Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase
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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 journal › Journal article › Research › peer-review
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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