Cited by 854Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesPI3K/AKT/mTOR signaling in cancer

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Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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Virkamäki, Antti, Ueki, Kohjiro, Kahn, C. Ronald·1999·Journal of Clinical Investigation

DOI 10.1172/jci6609PMC PMC408269

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Abstract

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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Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419
Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance
Hotamisligil, G. S., Shargill, N. S., & Spiegelman, B. M. (1993) · Science · doi:10.1126/science.7678183 · Cited by 7,518
Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L., & Spiegelman, B. M. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117936 · Cited by 3,543
Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes
Ullrich, A., Bell, J. R., Chen, E. Y., Herrera, R., Petruzzelli, L., Dull, T. J., Gray, A., Coussens, L. M., Liao, Y.-C., Tsubokawa, M., et al. (1985) · Nature · doi:10.1038/313756a0 · Cited by 2,251
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D. J., Gutierrez, J. S., Towery, H. H., Burks, D. J., Ren, J., Previs, S. F., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,775
PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
Spiegelman, B. M. (1998) · Diabetes · doi:10.2337/diabetes.47.4.507 · Cited by 1,730
Protein Kinase C: Structure, Function, and Regulation
Newton, A. C. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.48.28495 · Cited by 1,656
The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling
Lowenstein, E. J., Daly, R. J., Batzer, A., Li, W., Margolis, B. L., Lammers, R., Ullrich, A., Skolnik, E. Y., Bar‐Sagi, D., & Schlessinger, J. (1992) · Cell · doi:10.1016/0092-8674(92)90167-b · Cited by 1,632
The Structural Basis for 14-3-3:Phosphopeptide Binding Specificity
Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H. C. B., Gamblin, S. J., Smerdon, S. J., & Cantley, L. C. (1997) · Cell · doi:10.1016/s0092-8674(00)80487-0 · Cited by 1,604
The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling
Ebina, Y., Ellis, L., Jarnagin, K., Edery, M., Gráf, L., Clauser, É., Ou, J. J., Masiarz, F. R., Kan, Y. W., Goldfine, I. D., et al. (1985) · Cell · doi:10.1016/0092-8674(85)90334-4 · Cited by 1,477

Show all 176 references

Research works printed but not linked: 9

Van Horn, 1994, J Biochem, 269, 29
Liu, 1994, Recent Prog Horm Res, 49, 149
Cohen, 1997, Growth Regul, 410, 3
Imai, 1994, J Clin Endocrinol Metab, 79, 1655
Celi, 1995, J Clin Endocrinol Metab, 80, 2827
Friedman, 1997, Am J Physiol, 273, E1014
Ohsaka, 1997, Growth Regul, 402, 246
Poitout, 1998, Diabetes Metab, 24, 321
Rossetti, 1995, Clin Invest Med, 18, 255

