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PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice

The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the re...

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Autores principales: Deas, Emma, Piipari, Kaisa, Machhada, Asif, Li, Abi, Gutierrez-del-Arroyo, Ana, Withers, Dominic J., Wood, Nicholas W., Abramov, Andrey Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042854/
https://www.ncbi.nlm.nih.gov/pubmed/24806840
http://dx.doi.org/10.1098/rsob.140051
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author Deas, Emma
Piipari, Kaisa
Machhada, Asif
Li, Abi
Gutierrez-del-Arroyo, Ana
Withers, Dominic J.
Wood, Nicholas W.
Abramov, Andrey Y.
author_facet Deas, Emma
Piipari, Kaisa
Machhada, Asif
Li, Abi
Gutierrez-del-Arroyo, Ana
Withers, Dominic J.
Wood, Nicholas W.
Abramov, Andrey Y.
author_sort Deas, Emma
collection PubMed
description The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function.
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spelling pubmed-40428542014-06-06 PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice Deas, Emma Piipari, Kaisa Machhada, Asif Li, Abi Gutierrez-del-Arroyo, Ana Withers, Dominic J. Wood, Nicholas W. Abramov, Andrey Y. Open Biol Research The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function. The Royal Society 2014-05-07 /pmc/articles/PMC4042854/ /pubmed/24806840 http://dx.doi.org/10.1098/rsob.140051 Text en http://creativecommons.org/licenses/by/3.0/ © 2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research
Deas, Emma
Piipari, Kaisa
Machhada, Asif
Li, Abi
Gutierrez-del-Arroyo, Ana
Withers, Dominic J.
Wood, Nicholas W.
Abramov, Andrey Y.
PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title_full PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title_fullStr PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title_full_unstemmed PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title_short PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
title_sort pink1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042854/
https://www.ncbi.nlm.nih.gov/pubmed/24806840
http://dx.doi.org/10.1098/rsob.140051
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