Role of AMP-Activated Protein Kinase in the Control of Glucose Homeostasis
Abstract
Skeletal muscle insulin resistance is a hallmark feature of Type 2 diabetes. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway may bypass defective insulin signaling. To date, the exercise-responsive signaling molecules governing glucose metabolism in skeletal muscle are largely unknown. AMP-activated protein kinase (AMPK) has been suggested as one of the exercise-responsive signaling molecules involved in glucose homeostasis and consequently it has been heavily explored as a pharmacological target for the treatment of Type 2 diabetes. AMPK exists in heterotrimeric complexes composed of a catalytic alpha-subunit and regulatory beta- and gamma-subunits. The gamma3-isoform of AMPK is expressed specifically in skeletal muscle of humans and rodents and this tissue specific expression pattern offers selectivity in AMPK action. Furthermore, mutations in the AMPK gamma3-isoform may provide protection from diet-induced insulin resistance by increasing lipid oxidation in the presence of increased lipid supply. This review highlights the current understanding of the role of the regulatory AMPK gamma3-isoform in the control of skeletal muscle metabolism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle.
“In support of this, insulin also does not increase AMPK T172 or ACC S79/212 phosphorylation [74] and AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle [26,28,30,36,100] despite blunted TBC1D1 PAS and T590 phosphorylation in response to insulin [30,74].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [100]
Cited by
Sorted by citations
Apelin Stimulates Glucose Utilization in Normal and Obese Insulin-Resistant Mice
Dray, C., Knauf, C., Daviaud, D., Waget, A., Boucher, J., Buléon, M., Cani, P. D., Attané, C., Guigné, C., Carpéné, C., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.003 · Cited by 522 · see citing works
AMPK in skeletal muscle function and metabolism
Kjøbsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmøller, C. K., Shum, M., Marette, A., Mounier, R., Treebak, J. T., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700442r · Cited by 496 · see citing works
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 · see citing works
“org 212 phosphorylation [74] and AMPK α2, β2 and γ3 null and α2KD and β1β2 M-KO mice have normal insulin-stimulated glucose uptake in muscle [26,28,30,36,100] despite blunted TBC1D1 PAS and T590 phosphorylation in response to insulin [30,74].”
BackgroundFlachs, P., Rossmeisl, M., Bryhn, M., & Kopecký, J. (2008) · Clinical Science · doi:10.1042/cs20070456 · Cited by 284 · see citing works
Thong, F. S. L., Bilan, P. J., & Klip, A. (2007) · Diabetes · doi:10.2337/db06-0900 · Cited by 242 · see citing works
“Moreover, AMPK has emerged as a viable pharmacological target in the treatment of type 2 diabetes (36,37), and chronic treatment of obese rodents with an AMPK activator improved glucose tolerance (38).”
BackgroundExpanding role of AMPK in endocrinology
Kola, B., Boscaro, M., Rutter, G. A., Grossman, A. B., & Korbonits, M. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.05.006 · Cited by 200 · see citing works
The Effect of n-3 Fatty Acids on Glucose Homeostasis and Insulin Sensitivity
Flachs, P., Rossmeisl, M., & Kopecký, J. (2014) · Physiological Research · doi:10.33549/physiolres.932715 · Cited by 183 · see citing works
Bertrand, L., Ginion, A., Beauloye, C., Hebert, A. D., Guigas, B., Hue, L., & Vanoverschelde, J. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01269.2005 · Cited by 144 · see citing works
“Primarily considered as a cellular fuel gauge, AMPK is involved in the regulation of glucose and lipid metabolism in the liver, the skeletal muscle, the heart, and adipose tissues (3, 11, 23, 29, 48).”
BackgroundCellular energy sensing and signaling by AMP-activated protein kinase
Winder, W. W., & Thomson, D. M. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0008-7 · Cited by 141 · see citing works
“A second major consequence of the activation of AMPK in muscle is stimulation of glucose uptake and insulin sensitivity [8, 41, 46, 47, 86, 91, 203].”