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Ciaraldi, T. P. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-179-6_26 · Cited by 12
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Wadley, G. D., Bruce, C. R., Konstantopoulos, N., Macaulay, S. L., Howlett, K. F., Hawley, J. A., & Cameron‐Smith, D. (2004) · Diabetologia · doi:10.1007/s00125-003-1322-2 · Cited by 12
“After insulin binding, the insulin receptor (IR) undergoes autophosphorylation of tyrosine residues, stimulating its kinase activity and association of the adaptor proteins insulin receptor substrate (IRS)-1, IRS-2 and the Grb2-associated protein, which themselves are tyrosine-phosphorylated by the receptor [3, 4].”
Background
Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity
Merino, D. F. B., Coope, A., Caricilli, A. M., Prada, P. O., Saad, M. J. A., Velloso, L. A., & ARAUJO, E. P. D. (2013) · Journal of Endocrinology · doi:10.1530/joe-12-0562 · Cited by 11
Insulin Inhibits the Expression of Adiponectin and AdipoR2 mRNA in Cultured Bovine Adipocytes
Sun, Y. G., Zan, L., Wang, H. B., Guo, H., Yang, D.-C., Zhao, X. L., & Gui, L. (2009) · Asian-Australasian Journal of Animal Sciences · doi:10.5713/ajas.2009.90159 · Cited by 11
“Thus, it has been shown that the activated phosphorylated insulin receptor binds and phosphorylates insulin receptor substrate proteins and Shc, which in turn bind differentially to various downstream signaling proteins (Virkamaki et al., 1999).”
Background
Retinol binding protein 4 mediates MEHP-induced glucometabolic abnormalities in HepG2 cells
Wang, F., Chang, C. H., Li, R., Zhang, Z., Jiang, H., Zeng, N., Li, D., Chen, L., Xiao, Y., Chen, W. L., et al. (2019) · Toxicology · doi:10.1016/j.tox.2019.06.007 · Cited by 11
A novel non-alcoholic steatohepatitis animal model featured with insulin resistance, hepatic inflammation and fibrosis
Zhao, J., Zhou, G., Li, M., Li, W., Lü, J., Xiong, L. J., Liang, L., Zhao, Y., Xu, D., & Yu, J. Q. (2010) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2010.497938 · Cited by 11
“The liver and adipose tissues are not only end organs for the effects of IR, but they are also important regulators of carbohydrate and lipid homeostasis which are under the control of insulin signaling [25].”
Background
The effect of α- or β-casein addition to waxy maize starch on postprandial levels of glucose, insulin, and incretin hormones in pigs as a model for humans
Kett, A. P., Bruen, C. M., O’Halloran, F., Chaurin, V., Lawlor, P. G., O’Mahony, J. A., Giblin, L., & Fenelon, M. A. (2012) · Food & Nutrition Research · doi:10.3402/fnr.v56i0.7989 · Cited by 11
“Hyperinsulinemia can reduce insulin efficiency via downregulation of insulin receptors, resulting in insulin resistance (4) which, in addition to impaired pancreatic b-cell function, is a risk factor for type II diabetes (5).”
Background
The glucose-induced synthesis of insulin in liver
Ghosh, R., Karmohapatra, S. K., Bhattacharya, G., & Sinha, A. (2010) · Endocrine · doi:10.1007/s12020-010-9388-3 · Cited by 11
“Treatment of muscle cell suspension [14], well known target cells for insulin effect [15], with glucose under identical conditions failed to show the presence of insulin in the supernatant (Fig.”
Background
Pathogenesis of Type 2 Diabetes Mellitus
DeFronzo, R. A. (2018) · Endocrinology · doi:10.1007/978-3-319-27317-4_8-1 · Cited by 11
Insulin-Mediated Cellular Insulin Resistance Decreases Osmotic Shock-Induced Glucose Transport in 3T3-L1 Adipocytes
Janež, A., Worrall, D. S., & Olefsky, J. M. (2000) · Endocrinology · doi:10.1210/endo.141.12.7801 · Cited by 11
The Gordon Wilson Lecture. Lessons about the control of glucose homeostasis and the pathogenesis of diabetes from knockout mice.
Kahn, C. R. (2003) · PubMed Central · Cited by 11
Self-citation
An Artificial Intelligence Prediction Model of Insulin Sensitivity, Insulin Resistance, and Diabetes Using Genes Obtained through Differential Expression
González-Martín, J. M., Torres-Mata, L. B., Cazorla-Rivero, S., Fernández-Santana, C., Gómez-Bentolila, E., Clavo, B., & Rodríguez‐Esparragón, F. (2023) · Genes · doi:10.3390/genes14122119 · Cited by 10
“These diverse actions are initiated by speciﬁc binding to high-afﬁnity receptors on the plasma membrane of target cells [6,7], which then activate both a metabolic signaling pathway through PI-3 kinase and a mitogenic pathway through Ras/MAPK cascade.”
Background
Skeletal muscle–derived cell cultures as potent models in regenerative medicine research
Kelc, R., Trapečar, M., Vogrin, M., & Čenčič, A. (2012) · Muscle & Nerve · doi:10.1002/mus.23688 · Cited by 10
