Journal ArticleDOI
Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
Robert W. Myers,Hong-Ping Guan,Juliann Ehrhart,Aleksandr Petrov,Srinivasa Prahalada,Effie Tozzo,Xiaodong Yang,Marc M. Kurtz,Maria E. Trujillo,Dinko Gonzalez Trotter,Danqing Feng,Shiyao Xu,George J. Eiermann,Marie A. Holahan,Daniel Rubins,Stacey Conarello,Xiaoda Niu,Sandra C. Souza,Corin O. Miller,Jinqi Liu,Ku Lu,Wen Feng,Ying Li,Ronald E. Painter,James A. Milligan,Huaibing He,Franklin Liu,Aimie Ogawa,Douglas Wisniewski,Rory J. Rohm,Liyang Wang,Michelle Bunzel,Ying Qian,Wei Zhu,Hongwu Wang,Bindu Bennet,Lisa LaFranco Scheuch,Guillermo Fernandez,Cai Li,Michael Klimas,Gaochao Zhou,Margaret van Heek,Tesfaye Biftu,Ann E. Weber,David E. Kelley,Nancy A. Thornberry,Mark D. Erion,Daniel M. Kemp,Iyassu K. Sebhat +48 more
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TLDR
MK-8722 is developed, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes that induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia in rodents and rhesus monkeys.Abstract:
5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722–mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.read more
Citations
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Journal ArticleDOI
AMPK: guardian of metabolism and mitochondrial homeostasis.
Sébastien Herzig,Reuben J. Shaw +1 more
TL;DR: How AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology is discussed.
Journal ArticleDOI
AMPK: Sensing Glucose as well as Cellular Energy Status
Sheng-Cai Lin,D. Grahame Hardie +1 more
TL;DR: Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.
Journal ArticleDOI
AMP-activated protein kinase: the current landscape for drug development.
TL;DR: An overview of the physiological functions of AMPK is provided and the potential of this enzyme as a therapeutic target across diverse disease areas is discussed and Pharmacological activation of AM PK and the associated drug development challenges are assessed.
Journal ArticleDOI
AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control
TL;DR: The evolution, structure, and regulation of the AMPK and TOR pathways and the complex mechanisms by which they interact are discussed.
Journal ArticleDOI
AMPK in skeletal muscle function and metabolism.
Rasmus Kjøbsted,Janne R. Hingst,Joachim Fentz,Marc Foretz,Marc Foretz,Marc Foretz,Maria Nieves Sanz,Christian Pehmøller,Michael Shum,André Marette,Rémi Mounier,Jonas T. Treebak,Jørgen F. P. Wojtaszewski,Benoit Viollet,Benoit Viollet,Benoit Viollet,Louise Lantier +16 more
TL;DR: The role of AMPK in skeletal muscle during exercise and in exercise recovery is focused on and adaptations to exercise training, including skeletal muscle plasticity, are addressed, highlighting novel concepts and future perspectives that need to be investigated.
References
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Journal ArticleDOI
AMPK: a nutrient and energy sensor that maintains energy homeostasis
TL;DR: AMP-activated protein kinase conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.
Journal ArticleDOI
The selectivity of protein kinase inhibitors: a further update.
Jenny Bain,Lorna Plater,Matthew Elliott,Natalia Shpiro,C. James Hastie,Hilary McLauchlan,Iva V. Klevernic,J. Simon C. Arthur,Dario R. Alessi,Philip Cohen +9 more
TL;DR: Harmine has been identified as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro and the results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes.
Journal ArticleDOI
AMPK in Health and Disease
TL;DR: This review looks at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level and the possible role of AMPK in multiple common diseases.
Journal ArticleDOI
AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes.
William W. Winder,D. G. Hardie +1 more
TL;DR: Increased recruitment of the AMPK signaling system, either by exercise or pharmaceutical activators, may be effective in correcting insulin resistance in patients with forms of impaired glucose tolerance and Type 2 diabetes resulting from defects in the insulin signaling cascade.
Journal ArticleDOI
Exercise, GLUT4, and Skeletal Muscle Glucose Uptake
Erik A. Richter,Mark Hargreaves +1 more
TL;DR: Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.
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