Lee, J. O., Lee, S. K., Kim, J. H., Kim, N., You, G. Y., Moon, J. W., Kim, S. J., Park, S. H., & Kim, H. S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.361386 · Cited by 140 · see citing works
“Enhancement of insulin sensitivity and amelioration of insulin resistance by AMPK is well established (34, 35).”
BackgroundPositive Feedback Regulates Switching of Phosphate Transporters in S. cerevisiae
Wykoff, D. D., Rizvi, A. H., Raser, J. M., Margolin, B., & O’Shea, E. K. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.07.022 · Cited by 119 · see citing works
Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1
Yuan, H., Shyy, J. Y.-J., & Martins‐Green, M. M. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.026 · Cited by 129 · see citing works
“However, AMPK can also be activated in situations without detectable changes in the AMP/ATP ratio, such as in response to sheer stress [42,43], increased osmotic pressure [44] anti-diabetic drugs metformin [45] and thiazolidinediones [46,47], and in the regulation of whole body glucose homeostasis [48,49].”
Apelin/APJ system as a therapeutic target in diabetes and its complications
Hu, H., He, L., Li, L., & Chen, L. (2016) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2016.07.012 · Cited by 85 · see citing works
“AMP-activated protein kinase (AMPK) has been highlighted as a key factor to promote FAO and glucose transport, in order to energy supply [27].”
BackgroundMetformin induces Rab4 through AMPK and modulates GLUT4 translocation in skeletal muscle cells
Lee, J. O., Lee, S. K., Jung, J. H., Kim, J. H., You, G. Y., Kim, S. J., Park, S. H., Uhm, K., & Kim, H. S. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22410 · Cited by 82 · see citing works
“The mechanisms of the AMPK-induced anti-diabetic effects have previously been suggested (Winder and Hardie, 1999; Barnes and Zierath, 2005).”
BackgroundSignalling mechanisms in skeletal muscle: role in substrate selection and muscle adaptation
Hawley, J. A., Hargreaves, M., & Zierath, J. R. (2006) · Essays in Biochemistry · doi:10.1042/bse0420001 · Cited by 69 · see citing works
“Approaches in functional genomics reveal that AMPK is necessary and suffi cient for AICAR induced glucose transport [18].”
BackgroundInfluentialSelf-citationDiet, obesity and diabetes: a current update
Walker, C. G., Zariwala, M. G., Holness, M. J., & Sugden, M. C. (2006) · Clinical Science · doi:10.1042/cs20060150 · Cited by 62 · see citing works
Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin
Zhang, Y., Wang, Y., Lou, Y., Luo, M., Lu, Y., Li, Z., Wang, Y., & Miao, L. (2018) · Peptides · doi:10.1016/j.peptides.2018.09.006 · Cited by 66 · see citing works
“In particular, Apelin activates mitochondrial DNA replication and transcription via the AMPK and Akt pathways in mice, and thus increases muscle mitochondrial density and mitochondrial respiratory capacity and promotes fatty acid oxidation and glucose transport [132,133].”
Ma, Y., Yang, I., Tsai, H., Huang, C., Juo, S. H., & Wang, J. (2013) · DNA and Cell Biology · doi:10.1089/dna.2013.2161 · Cited by 62 · see citing works
“The major regulatory pathways of glucose metabolism are largely mediated through insulin receptor signaling and the AMP-activated protein kinase signaling pathways (Barnes and Zierath, 2005; Tomas et al., 2012).”
BackgroundChen, D., Wang, Y., Wu, K., & Wang, X. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061547 · Cited by 66 · see citing works
Dai, Y., Amenov, A., Ignatyeva, N., Koschinski, A., Xu, H., Soong, P. L., Tiburcy, M., Linke, W. A., Zaccolo, M., Hasenfuss, G. P., et al. (2020) · Scientific Reports · doi:10.1038/s41598-019-56597-3 · Cited by 55 · see citing works
Mining frequent patterns for AMP-activated protein kinase regulation on skeletal muscle
Chen, Q., & Chen, Y. P. (2006) · BMC Bioinformatics · doi:10.1186/1471-2105-7-394 · Cited by 44 · see citing works
“Recent experimental results also demonstrate this [4,23,24].”