“As such, these tissues have been used in studies of genetic muscule diseases(10) and cardiac grafting,(11) in microgravity experiments to study the effects of low-gravity environments on muscles,(12) and, as major target cells of insulin action, in studies on their role in diabetes mellitus.(13,14) In recent years, sk…”
Method
Oxidative Stress in Type 2 Diabetes Mellitus
Abdul‐Ghani, M. A., & DeFronzo, R. A. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-420-9_11 · Cited by 10
“In muscle, IRS-1 serves as the major docking protein that interacts with the insulin receptor tyrosine kinase and undergoes tyrosine phosphorylation in regions containing amino acid sequence motifs (YXXM or YMXM) that, when phosphorylated, serve as recognition sites for proteins containing src-homology 2 (SH2) domains…”
Background
Topology Mapping of Insulin-Regulated Glucose Transporter GLUT4 Using Computational Biology
Chakraborty, C., Bandyopadhyay, S., Maulik, U., & Agoramoorthy, G. (2013) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-013-9644-2 · Cited by 10
Electrochemically monitoring the binding of concanavalin A and ovalbumin
Sugawara, K., Yugami, A., Kadoya, T., & Hosaka, K. (2011) · Talanta · doi:10.1016/j.talanta.2011.04.003 · Cited by 10
Single nucleotide polymorphisms on SHIP2 is associated with Type 2 diabetes mellitus in Chinese Han population.
Ym, H., Qj, L., Ry, W., Cao, Y.-P., Zhang, Y., & Lf, Z. (2015) · PubMed · Cited by 10
Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice
Sundaresan, A., Radhiga, T., & Pugalendi, K. V. (2016) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-016-0484-6 · Cited by 11
“Insulin resistance is a central feature of many physiological and pathological states and can be the result of a wide variety of biochemical defects in the insulin action cascade [38].”
Background
Dominant Negative α-Subunit of FTase Inhibits Effects of Insulin and IGF-I in MCF-7 Cells
Solomon, C. S., & Goalstone, M. L. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6471 · Cited by 10
Insulin Receptor Antibodies Inhibit Insulin Uptake by the Liver: In Vivo 123 I-Insulin Scintigraphic Scanning and in Vitro Characterization in Autoimmune Hypoglycemia
Dozio, N., Sarugeri, E., Scavini, M., Beretta, A., Belloni, C., Dosio, F., Savi, A., Fazio, F., Sodoyez‐Goffaux, F., & Pozza, G. (2001) · Journal of Investigative Medicine · doi:10.2310/6650.2001.34094 · Cited by 10
Looking for an insulin pill? Use the BRET methodology!
Issad, T., Boute, N., Boubekeur, S., Lacasa, D., & Siquier-Pernet, K. (2003) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70016-2 · Cited by 10
“This stimulates the tyrosine kinase activity of the receptor towards intracellular substrates that play crucial roles in the transmission of the signal [2-4].”
Background
Adeno-associated virus-mediated expression of myostatin propeptide improves the growth of skeletal muscle and attenuates hyperglycemia in db/db mice
Jiang, J. G., Shen, G. F., Li, J., Qiao, C., Xiao, B., Yan, H. M., Wang, D. W., & Xiao, X. (2016) · Gene Therapy · doi:10.1038/gt.2016.85 · Cited by 9
CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation
Benedet, P. O., Safikhan, N., Pereira, M. J., Lum, B. M., Botezelli, J. D., Kuo, C., Wu, H., Craddock, B. P., Miller, W. T., Eriksson, J. W., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104906 · Cited by 9
“,61 – 66 These are located in the cell or cell membrane, where they variably modulate IR activity and insulin sensitivity.”
Background
Syndromes of Extreme Insulin Resistance
Grunberger, G., & Alfonso, B. (2009) · Springer eBooks · doi:10.1007/978-0-387-09841-8_17 · Cited by 9
Molecular Basis of Insulin Resistance and Its Relation to Metabolic Syndrome
Arora, S. (2012) · InTech eBooks · doi:10.5772/50337 · Cited by 9
Differential subcellular localization of insulin receptor substrates depends on C-terminal regions and importin β
Kabuta, T., Take, K., Kabuta, C., Hakuno, F., & Takahashi, S. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.09.106 · Cited by 9
“Activation of the downstream signaling pathways triggered by these molecules has been reported to mediate the various biological effects of insulin and IGF, such as metabolic regulation, and induction of cell growth or differentiation [4].”
Background
PTPase inhibition restores ERK1/2 phosphorylation and protects mammary epithelial cells from apoptosis
Furlong, F. M., Finlay, D., & Martin, F. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.260 · Cited by 9
Association of the ADIPOQ T45G polymorphism with insulin resistance and blood glucose: A meta-analysis
Cao, D., Ouyang, S., Liu, Z., Ma, F., & Wu, J. (2014) · Endocrine Journal · doi:10.1507/endocrj.ej13-0444 · Cited by 9
“In recent years, numerous studies have revealed abundant information about the molecular mechanism of IR [3, 4].”
Modulation of Growth Factor Receptors in Membrane Microdomains
