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Insulin Signaling in Health and Disease
Abstract
The signaling pathways used by insulin have been identified [M. White, Insulin Signaling Pathway, Sci. STKE (Connections Map, as seen November 2003), http://stke.sciencemag.org/cgi/cm/cmp_12069]. Now our challenge is to understand how the failure of these signals is associated with obesity and the progressive failure of pancreatic beta cells that leads to diabetes. Whether better management of chronic inflammation can improve insulin action is an important area of investigation. Drugs that stimulate IRS2 (insulin receptor substrate protein 2) synthesis or signaling might be a good starting point. This knowledge will lead to rational strategies that prevent or cure diabetes.
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“Physiologically, IRS-1 is phosphorylated at tyrosine residues by the tyrosine kinase activity of the IR, which activates downstream signaling in the insulin pathway (Araki et al., 1994; White, 2003).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as White, 2003
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“On the other hand, inhibitory serine phosphorylation (pSer) of IRS-1 and IRS-2, the best studied components of the IRS family, causes their dissociation from the IR and decreases tyrosine phosphorylation (pTyr) (60).”
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“The interaction with insulin induces autophosphorylation of the receptor and the recruitment and phosphorylation of insulin receptor substrate (IRS) proteins and activation of associated downstream signalling cascades, for example, phsosphatidylinositol-3-kinase (PI3K) and protein kinase B (Akt) [14, 15].”
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“Erk1/2 MAPK signaling pathway stimulates cell proliferation and suppresses differentia transduction cascades, including the phosphatidylinositol 3-kinase (PI3K)-Akt cascade and the Raf-Mek-Erk1/2 cascade (Dupont and LeRoith, 2001; White, 2003), through the adaptor molecules.”
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“Depending upon the tissue site, dysregulation of these heterologous signaling mechanisms can progress to glucose intolerance, hyperinsulinemia, dysregulated lipid metabolism, and insulin resistance (White 2003).”
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“Interaction with insulin fosters the autophosphorylation of the receptor with the phosphorylation and recruitment of insulin receptor substrate (IRS) proteins and the stimulation of other related downstream signaling cascades, such as protein kinase B (Akt) and phosphatidylinositol-3-kinase (PI3K) [184].”
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Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
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“Published by Elsevier Inc of the IR tyrosine kinase.(1) Insulin receptor substrates (IRSs) 1 to 4, as well as other cellular proteins, are targeted for phosphorylation by the activated IR.”
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BackgroundInsulin-Like Effects of Visfatin on Human Osteoblasts
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Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
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Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes
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“Second messenger pathways affected by the IRS proteins include phosphatidylinositol 3-kinase, GRB2, NCK, CRK, fyn, SHB, SOCS1, SOCS3, and SHP2 (7).”
BackgroundChapter 21 Interleukin‐6 and Insulin Resistance
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“Subsequent phosphorylation of IRS by IR initiates the assembly and activation of downstream signaling pathways (White, 2003).”
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“It is well know that proinflammatory cytokines, such as IL-1β can compromise insulin/IGF-1 signaling in a variety of peripheral tissues [65, 78, 81], a condition referred to as “insulin resistance”.”
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“Although different ligand binding affinity and selectivity have been reported for insulin receptors, the physiological significance of the splice variance, post-translational modification and homo- or heterodimerization between different insulin receptors and IGF-1 receptor remain largely unknown (Figure 3B) [86,93].”
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“pathways such as the phosphatidylinositol 3 kinase (PI3 kinase) and the mitogen-activated protein kinase (MAPK) cascades [11] (Fig.”
BackgroundExendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function
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“FOXO1 is activated in the fasted state to promote gluconeogenesis in the liver, but in postprandial state hepatic FOXO1 is inhibited by insulin, which facilitates gene expression that drives the metabolism of glucose to acetate for oxidation or conversion into fatty acids (25, 117).”
BackgroundResistin- and Obesity-associated Metabolic Diseases
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“B [21] or Jun-kinase [22] , in part via serine phosphorylation of the Insulin Receptor Substrates 1 and 2 [23] .”
