Cargando…
Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia
AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895783/ https://www.ncbi.nlm.nih.gov/pubmed/20465544 http://dx.doi.org/10.1042/BJ20100231 |
_version_ | 1782183291170848768 |
---|---|
author | Beall, Craig Piipari, Kaisa Al-Qassab, Hind Smith, Mark A. Parker, Nadeene Carling, David Viollet, Benoit Withers, Dominic J. Ashford, Michael L. J. |
author_facet | Beall, Craig Piipari, Kaisa Al-Qassab, Hind Smith, Mark A. Parker, Nadeene Carling, David Viollet, Benoit Withers, Dominic J. Ashford, Michael L. J. |
author_sort | Beall, Craig |
collection | PubMed |
description | AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPKα2 in β-cells and a population of hypothalamic neurons (RIPCreα2KO mice) and RIPCreα2KO mice lacking AMPKα1 (α1KORIPCreα2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured β-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCreα2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in α1KORIPCreα2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCreα2KO and α1KORIPCreα2KO mice, and conversely GSIS was impaired. β-Cells lacking AMPKα2 or expressing a kinase-dead AMPKα2 failed to hyperpolarize in response to low glucose, although K(ATP) (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCreα2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse β-cell hyperpolarization, mimicking the effect of AMPKα2 loss. These results show that AMPKα2 activity is necessary to maintain normal pancreatic β-cell glucose sensing, possibly by maintaining high β-cell levels of UCP2. |
format | Text |
id | pubmed-2895783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-28957832010-07-07 Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia Beall, Craig Piipari, Kaisa Al-Qassab, Hind Smith, Mark A. Parker, Nadeene Carling, David Viollet, Benoit Withers, Dominic J. Ashford, Michael L. J. Biochem J Research Article AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPKα2 in β-cells and a population of hypothalamic neurons (RIPCreα2KO mice) and RIPCreα2KO mice lacking AMPKα1 (α1KORIPCreα2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured β-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCreα2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in α1KORIPCreα2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCreα2KO and α1KORIPCreα2KO mice, and conversely GSIS was impaired. β-Cells lacking AMPKα2 or expressing a kinase-dead AMPKα2 failed to hyperpolarize in response to low glucose, although K(ATP) (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCreα2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse β-cell hyperpolarization, mimicking the effect of AMPKα2 loss. These results show that AMPKα2 activity is necessary to maintain normal pancreatic β-cell glucose sensing, possibly by maintaining high β-cell levels of UCP2. Portland Press Ltd. 2010-06-28 2010-07-15 /pmc/articles/PMC2895783/ /pubmed/20465544 http://dx.doi.org/10.1042/BJ20100231 Text en © 2010 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Beall, Craig Piipari, Kaisa Al-Qassab, Hind Smith, Mark A. Parker, Nadeene Carling, David Viollet, Benoit Withers, Dominic J. Ashford, Michael L. J. Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title | Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title_full | Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title_fullStr | Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title_full_unstemmed | Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title_short | Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
title_sort | loss of amp-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895783/ https://www.ncbi.nlm.nih.gov/pubmed/20465544 http://dx.doi.org/10.1042/BJ20100231 |
work_keys_str_mv | AT beallcraig lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT piiparikaisa lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT alqassabhind lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT smithmarka lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT parkernadeene lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT carlingdavid lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT violletbenoit lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT withersdominicj lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia AT ashfordmichaellj lossofampactivatedproteinkinasea2subunitinmousebcellsimpairsglucosestimulatedinsulinsecretionandinhibitstheirsensitivitytohypoglycaemia |