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Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis

Chronic hyperinsulinemia, in vivo, increases the resistance of peripheral tissues to insulin by desensitizing insulin signaling. Insulin, in a heterologous manner, can also cause IGF-1 resistance. The aim of the current study was to investigate whether insulin-mediated insulin and IGF-1 resistance d...

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Autores principales: Rachdaoui, Nadia, Polo-Parada, Luis, Ismail-Beigi, Faramarz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344346/
https://www.ncbi.nlm.nih.gov/pubmed/30697602
http://dx.doi.org/10.1210/js.2018-00140
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author Rachdaoui, Nadia
Polo-Parada, Luis
Ismail-Beigi, Faramarz
author_facet Rachdaoui, Nadia
Polo-Parada, Luis
Ismail-Beigi, Faramarz
author_sort Rachdaoui, Nadia
collection PubMed
description Chronic hyperinsulinemia, in vivo, increases the resistance of peripheral tissues to insulin by desensitizing insulin signaling. Insulin, in a heterologous manner, can also cause IGF-1 resistance. The aim of the current study was to investigate whether insulin-mediated insulin and IGF-1 resistance develops in pancreatic β-cells and whether this resistance results in β-cell decompensation. Chronic exposure of rat islets or INS1E β-cells to increasing concentrations of insulin decreased Akt(S473) phosphorylation in response to subsequent acute stimulation with 10 nM insulin or IGF-1. Prolonged exposure to high insulin levels not only inhibited Akt(S473) phosphorylation, but it also resulted in a significant inhibition of the phosphorylation of P70S6 kinase and Erk(1/2) phosphorylation in response to the acute stimulation by glucose, insulin, or IGF-1. Decreased activation of Akt, P70S6K, and Erk(1/2) was associated with decreased insulin receptor substrate 2 tyrosine phosphorylation and insulin receptor β-subunit abundance; neither IGF receptor β-subunit content nor its phosphorylation were affected. These signaling impairments were associated with decreased SERCA2 expression, perturbed plasma membrane calcium current and intracellular calcium handling, increased endoplasmic reticulum stress markers such as eIF2α(S51) phosphorylation and Bip (GRP78) expression, and increased islet and β-cell apoptosis. We demonstrate that prolonged exposure to high insulin levels induces not only insulin resistance, but in a heterologous manner causes resistance to IGF-1 in rat islets and insulinoma cells resulting in decreased cell survival. These findings suggest the possibility that chronic exposure to hyperinsulinemia may negatively affect β-cell mass by increasing β-cell apoptosis.
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spelling pubmed-63443462019-01-29 Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis Rachdaoui, Nadia Polo-Parada, Luis Ismail-Beigi, Faramarz J Endocr Soc Research Article Chronic hyperinsulinemia, in vivo, increases the resistance of peripheral tissues to insulin by desensitizing insulin signaling. Insulin, in a heterologous manner, can also cause IGF-1 resistance. The aim of the current study was to investigate whether insulin-mediated insulin and IGF-1 resistance develops in pancreatic β-cells and whether this resistance results in β-cell decompensation. Chronic exposure of rat islets or INS1E β-cells to increasing concentrations of insulin decreased Akt(S473) phosphorylation in response to subsequent acute stimulation with 10 nM insulin or IGF-1. Prolonged exposure to high insulin levels not only inhibited Akt(S473) phosphorylation, but it also resulted in a significant inhibition of the phosphorylation of P70S6 kinase and Erk(1/2) phosphorylation in response to the acute stimulation by glucose, insulin, or IGF-1. Decreased activation of Akt, P70S6K, and Erk(1/2) was associated with decreased insulin receptor substrate 2 tyrosine phosphorylation and insulin receptor β-subunit abundance; neither IGF receptor β-subunit content nor its phosphorylation were affected. These signaling impairments were associated with decreased SERCA2 expression, perturbed plasma membrane calcium current and intracellular calcium handling, increased endoplasmic reticulum stress markers such as eIF2α(S51) phosphorylation and Bip (GRP78) expression, and increased islet and β-cell apoptosis. We demonstrate that prolonged exposure to high insulin levels induces not only insulin resistance, but in a heterologous manner causes resistance to IGF-1 in rat islets and insulinoma cells resulting in decreased cell survival. These findings suggest the possibility that chronic exposure to hyperinsulinemia may negatively affect β-cell mass by increasing β-cell apoptosis. Endocrine Society 2018-11-01 /pmc/articles/PMC6344346/ /pubmed/30697602 http://dx.doi.org/10.1210/js.2018-00140 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Rachdaoui, Nadia
Polo-Parada, Luis
Ismail-Beigi, Faramarz
Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title_full Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title_fullStr Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title_full_unstemmed Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title_short Prolonged Exposure to Insulin Inactivates Akt and Erk(1/2) and Increases Pancreatic Islet and INS1E β-Cell Apoptosis
title_sort prolonged exposure to insulin inactivates akt and erk(1/2) and increases pancreatic islet and ins1e β-cell apoptosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344346/
https://www.ncbi.nlm.nih.gov/pubmed/30697602
http://dx.doi.org/10.1210/js.2018-00140
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