Cited by 117Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

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Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscle

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Chopra, I., Li, H. F., Wang, H., Webster, K. A.·2012·Diabetologia

DOI 10.1007/s00125-011-2407-yPMC PMC4648248

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Abstract

Aims/hypothesis Muscle may experience hypoglycaemia during ischaemia or insulin infusion. During severe hypoglycaemia energy production is blocked, and an increase of AMP:ATP activates the energy sensor and putative insulin-sensitiser AMP-activated protein kinase (AMPK). AMPK promotes energy conservation and survival by shutting down anabolism and activating catabolic pathways. We investigated the molecular mechanism of a unique glucose stress defence pathway involving AMPK-dependent, insulin-independent activation of the insulin signalling pathway.Methods Cardiac or skeletal myocytes were subjected to glucose and insulin-free incubation for increasing intervals up to 20 h. AMPK, and components of the insulin signalling pathway and their targets were quantified by western blot using phosphor-specific antibodies. Phosphomimetics were used to determine the function of IRS-1 Ser789 phosphorylation and in vitro [³²P]ATP kinase assays were used to measure the phosphorylation of the purified insulin receptor by AMPK.Results Glucose deprivation increased Akt-Thr308 and Akt-Ser473 phosphorylation by almost tenfold. Phosphorylation of glycogen synthase kinase 3 beta increased in parallel, but phosphorylation of ribosomal 70S subunit-S6 protein kinase and mammalian target of rapamycin decreased. AMPK inhibitors blocked and aminoimidazole carboxamide ribonucleotide (AICAR) mimicked the effects of glucose starvation. Glucose deprivation increased the phosphorylation of IRS-1 on serine-789, but phosphomimetics revealed that this conferred negative regulation. Glucose deprivation enhanced tyrosine phosphorylation of IRS-1 and the insulin receptor, effects that were blocked by AMPK inhibition and mimicked by AICAR. In vitro kinase assays using purified proteins confirmed that the insulin receptor is a direct target of AMPK.Conclusions/interpretation AMPK phosphorylates and activates the insulin receptor, providing a direct link between AMPK and the insulin signalling pathway; this pathway promotes energy conservation and survival of muscle exposed to severe glucose deprivation.

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Authors: Chopra, I., Li, H. F., Wang, H., & Webster, K. A.
Affiliations: University of Miami (US)
Corresponding author: Webster, K. A.
ORCID: Webster, K. A.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2011-12-30
Volume: 55
Issue: 3
Pages: 783-794
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-011-2407-y
PMC: PMC4648248
OpenAlex: W2038901278
Cited by: 116
References: 51
Citations by year: 2026: 4 · 2025: 5 · 2024: 9 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 6
FWCI: 2.46
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (1r21hl069812-01)
National Heart, Lung, and Blood Institute (HL-69812, HL44578, R01HL072924, R01HL044578)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: AMPK, insulin receptor, insulin signaling pathway, glucose deprivation, hypoglycemia, Akt phosphorylation, glycogen synthase kinase-3β, AICAR, skeletal myocytes, cardiomyocytes
MeSH terms: Animals, Animals, Newborn, Cells, Cultured, Humans, Hypoglycemia, Hypoglycemic Agents, Ligands, Phosphorylation, Protein Processing, Post-Translational, Receptor, Insulin, Recombinant Proteins, Signal Transduction, Muscle, Skeletal, Myocytes, Cardiac, Protein Kinase Inhibitors, Mutant Proteins, Rats, AMP-Activated Protein Kinases, Insulin Receptor Substrate Proteins, Hep G2 Cells

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Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscle

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