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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
Open accessAbstract
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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“Alternative studies show that IRS1 S789 phosphorylation is negatively associated with insulin signaling [146-149].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [146]
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“Instead, activation of AMPK by glucose deprivation or AICAR promotes tyrosine phosphorylation of IR and IRS-1 as well as Akt T308 and S473 phosphorylation [146].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [146]
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“Recently, AMPK was found to phosphorylate the IR in response to glucose deprivation; conditions that also suppresses mTOR activity [146].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [146]
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849
Watterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,672
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling
Towler, M. C., & Hardie, D. G. (2007) · Circulation Research · doi:10.1161/01.res.0000256090.42690.05 · Cited by 1,262
AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome
Zhang, B. B., Zhou, G., & Li, C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.012 · Cited by 1,042
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
Gual, P., Le Marchand-Brustel, Y., & Tanti, J.-F. (2005) · Biochimie · doi:10.1016/j.biochi.2004.10.019 · Cited by 912 · cited 1×
“Although positive regulatory IRS-1-Ser/Thr sites have been reported [11, 17, 48, 49], none of these sites contain sequences with significant homology to the AMPK consensus.”
AMP-Activated Protein Kinase – Development of the Energy Sensor Concept
Hardie, D. G., Hawley, S. A., & Scott, J. W. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108944 · Cited by 813
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Ghosh, A., Gao, L., Thakur, A., Siu, P. M., & Lai, C. W. K. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0357-5 · Cited by 432
AMPK and Exercise: Glucose Uptake and Insulin Sensitivity
O'Neill, H. M. (2013) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2013.37.1.1 · Cited by 295
Zheng, T., Yang, X., Wu, D., Xing, S., Bian, F., Li, W., Chi, J., Bai, X., Wu, G., Chen, X., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13120 · Cited by 230
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Metadata
- 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
- Published
- 2011-12-30
- Volume
- 55
- Issue
- 3
- Pages
- 783-794
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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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