ResultPhospholipase D1 Mediates AMP-Activated Protein Kinase Signaling for Glucose Uptake
Kim, J. H., Park, J.-M., Yea, K., Kim, H. W., Suh, P., & Ryu, S. H. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009600 · Cited by 41 · see citing works
“Previous studies have reported that AMPK activity is involved in glucose homeostasis in a variety of cells [1], [10], and that PLD activity is required for glucose uptake in muscles and adipocytes [21], [23], [26].”
BackgroundXiao, X., Su, G., Brown, S. N., Chen, L., Ren, J., & Zhao, P. (2009) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2009.03.011 · Cited by 34 · see citing works
“AMPK was initially found to be an important regulator of fatty acid oxidation in heart [17] and skeletal muscle [18] but has also emerged as an important mediator of glucose metabolism [19].”
Moroz, M. A., Kochetkov, T., Cai, S., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1430 · Cited by 31 · see citing works
Pharmacological Targeting of Adipocytes/Fat Metabolism for Treatment of Obesity and Diabetes
Pilch, P. F., & Bergenhem, N. C. H. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.026104 · Cited by 30 · see citing works
“The metabolic sensor AMP-activated protein kinase is stimulated upon exercise and may augment lipid and glucose metabolism in muscle (Barnes and Zierath, 2005; Kahn et al., 2005), prompting interest in a small-molecule drug that can activate this protein; in effect, an exercise pill.”
BackgroundGu, X., Zhao, H., Sui, Y., Guan, J. Z., Chan, J. C. N., & Tong, P. C. Y. (2010) · Acta Diabetologica · doi:10.1007/s00592-010-0184-6 · Cited by 29 · see citing works
“AMPK is a master switch that inhibits gluconeogenesis, glycolysis, lipogenesis and cholesterol formation in the liver [21].”
BackgroundChatterjee, A., Villarreal, G., Oh, D., Kang, M. H., & Rhee, D. J. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12755 · Cited by 28 · see citing works
“Within the mammalian kingdom, each subunit has multiple isoforms, a1 and a2; b1 and b2; c1, c2, and c3; in humans, each encoded at a distinct genetic locus within the genome, yielding a total of 12 possible heterotrimeric combinations that appear to be distributed throughout the body in a tissue-specific manner.(35) T…”
BackgroundMorin reduces inflammatory responses and alleviates lipid accumulation in hepatocytes
Wu, L., Wang, Y., Chi, G., Shen, B., Tian, Y., Li, Z., Han, L., Zhang, Q., & Feng, H. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28578 · Cited by 23 · see citing works
“AMPK is influenced by AMP/ATP ratios and emerges as a significant mediator involved in glucose homeostasis (Barnes & Zierath, 2005).”
BackgroundWu, U., Cha, Y., Huang, X., Liu, J., Chen, Z., Wang, F., Xu, J., Sheng, L., & Ding, H. (2015) · PubMed Central · Cited by 18 · see citing works
Wang, C., Luo, D., Zheng, L. P., & Zhao, M. (2023) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.13187 · Cited by 18 · see citing works
Dall’Olio, S., Scotti, E., Costa, L. N., et al. (2017) · Meat Science · doi:10.1016/j.meatsci.2017.09.012 · Cited by 12 · see citing works
Finck, B. N. (2006) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.4.2.161 · Cited by 12 · see citing works
de Pádua, M. F., de Pádua, T. F., Pauli, J. R., de Souza, C. T., da Silva, A. S. R., Ropelle, E. C. C., Cintra, D. E., Carvalheira, J. B. C., & Ropelle, E. R. (2009) · Revista Brasileira de Medicina do Esporte · doi:10.1590/s1517-86922009000300003 · Cited by 11 · see citing works
Çınar, V., Polat, Y., Moğulkoç, R., Nizamlıoğlu, M., & Baltacı, A. K. (2008) · PubMed · Cited by 9 · see citing works
Skeletal muscle lipid metabolism and the adipomuscular axis
Sugden, M. C., & Holness, M. J. (2006) · Future Lipidology · doi:10.2217/17460875.1.2.153 · Cited by 7 · see citing works
“In muscle, the predominant isoforms are the α2 [35], β2 and γ3 isoforms [36].”