Rojas-Gutierrez, E., Muñoz‐Arenas, G., Treviño, S., Espinosa, B., Chávez, R., Rojas, K., Flores, G., Díaz, A., & Guevara, J. (2017) · Synapse · doi:10.1002/syn.21990 · Cited by 205
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Das, D., & Arur, S. (2017) · Molecular Reproduction and Development · doi:10.1002/mrd.22806 · Cited by 183
“Additionally, insulin receptor substrates—PI3K, AKT, and RAS-ERK—are all regulated downstream of insulin signaling inmammals (Belfiore et al., 2009;Taguchi&White, 2008; Taniguchi et al., 2006;White, 2003),Drosophila (Badisco, Wielendaele, &”
BackgroundMartin, B., Golden, E., Carlson, O. D., Pistell, P. J., Zhou, J., Kim, W., Frank, B. P., Thomas, S., Chadwick, W., Greig, N. H., et al. (2008) · Diabetes · doi:10.2337/db08-0799 · Cited by 181
“Defective insulin receptor substrate (IRS)/PI3K signaling is implicated in insulin resistance in peripheral tissues (40) and presumably may be causing neuronal/ hypothalamic insulin resistance in HD patients.”
BackgroundBarone, E., Domenico, F. D., Marzia Perluigi, A., & Butterfield, D. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 182
cJun NH2-terminal kinase 1 (JNK1): Roles in metabolic regulation of insulin resistance
Sabio, G., & Davis, R. J. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.004 · Cited by 170
“Indeed, obesity causes chronic low-grade inflammatory responses that lead to activation of stress pathways (including the cJun NH2terminal kinase JNK1) that play critical roles in the etiology of obesity-induced insulin resistance [4–7].”
BackgroundTejada, T., Catanuto, P., Ijaz, A., Santos, J. V., Xia, X., Sanchez, P., Sanabria, N. Y., Lenz, O., Elliot, S. J., & Fornoni, A. (2008) · Kidney International · doi:10.1038/ki.2008.109 · Cited by 170
A causal role for hyperinsulinemia in obesity
Templeman, N. M., Skovsø, S., Page, M. M., Lim, G. E., & Johnson, J. D. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0449 · Cited by 168
Craft, S. (2006) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000213866.86934.7e · Cited by 167
Qi, Y., Xu, Z., Zhu, Q., Thomas, C., Kumar, R., Feng, H., Dostal, D. E., White, M. F., Baker, K. M., & Guo, S. (2013) · Diabetes · doi:10.2337/db13-0095 · Cited by 167
“Activation of PI-3K generates phosphatidylinositol(3-5)triphosphate (PIP3), recruiting the 3-phosphoinositide– dependent protein kinase-1 and -2 (PDK1 and PDK2) and Akt to the plasma membrane, where Akt is activated by PDK1-mediated phosphorylation at T(308) and PDK2-mediated phosphorylation at S(473) (7,8).”
BackgroundWhite, M. F. (2006) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y06-008 · Cited by 164
Esposito, D., Damsud, T., Wilson, M., Grace, M. H., Strauch, R. C., Li, X., Lila, M. A., & Komarnytsky, S. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b00963 · Cited by 163
Insulin resistance induced by tumor necrosis factor-α in myocytes and brown adipocytes12
Lorenzo, M., Fernández‐Veledo, S., Vila‐Bedmar, R., García‐Guerra, L., de Álvaro, C., & Nieto-Vázquez, I. (2007) · Journal of Animal Science · doi:10.2527/jas.2007-0462 · Cited by 161
Bergan‐Roller, H. E., & Sheridan, M. A. (2017) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2017.07.028 · Cited by 160
Guo, S., Copps, K. D., Dong, X. C., Park, S., Cheng, Z., Pocai, A., Rossetti, L., Sajan, M. P., Farese, R. V., & White, M. F. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00138-09 · Cited by 152
“Insulin regulates systemic metabolism by activating the insulin receptor tyrosine kinase, resulting in the activation of pathways that coordinate metabolic flux, cellular growth, and survival (42, 43).”
BackgroundThe Paradox of Akt-mTOR Interactions
Vadlakonda, L., Dash, A., Pasupuleti, M., Kumar, K. A., & Reddanna, P. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00165 · Cited by 156
“org/cgi/cm/CMP_12069?cookietest=yes) (White, 2003).”
