Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase

Aims/hypothesis: Although targeted in extrapancreatic tissues by several drugs used to treat type 2 diabetes, the role of AMP-activated protein kinase (AMPK) in the control of insulin secretion is still debatable. Previous studies have used pharmacological activators of limited selectivity and speci...

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Main Authors: Nguyen-Tu, Marie-Sophie, Harris, Joseph, Martinez-Sanchez, Aida, Chabosseau, Pauline, Hu, Ming, Georgiadou, Eleni, Pollard, Alice, Otero, Pablo, Lopez-Noriega, Livia, Leclerc, Isabelle, Sakamoto, Kei, Schmoll, Dieter, Smith, David M., Carling, David, Rutter, Guy A.
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/163901
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-163901
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
AMP-Activated Protein Kinase
Insulin Secretion
spellingShingle Science::Medicine
AMP-Activated Protein Kinase
Insulin Secretion
Nguyen-Tu, Marie-Sophie
Harris, Joseph
Martinez-Sanchez, Aida
Chabosseau, Pauline
Hu, Ming
Georgiadou, Eleni
Pollard, Alice
Otero, Pablo
Lopez-Noriega, Livia
Leclerc, Isabelle
Sakamoto, Kei
Schmoll, Dieter
Smith, David M.
Carling, David
Rutter, Guy A.
Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
description Aims/hypothesis: Although targeted in extrapancreatic tissues by several drugs used to treat type 2 diabetes, the role of AMP-activated protein kinase (AMPK) in the control of insulin secretion is still debatable. Previous studies have used pharmacological activators of limited selectivity and specificity, and none has examined in primary pancreatic beta cells the actions of the latest generation of highly potent and specific activators that act via the allosteric drug and metabolite (ADaM) site. Methods: AMPK was activated acutely in islets isolated from C57BL6/J mice, and in an EndoC-βH3 cell line, using three structurally distinct ADaM site activators (991, PF-06409577 and RA089), with varying selectivity for β1- vs β2-containing complexes. Mouse lines expressing a gain-of-function mutation in the γ1 AMPK subunit (D316a) were generated to examine the effects of chronic AMPK stimulation in the whole body, or selectively in the beta cell. Results: Acute (1.5 h) treatment of wild-type mouse islets with 991, PF-06409577 or RA089 robustly stimulated insulin secretion at high glucose concentrations (p<0.01, p<0.05 and p<0.001, respectively), despite a lowering of glucose-induced intracellular free Ca2+ dynamics in response to 991 (AUC, p<0.05) and to RA089 at the highest dose (25 μmol/l) at 5.59 min (p<0.05). Although abolished in the absence of AMPK, the effects of 991 were observed in the absence of the upstream kinase, liver kinase B1, further implicating ‘amplifying’ pathways. In marked contrast, chronic activation of AMPK, either globally or selectively in the beta cell, achieved using a gain-of-function mutant, impaired insulin release in vivo (p<0.05 at 15 min following i.p. injection of 3 mmol/l glucose) and in vitro (p<0.01 following incubation of islets with 17 mmol/l glucose), and lowered glucose tolerance (p<0.001). Conclusions/interpretation: AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Nguyen-Tu, Marie-Sophie
Harris, Joseph
Martinez-Sanchez, Aida
Chabosseau, Pauline
Hu, Ming
Georgiadou, Eleni
Pollard, Alice
Otero, Pablo
Lopez-Noriega, Livia
Leclerc, Isabelle
Sakamoto, Kei
Schmoll, Dieter
Smith, David M.
Carling, David
Rutter, Guy A.
format Article
author Nguyen-Tu, Marie-Sophie
Harris, Joseph
Martinez-Sanchez, Aida
Chabosseau, Pauline
Hu, Ming
Georgiadou, Eleni
Pollard, Alice
Otero, Pablo
Lopez-Noriega, Livia
Leclerc, Isabelle
Sakamoto, Kei
Schmoll, Dieter
Smith, David M.