BackgroundLong, Y. C., & Zierath, J. R. (2005) · Diabetologia · doi:10.1007/s00125-005-0032-3 · Cited by 4 · see citing works
“The role of AMPK in glucose and lipid metabolism is gaining acceptance through functional genomics [7].”
BackgroundSelf-citationÇınar, V., Moğulkoç, R., Baltacı, A. K., & Bostanci, O. (2009) · Biological Trace Element Research · doi:10.1007/s12011-009-8409-7 · Cited by 2 · see citing works
“It was emphasized that this transport independently from insulin [14-16].”
BackgroundLuo, G., Ai, Y., Yu, L., Wang, S., & Ren, Z. (2023) · Animals · doi:10.3390/ani13030446 · Cited by 1 · see citing works
“Studies have shown that FABP3 [23], COL6A5 [24], FAM13A [25], MYOZ2 [26,27], EGR2 [28], SOX9 [29], IRX5 [30], PRKAG 3 [31], ABCA1 [32], ADRB1 [33], ADAMTS18 [34,35] and GLI2 [36,37] are important factors in the regulation of fat deposition.”
Lee, S., 조진경, 김태경, et al. (2010) · Exercise Science · doi:10.15857/ksep.2010.19.2.155 · Cited by 1 · see citing works
Woodworth‐Hobbs, M. E. (2009) · doi:10.33915/etd.2812 · Cited by 1 · see citing works
“These studies examining the effects of AICAR and metformin on AMPK activity and subsequent FA oxidation and mitochondrial oxidative capacity identify the possible value of AMPK-activating treatments in controlling insulin resistance (4) through changes in lipid homeostasis.”
BackgroundInfluentialEmerging Roles of Phospholipase D in Pathophysiological Signaling
Lee, C. S., Ghim, J., Jang, J., et al. (2014) · Springer eBooks · doi:10.1007/978-1-4939-0464-8_22
“well-balanced mechanism and an essential process for cell survival and growth [ 92 ].”
Resistance training in the treatment of diabetes mellitus II: a narrative review
Saborosa, G. P., Freitas, R. D. O., & da Silva, S. F. (2022) · Multidisciplinary Reviews · doi:10.31893/multirev.2022016
Moroz, M. A., Kochetkov, T., Cai, S., et al. (2023) · doi:10.1158/1078-0432.c.6520382
- Authors
- Barnes, B., & Zierath, J.
- Affiliations
- Karolinska Institutet (SE)
- ORCID
- Zierath, J.
- Venue
- Current Molecular Medicine
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2005-05-01
- Volume
- 5
- Issue
- 3
- Pages
- 341-348
- ISSN
- 1566-5240 (ISSN-L)
- OpenAlex
- W2095196762
- Cited by
- 45
- References
- 0
- Citations by year
- 2023: 3 · 2022: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- AMPK, glucose homeostasis, skeletal muscle insulin resistance, type 2 diabetes, physical activity, glucose transport, insulin-independent glucose uptake, lipid oxidation, AMPK signaling
- MeSH terms
- Animals, Biological Transport, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Insulin Resistance, Mice, Transgenic, Models, Biological, Multienzyme Complexes, Muscle Contraction, Mutation, Physical Conditioning, Animal, Exercise, Protein Serine-Threonine Kinases, Mice, Knockout, Muscle, Skeletal, Protein Isoforms, Mice, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