BackgroundToll-like receptors, inflammation, metabolism and obesity
Fresno, M., Álvarez, R., & Cuesta, N. (2011) · Archives of Physiology and Biochemistry · doi:10.3109/13813455.2011.562514 · Cited by 150
Central Nervous System Regulation of Food Intake
Schwartz, M. W. (2006) · Obesity · doi:10.1038/oby.2006.275 · Cited by 150
“Moreover, impaired signal transduction through the IRS-PI3K mechanism is implicated in the pathogenesis of insulin resistance in common metabolic disorders such as obesity and type 2 diabetes (49,50).”
BackgroundInfluentialInsulin/IGF signaling drives cell proliferation in part via Yorkie/YAP
Straßburger, K., Tiebe, M., Pinna, F., Breuhahn, K., & Teleman, A. A. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.05.008 · Cited by 150
Diabetic cardiomyopathy: mechanisms and therapeutic targets
Battiprolu, P. K., Gillette, T. G., Wang, Z. V., Lavandero, S., & Hill, J. A. (2010) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2010.08.001 · Cited by 144
Slattery, M. L., Sweeney, C., Edwards, S. L., Herrick, J. S., Baumgartner, K. B., Wolff, R. K., Murtaugh, M. A., Baumgartner, R., Giuliano, A. R., & Byers, T. (2006) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9292-y · Cited by 138
“Adipose tissue is involved in production of cytokines, key elements in inflammation signaling [31, 32]; chronic inflammation is seen as being a key element in insulin-induced obesity [33, 34].”
BackgroundInsulin receptor endocytosis in the pathophysiology of insulin resistance
Hall, C., Yu, H., & Choi, E. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0456-3 · Cited by 149
Insulin receptor substrate proteins and diabetes
Lee, Y. H., & White, M. F. (2004) · Archives of Pharmacal Research · doi:10.1007/bf02980074 · Cited by 136
Insulin dysfunction and Tau pathology
Khoury, N. B. E., Gratuze, M., Papon, M.-A., Bretteville, A., & Planel, E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00022 · Cited by 133
“Muscle biopsies of insulin resistant subjects revealed a reduction in the enzymatic activity and phosphorylation state of kinases and substrates involved in the IR signaling pathway (for review, see Schulingkamp et al., 2000; White, 2003; Pirola et al., 2004; Youngren, 2007).”
BackgroundHaj, F. G., Zabolotny, J. M., Kim, Y., Kahn, B. B., & Neel, B. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413240200 · Cited by 132
Solomon, S. S., Majumdar, G., Martinez-Hernandez, A., & Raghow, R. (2008) · Life Sciences · doi:10.1016/j.lfs.2008.06.024 · Cited by 132
MicroRNAs in Metabolism and Metabolic DiseasesPreprint
Rottiers, V., Najafi-Shoushtari, S. H., Kristo, F., Gurumurthy, S., Zhong, L., Li, Y., Cohen, D. E., Gerszten, R. E., Bardeesy, N. M., Mostoslavsky, R., et al. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011049 · Cited by 124
Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination
Papaconstantinou, J. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.025 · Cited by 127
Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3
Clodfelder‐Miller, B., Sarno, P. D., Zmijewska, A. A., Song, L., & Jope, R. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508824200 · Cited by 128
Broussard, S. R., McCusker, R. H., NOVAKOFSKI, J. E., Strle, K., Shen, W. H., Johnson, R. W., Dantzer, R., & Kelley, K. W. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.12.7713 · Cited by 123
“candidate for augmenting insulin action in type 2 diabetes (59).”
Background
Metadata
- Authors
- White, M. F.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- White, Morris F.
- ORCID
- White, Morris F.
- Venue
- Science
- Published
- 2003-12-05
- Volume
- 302
- Issue
- 5651
- Pages
- 1710-1711
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2115177689
- Cited by
- 733
- References
- 19
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 13 · 2023: 21 · 2022: 24 · 2021: 35 · 2020: 32 · 2019: 30 · 2018: 36 · 2017: 35 · 2016: 39 · 2015: 47 · 2014: 35 · 2013: 39 · 2012: 50
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin signaling, insulin resistance, obesity, type 2 diabetes, pancreatic beta-cell failure, chronic inflammation, insulin receptor substrate 2
- MeSH terms
- Animals, Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Humans, Inflammation, Insulin, Insulin Resistance, Islets of Langerhans, Models, Biological, Obesity, Phosphoproteins, Phosphorylation, Receptor, Insulin, Somatomedins, Signal Transduction, Cytokines, Intracellular Signaling Peptides and Proteins, Mice, Insulin Receptor Substrate Proteins
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