The DOI matches its Crossref record; 183 of the 185 references it cites were found in a registry or an index.
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Open accessAbstract
The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
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“Insulin resistance in adipocytes is associated with impaired phosphorylation of insulin receptor substrate 1 (IRS-1) in obesity, which is further impaired in T2DM”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Copps and White, 2012
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Cites
3 retracted
Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
Liu, Y., Paz, K., Herschkovitz, A., Alt, A., Tennenbaum, T., Sampson, S. R., Ohba, M., Kuroki, T., LeRoith, D., & Zick, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007281200 · Cited by 159
RetractedHerschkovitz, A., Liu, Y., Ilan, E., Ronen, D., Boura‐Halfon, S., & Zick, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610949200 · Cited by 98
RetractedG Protein–Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity
García‐Guerra, L., Nieto-Vázquez, I., Vila‐Bedmar, R., Jurado-Pueyo, M., Zalba, G., Dı́ez, J., Murga, C., Fernández‐Veledo, S., Mayor, F., & Lorenzo, M. (2010) · Diabetes · doi:10.2337/db10-0771 · Cited by 92
RetractedPhosphorylation 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 · cited 2×
“In contrast, ‘priming’ phosphorylation of AKT at S473—by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) [21] (Fig.”
BackgroundEndoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · cited 1×
“phosphorylation is frequently used as evidence of insulin resistance (or its resolution) in mice, despite the influence of insulin on S307 phosphorylation and the probable contribution of other phospho-S/Ts [44].”
BackgroundNewgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · cited 1×
“Increased plasma BCAA levels in obese, insulin-resistant persons have long been regarded as part of an insulin-resistant metabolic ‘signature’ [110, 111], but supplementation of rodent diets with mixed BCAA or leucine has not clarified that this is diabetogenic [111, 112].”
BackgroundSkeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes
DeFronzo, R. A., & Tripathy, D. (2009) · Diabetes Care · doi:10.2337/dc09-s302 · Cited by 2,102 · cited 2×
“Prospective studies first identify insulin resistance in human skeletal muscle, which is thought to contribute, via a dys-metabolic process, to the emergence of phenotypic disease [3, 74].”
BackgroundCho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., & Birnbaum, M. J. (2001) · Science · doi:10.1126/science.292.5522.1728 · Cited by 1,860 · cited 2×
“but not Akt1, gene deletion in mice causes a diabetes-like phenotype [22].”
BackgroundAbsence 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 · cited 3×
“1b); S6K2 can also phosphorylate IRS1 in vitro, but does not compensate for loss of S6K1 in knockout mice [51, 106].”
BackgroundAdipose tissue as an endocrine organ
Galić, S., Oakhill, J. S., & Steinberg, G. R. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.08.018 · Cited by 1,654 · cited 1×
“IKKβ and JNK—Impaired glucose uptake and/or insulin resistance within adipose tissue can contribute to the development of type 2 diabetes [164], likely by altering its secretion of adipokines, such as adiponectin or retinol-binding protein 4 (reviewed in [165]).”
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Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Diabetes mellitus: The epidemic of the century
Kharroubi, A. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i6.850 · Cited by 1,352
Insulin action and resistance in obesity and type 2 diabetes
Czech, M. P. (2017) · Nature Medicine · doi:10.1038/nm.4350 · Cited by 1,258
Insulin resistance: review of the underlying molecular mechanisms
Yaribeygi, H., Farrokhi, F. R., Butler, A. E., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.27603 · Cited by 929
“This process creates a suitable binding site for IRS‐1 that is then activated via phosphorylation by different insulin‐induced kinases such as PKC, SIK2, AKT, S6K1, mTOR, extracellular signal‐regulated kinase 1/2 (ERK1/2), and ROCK1 (Copps & White, 2012; Kiselyov et al., 2009).”
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Metadata
- Authors
- Copps, K. D., & White, M. F.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- White, M. F.
- ORCID
- White, M. F.
- Venue
- Diabetologia
- Published
- 2012-08-08
- Volume
- 55
- Issue
- 10
- Pages
- 2565-2582
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC4011499
- OpenAlex
- W1982479748
- Cited by
- 1,017
- References
- 185
- Citations by year
- 2026: 72 · 2025: 56 · 2024: 76 · 2023: 83 · 2022: 103 · 2021: 113 · 2020: 83 · 2019: 76 · 2018: 75 · 2017: 70 · 2016: 59 · 2015: 63 · 2014: 51 · 2013: 31 · 2012: 5
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01dk098655-08)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01- DK098655, R01DK038712)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin receptor substrate, IRS-1, insulin receptor substrate 2, serine/threonine phosphorylation, insulin sensitivity, insulin resistance, diabetes mellitus, insulin signaling, AMPK, glycogen synthase kinase-3, protein kinase C, Akt, mTOR, hyperinsulinemia, metabolic disorders
- MeSH terms
- Animals, Diabetes Mellitus, Humans, Insulin Resistance, Mice, Transgenic, Phosphorylation, Serine, Threonine, Signal Transduction, Mice, Knockout, Models, Animal, Mice, Insulin Receptor Substrate Proteins
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