LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia
Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth...
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doaj-4f54fb1ea32f4d228578aa597d3cc5242020-11-25T00:55:11ZengElsevierMolecular Metabolism2212-87782015-04-014427728610.1016/j.molmet.2015.01.006LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemiaGao Sun0Gabriela da Silva Xavier1Tracy Gorman2Claire Priest3Antonia Solomou4David J. Hodson5Marc Foretz6Benoit Viollet7Pedro-Luis Herrera8Helen Parker9Frank Reimann10Fiona M. Gribble11Stephanie Migrenne12Christophe Magnan13Anna Marley14Guy A. Rutter15Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UKSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UKAstraZeneca, Alderley Edge, Cheshire, UKAstraZeneca, Alderley Edge, Cheshire, UKSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UKSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UKInserm, U1016, Institut Cochin, Paris, FranceInserm, U1016, Institut Cochin, Paris, FranceDepartment of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, Geneva, SwitzerlandCambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UKCambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UKCambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UKUniversity Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, FranceUniversity Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, FranceAstraZeneca, Alderley Edge, Cheshire, UKSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose. http://www.sciencedirect.com/science/article/pii/S2212877815000198LKB1AMPKGlucagon secretionPPGKnockoutAlpha cell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gao Sun Gabriela da Silva Xavier Tracy Gorman Claire Priest Antonia Solomou David J. Hodson Marc Foretz Benoit Viollet Pedro-Luis Herrera Helen Parker Frank Reimann Fiona M. Gribble Stephanie Migrenne Christophe Magnan Anna Marley Guy A. Rutter |
spellingShingle |
Gao Sun Gabriela da Silva Xavier Tracy Gorman Claire Priest Antonia Solomou David J. Hodson Marc Foretz Benoit Viollet Pedro-Luis Herrera Helen Parker Frank Reimann Fiona M. Gribble Stephanie Migrenne Christophe Magnan Anna Marley Guy A. Rutter LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia Molecular Metabolism LKB1 AMPK Glucagon secretion PPG Knockout Alpha cell |
author_facet |
Gao Sun Gabriela da Silva Xavier Tracy Gorman Claire Priest Antonia Solomou David J. Hodson Marc Foretz Benoit Viollet Pedro-Luis Herrera Helen Parker Frank Reimann Fiona M. Gribble Stephanie Migrenne Christophe Magnan Anna Marley Guy A. Rutter |
author_sort |
Gao Sun |
title |
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
title_short |
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
title_full |
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
title_fullStr |
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
title_full_unstemmed |
LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
title_sort |
lkb1 and ampkα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2015-04-01 |
description |
Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear.
Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre.
Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets.
Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
|
topic |
LKB1 AMPK Glucagon secretion PPG Knockout Alpha cell |
url |
http://www.sciencedirect.com/science/article/pii/S2212877815000198 |
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