Carling, David
Rutter, Guy A.
author_sort Nguyen-Tu, Marie-Sophie
title Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
title_short Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
title_full Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
title_fullStr Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
title_full_unstemmed Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
title_sort opposing effects on regulated insulin secretion of acute vs chronic stimulation of amp-activated protein kinase
publishDate 2022
url https://hdl.handle.net/10356/163901
_version_ 1759854008789368832
spelling sg-ntu-dr.10356-1639012023-03-05T16:53:32Z Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase Nguyen-Tu, Marie-Sophie Harris, Joseph Martinez-Sanchez, Aida Chabosseau, Pauline Hu, Ming Georgiadou, Eleni Pollard, Alice Otero, Pablo Lopez-Noriega, Livia Leclerc, Isabelle Sakamoto, Kei Schmoll, Dieter Smith, David M. Carling, David Rutter, Guy A. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine AMP-Activated Protein Kinase Insulin Secretion Aims/hypothesis: Although targeted in extrapancreatic tissues by several drugs used to treat type 2 diabetes, the role of AMP-activated protein kinase (AMPK) in the control of insulin secretion is still debatable. Previous studies have used pharmacological activators of limited selectivity and specificity, and none has examined in primary pancreatic beta cells the actions of the latest generation of highly potent and specific activators that act via the allosteric drug and metabolite (ADaM) site. Methods: AMPK was activated acutely in islets isolated from C57BL6/J mice, and in an EndoC-βH3 cell line, using three structurally distinct ADaM site activators (991, PF-06409577 and RA089), with varying selectivity for β1- vs β2-containing complexes. Mouse lines expressing a gain-of-function mutation in the γ1 AMPK subunit (D316a) were generated to examine the effects of chronic AMPK stimulation in the whole body, or selectively in the beta cell. Results: Acute (1.5 h) treatment of wild-type mouse islets with 991, PF-06409577 or RA089 robustly stimulated insulin secretion at high glucose concentrations (p<0.01, p<0.05 and p<0.001, respectively), despite a lowering of glucose-induced intracellular free Ca2+ dynamics in response to 991 (AUC, p<0.05) and to RA089 at the highest dose (25 μmol/l) at 5.59 min (p<0.05). Although abolished in the absence of AMPK, the effects of 991 were observed in the absence of the upstream kinase, liver kinase B1, further implicating ‘amplifying’ pathways. In marked contrast, chronic activation of AMPK, either globally or selectively in the beta cell, achieved using a gain-of-function mutant, impaired insulin release in vivo (p<0.05 at 15 min following i.p. injection of 3 mmol/l glucose) and in vitro (p<0.01 following incubation of islets with 17 mmol/l glucose), and lowered glucose tolerance (p<0.001). Conclusions/interpretation: AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators. Published version GAR was supported by a Wellcome Trust Investigator (WT212625/Z/18/Z) Award, and an MRC Programme grant (MR/ R022259/1). AMS was support by an MRC New Investigator Research Grant (MR/P023223/1). This project has received funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115881 (RHAPSODY) to GAR. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center based at the University of Copenhagen, Denmark, and is partially funded by an unconditional donation from the Novo Nordisk Foundation (grant no. NNF18CC0034900). 2022-12-21T06:35:21Z 2022-12-21T06:35:21Z 2022 Journal Article Nguyen-Tu, M., Harris, J., Martinez-Sanchez, A., Chabosseau, P., Hu, M., Georgiadou, E., Pollard, A., Otero, P., Lopez-Noriega, L., Leclerc, I., Sakamoto, K., Schmoll, D., Smith, D. M., Carling, D. & Rutter, G. A. (2022). Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase. Diabetologia, 65(6), 997-1011. https://dx.doi.org/10.1007/s00125-022-05673-x 0012-186X https://hdl.handle.net/10356/163901 10.1007/s00125-022-05673-x 65 2-s2.0-85126294988 6 65 997 1011 en Diabetologia © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. application/pdf