function is crucial for metabolic health.
- Insulin secretion is tightly regulated by complex intracellular signaling pathways.
Purpose of the Study:
- To investigate the molecular mechanisms by which TCDD affects insulin secretion in mouse pancreatic islets and beta-cells.
- To elucidate the role of Akt-mTOR-p70S6K, AMPK, and ERK1/2 pathways in TCDD-induced changes in insulin release and ATP production.
Main Methods:
- Transcriptomic analysis and Ingenuity Pathway Analysis (IPA) of ex-vivo TCDD-treated pancreatic islets.
- Functional studies using ex-vivo islets and the Min-6 mouse beta-cell line.
- Western blot analysis to assess protein pathway activation and expression.
- Measurement of cellular ATP levels and glucose-stimulated insulin secretion (GSIS).
Main Results:
- TCDD (0.1 nM) stimulated basal insulin secretion and activated ERK1/2, decreasing pyruvate dehydrogenase kinase (PDK) expression, leading to higher ATP levels and enhanced GSIS.
- TCDD (0.1 nM) inhibited the AMPK pathway, while TCDD (1 nM) inhibited the Akt-mTOR pathway, cellular ATP production, and GSIS.
- Experimental findings in Min-6 cells corroborated IPA of transcriptomic data.
Conclusions:
- TCDD exposure elevates basal insulin release in pancreatic islets and beta-cells.
- Modulation of Akt-mTOR-p70S6K, AMPK, and ERK1/2 pathways is a key mechanism underlying TCDD's effects on beta-cell ATP production and insulin secretion.
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