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

Research output: Contribution to journalJournal articlepeer-review

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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.

In: Diabetologia, Vol. 65, 2022, p. 997-1011.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Nguyen-Tu, M-S, 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, DM, Carling, D & Rutter, GA 2022, 'Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase', Diabetologia, vol. 65, pp. 997-1011. https://doi.org/10.1007/s00125-022-05673-x

APA

Nguyen-Tu, M-S., 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, 997-1011. https://doi.org/10.1007/s00125-022-05673-x

Vancouver

Nguyen-Tu M-S, Harris J, Martinez-Sanchez A, Chabosseau P, Hu M, Georgiadou E et al. Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase. Diabetologia. 2022;65:997-1011. https://doi.org/10.1007/s00125-022-05673-x

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. / Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase. In: Diabetologia. 2022 ; Vol. 65. pp. 997-1011.

Bibtex

@article{6e1f6e3de72342b3a6abfbd99b149c45,
title = "Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase",
abstract = "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-beta H3 cell line, using three structurally distinct ADaM site activators (991, PF-06409577 and RA089), with varying selectivity for beta 1- vs beta 2-containing complexes. Mouse lines expressing a gain-of-function mutation in the gamma 1 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 (pConclusions/interpretation AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators.",
keywords = "991, AMP-activated protein kinase, AMPK, ATP/ADP, Beta cell, Ca2+, Insulin secretion, LKB1, PF-06409577, RA089, Type 2 diabetes, BETA-CELLS, GLUCOSE, PHOSPHORYLATION, DISCOVERY, MEMBRANE, TARGETS",
author = "Marie-Sophie Nguyen-Tu and Joseph Harris and Aida Martinez-Sanchez and Pauline Chabosseau and Ming Hu and Eleni Georgiadou and Alice Pollard and Pablo Otero and Livia Lopez-Noriega and Isabelle Leclerc and Kei Sakamoto and Dieter Schmoll and Smith, {David M.} and David Carling and Rutter, {Guy A.}",
year = "2022",
doi = "10.1007/s00125-022-05673-x",
language = "English",
volume = "65",
pages = "997--1011",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",

}

RIS

TY - JOUR

T1 - Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase

AU - Nguyen-Tu, Marie-Sophie

AU - Harris, Joseph

AU - Martinez-Sanchez, Aida

AU - Chabosseau, Pauline

AU - Hu, Ming

AU - Georgiadou, Eleni

AU - Pollard, Alice

AU - Otero, Pablo

AU - Lopez-Noriega, Livia

AU - Leclerc, Isabelle

AU - Sakamoto, Kei

AU - Schmoll, Dieter

AU - Smith, David M.

AU - Carling, David

AU - Rutter, Guy A.

PY - 2022

Y1 - 2022

N2 - 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-beta H3 cell line, using three structurally distinct ADaM site activators (991, PF-06409577 and RA089), with varying selectivity for beta 1- vs beta 2-containing complexes. Mouse lines expressing a gain-of-function mutation in the gamma 1 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 (pConclusions/interpretation AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators.

AB - 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-beta H3 cell line, using three structurally distinct ADaM site activators (991, PF-06409577 and RA089), with varying selectivity for beta 1- vs beta 2-containing complexes. Mouse lines expressing a gain-of-function mutation in the gamma 1 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 (pConclusions/interpretation AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators.

KW - 991

KW - AMP-activated protein kinase

KW - AMPK

KW - ATP/ADP

KW - Beta cell

KW - Ca2+

KW - Insulin secretion

KW - LKB1

KW - PF-06409577

KW - RA089

KW - Type 2 diabetes

KW - BETA-CELLS

KW - GLUCOSE

KW - PHOSPHORYLATION

KW - DISCOVERY

KW - MEMBRANE

KW - TARGETS

U2 - 10.1007/s00125-022-05673-x

DO - 10.1007/s00125-022-05673-x

M3 - Journal article

C2 - 35294578

VL - 65

SP - 997

EP - 1011

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

ER -

ID: 301629686