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Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance
Open accessAbstract
Perspective Figure 1 Schematic illustration of major signaling pathways of insulin action.The phosphorylated insulin receptor binds and phosphorylates IRS proteins and Shc, which bind differentially to various downstream signaling proteins.PI3-kinase is critical for metabolic actions of insulin, such as glucose transport, glycogen synthesis, and protein synthesis, whereas Grb-2/SOS complex, which activates the MAP kinase cascade, is critical in mitogenic response.PI3-kinase probably modulates the mitogenic response as well.This series continues from the March 1999, no.6, issue.
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“Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [143]
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“The phosphorylated tyrosine residues of IRS-1 mediate an association with the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to activation of the enzyme [138–140, 143, 144].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [143]
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“Tyrosyl phosphorylation of IRS-1 promotes the interaction of IRS-1 and SH2 domain-containing proteins, including PI 3-kinase, Grb2, Nck, Fyn, and SHP-2, leading to the activation of signaling pathways mediated by these molecules (77, 79).”
BackgroundInfluentialMechanisms of Hepatic Very Low-Density Lipoprotein Overproduction in Insulin Resistance
Adeli, K., Taghibiglou, C., Van Iderstine, S. C., & Lewis, G. F. (2001) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(01)00084-6 · Cited by 194
Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling
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“Once phosphorylated, Akt contributes to various biological processes including regulation of glucose uptake (Virkamaki et al. 1999).”
BackgroundReducing Plasma Membrane Sphingomyelin Increases Insulin Sensitivity
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“It has been suggested that lipid rafts play an important role in the pathogenesis of insulin resistance (61).”
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“The insulin resistance/metabolic syndrome—characterized by the variable coexistence of hyperinsulinemia, dislipidemia, obesity, and hypertension—is influenced by both environmental and genetic background, the latter being mostly unknown (Trischitta et al. 1997; Virkamaki et al. 1999).”
BackgroundSelective Insulin Resistance in the Polycystic Ovary Syndrome
Book, C. B., & Dunaif, A. E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.6010 · Cited by 199
“Phosphorylated tyrosine residues on these substrates then bind to a variety of molecules to activate signaling pathways, such as those mediating carbohydrate metabolism, lipogenesis, protein synthesis, gene transcription, and cell growth/differentiation (12, 13 ).”
BackgroundResultInfluentialMetabolic programming in animals
Ozanne, S. E. (2001) · British Medical Bulletin · doi:10.1093/bmb/60.1.143 · Cited by 178
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“Several acquired factors including hyperinsulinemia, hyperglycemia, tumor necrosis factor-a (TNF-a), increased circulating free fatty acids, ceramide and nuclear factor kappa-B have been implicated in altering insulin signaling in patients with obesity and T2D via one or more of the above mechanisms [33].”
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“PI 3-kinase is recognized as the critical molecule for mediating the various metabolic actions of insulin (16, 42, 53).”
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Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies
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“phosphorylation of Akt is necessary for increased glucose uptake, whereas Ser(473) phosphorylation is not (32, 59).”
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Enhanced Mitogenic Signaling in Skeletal Muscle of Women With Polycystic Ovary Syndrome
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“There is considerable evidence that the MEK/ERK1/2 signaling pathway is involved in serine phosphorylation of IRS-1 (25,29–32), resulting in decreased IRS-1 tyrosine phosphorylation and inhibition of association with PI 3-kinase (33), a critical step for propagating the insulin signal to metabolic pathways (10,11).”
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Hoyer, S. (2002) · Journal of Neural Transmission · doi:10.1007/s007020200082 · Cited by 161
“In myoblasts, and in all likelihood in neurons, too, insulin has been found to induce mitogenesis throughout two independent pathways acting in synergy, PI-3 kinase/p 70 S 6 kinase, and p43/p44-MAP kinase ( Virkamaki et al., 1999 ) along with an increase in the proportion of proliferating cells in S and G2/M phases of…”
BackgroundMunir, I., Yen, H.-W., Geller, D. H., Torbati, D., Bierden, R. M., Weitsman, S. R., Agarwal, S. K., & Magoffin, D. A. (2003) · Endocrinology · doi:10.1210/en.2003-0329 · Cited by 163
The Phosphotyrosine Interactome of the Insulin Receptor Family and Its Substrates IRS-1 and IRS-2
Hanke, S., & Mann, M. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800407-mcp200 · Cited by 165
“Fyn has been reported to bind to IRS-1 and IRS-2 (47) and to tyrosine phosphorylated Cbl after insulin stimulation (78).”
BackgroundInsulin 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
RetractedKabayama, K. (2004) · Glycobiology · doi:10.1093/glycob/cwh135 · Cited by 155
“Similarities between these cell culture results and the findings in many cases of clinical insulin resistance ( Virkamaki et al., 1999 ), thereby suggesting a potential role for microdomains in the pathogenesis of this disorder.”
BackgroundResult
Metadata
- Authors
- Virkamäki, A., Ueki, K., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Kahn, C. Ronald
- Venue
- Journal of Clinical Investigation
- Published
- 1999-04-01
- Volume
- 103
- Issue
- 7
- Pages
- 931-943
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC408269
- OpenAlex
- W2095252238
- Cited by
- 854
- References
- 176
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 15 · 2023: 8 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 16 · 2018: 13 · 2017: 21 · 2016: 22 · 2015: 26 · 2014: 24 · 2013: 27 · 2012: 31
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Foundation for the Study of Diabetes
- National Institutes of Health (DK31036)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031036, DK 33201, R01DK031036, DK45935, DK31036, R01DK045935, R01DK033201)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- insulin signaling, insulin resistance, protein-protein interaction, insulin receptor, Shc, PI3-kinase, MAP kinase cascade, glucose transport, glycogen synthesis, mitogen response
- MeSH terms
- Animals, Humans, Insulin, Insulin Resistance, Phosphorylation, Protein Binding, Receptor, Insulin, Signal Transduction, Gene Targeting, src Homology Domains, Phosphatidylinositol 3-Kinases
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