Inokuchi, J., & Kabayama, K. (2008) · Trends in Glycoscience and Glycotechnology · doi:10.4052/tigg.20.353 · Cited by 9
Insulin Signaling in Adipocytes Differentiated from Mouse Stromal MC3T3-G2/PA6 Cells
Morito, S., Yaguchi, K., Imada, M., Tachikawa, C., Nomura, M., Moritani, S., Igarashi, M., Yokogawa, K., & Miyamoto, K. (2005) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.28.2040 · Cited by 9
Secretion of atherogenic risk factor apolipoprotein B‐100 is increased by a potential mechanism of JNK/PKC‐mediated insulin resistance in liver cells
Jin, U., Kang, Y., Chang, Y., & Kim, C. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21462 · Cited by 9
“These events lead to activation of multiple signaling pathways including glucose uptake, glycogen synthesis, mitogenesis, or gene expression [Virkamaki et al., 1999; Pederson et al., 2001; Jiang et al., 2004].”
Background
Inhibition of Phosphatidylinositol-3-kinase Enhances Insulin Stimulation of Insulin Receptor Substrate 1 Tyrosine Phosphorylation and Extracellular Signal-Regulated Kinases in Mouse R − Fibroblasts
Choi, W. S., & Sung, C. K. (2004) · Journal of Receptors and Signal Transduction · doi:10.1081/rrs-120034229 · Cited by 9
“Phosphatidylinositol-3-kinase (PI3K) is a crucial enzyme implicated in many biological functions of insulin in cells including glucose transport, glycogen synthesis, protein synthesis and mitogenesis (1,2).”
BackgroundInfluential
Insulin-sensitising agents: beyond thiazolidinediones
Petrie, J. R., & Perry, C. G. (2002) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.7.1.165 · Cited by 9
Mechanisms of Insulin Signal Transduction
Garvey, W. T. (2004) · Wiley eBooks · doi:10.1002/0470862092.d0301 · Cited by 10
Cloning of the Mouse Insulin Receptor Substrate-3 (mIRS-3) Promoter, and Its Regulation by p53
Sciacchitano, S., Orecchio, A., Lavra, L., Misiti, S., Giacchini, A., Zani, M., Danese, D., Gurtner, A., Soddu, S., Mario, U. D., et al. (2002) · Molecular Endocrinology · doi:10.1210/me.16.7.1577 · Cited by 9
Associations of INPPL1 (+1893CC/AA and + 2945AA/GG) exonic polymorphisms with the risk of type 2 diabetes mellitus in North Indian population: A case control study
Singh, J., Kumar, V., Bala, K., Aneja, A., & Singh, J. (2021) · Meta Gene · doi:10.1016/j.mgene.2021.100929 · Cited by 8
Computational Evaluation of Phytocompounds From Selective Medicinal Plants as Potential Antidiabetic Agents
Kumar, V., Sharma, N., Mishra, V. K., Mall, S., Kumar, A., Dev, K., & Patel, C. (2025) · Chemistry & Biodiversity · doi:10.1002/cbdv.202403368 · Cited by 9
Nano Chromium Picolinate Improves Gene Expression Associated with Insulin Signaling in Porcine Skeletal Muscle and Adipose Tissue
Hung, A., Leury, B. J., Sabin, M. A., Fahri, F., DiGiacomo, K., Lien, T., & Dunshea, F. R. (2020) · Animals · doi:10.3390/ani10091685 · Cited by 8
“Serine phosphorylation of IRS1 can decrease IRS1 activity, due to conformational changes, causing IRS1 to be unable to associate with IR [37].”
Background
Effects of pulsatile secretion of growth hormone (GH) on fat deposition in human GH transgenic rats
Furuhata, Y., Nishihara, M., & Takahashi, M. (2002) · Nutrition Research Reviews · doi:10.1079/nrr200243 · Cited by 8
“In addition, the studies of GHD subjects have shown increased fat accumulation, which is one of the major risk factors for developing non-insulindependent diabetes mellitus (NIDDM) with insulin resistance (Kopelman, 2000); insulin resistance can occur in the state of GH deficiency.”
BackgroundInfluential
Proteomics and Precision Medicine
Ding, C., Qin, Z., Li, Y., Shi, W., Li, L., Zhan, D., & Yang, W. (2019) · Small Methods · doi:10.1002/smtd.201900075 · Cited by 9
Effects of artemisinin and TSP-1-human endometrial-derived stem cells on a streptozocin-induced model of Alzheimer’s disease and diabetes in Wistar rats
Poorgholam, P., Yaghmaei, P., Noureddini, M., & Zahra, H. (2021) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2021-013 · Cited by 8
Preoperative feeding does not reverse postoperative insulin resistance in skeletal muscle in the rat
Strömmer, L., Isaksson, B., Arnelo, U., Lundkvist, I., Östenson, C., Wickbom, M., Herrington, M. K., & Permert, J. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80013-x · Cited by 8

Authors: Virkamäki, A., Ueki, K., & Kahn, C. R.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: Kahn, C. Ronald
ORCID: Ueki, Kohjiro
Kahn, C. Ronald
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-04-01
Volume: 103
Issue: 7
Pages: 931-943
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci6609
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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Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

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