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 insulin receptor, which activates downstream signaling in the insulin pathway.
“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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“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”.”
BackgroundNutrient regulation of insulin secretion and action
Newsholme, P., Cruzat, V. F., Arfuso, F., & Keane, K. N. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0616 · Cited by 218 · see citing works
“This pathway is related to the glucose transport machinery via migration and activation of protein kinase B (PKB/Akt) and atypical PKC (aPKC) (White 2003).”
BackgroundInsulin receptor signaling in the development of neuronal structure and function
Chiu, S., & Cline, H. T. (2010) · Neural Development · doi:10.1186/1749-8104-5-7 · Cited by 217 · see citing works
“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].”
BackgroundInfluentialControl of energy homeostasis by insulin and leptin: Targeting the arcuate nucleus and beyond
Könner, A. C., Klöckener, T., & Brüning, J. C. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2009.03.027 · Cited by 215 · see citing works
“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
Park, S., Dong, X. C., Fisher, T. L., Dunn, S., Omer, A., Weir, G. C., & White, M. F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508307200 · Cited by 207 · see citing works
Insulin Signal Transduction Perturbations in Insulin Resistance
Khalid, M., Alkaabi, J., Khan, M. A. B., & Adem, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168590 · Cited by 233 · see citing works
“Insulin-mediated glucose uptake and storage under anabolic conditions in insulin-sensitive tissues are facilitated by the recruitment of GLUT to the cell surface, which is governed by distinct signaling pathways and is crucial for insulin sensitivity [25,28].”
BackgroundSlaaby, R., Schäffer, L., Lautrup-Larsen, I., Andersen, A. S., Shaw, A. C., Mathiasen, I. S., & Brandt, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605189200 · Cited by 198 · see citing works
Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models
Cheng, Z., & White, M. F. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3370 · Cited by 194 · see citing works
“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
Lazar, M. A. (2007) · Hormone and Metabolic Research · doi:10.1055/s-2007-985897 · Cited by 195 · see citing works
“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 198 · see citing works
Conserved insulin signaling in the regulation of oocyte growth, development, and maturation
Das, D., & Arur, S. (2017) · Molecular Reproduction and Development · doi:10.1002/mrd.22806 · Cited by 183 · see citing works
“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 · see citing works
“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., Perluigi, M., & Butterfield, D. (2021) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 155 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
Craft, S. (2006) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000213866.86934.7e · Cited by 167 · see citing works
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 · see citing works
“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 163 · see citing works
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 155 · see citing works
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 156 · see citing works
Bergan‐Roller, H. E., & Sheridan, M. A. (2017) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2017.07.028 · Cited by 155 · see citing works
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 150 · see citing works
“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 149 · see citing works
“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 145 · see citing works
Central Nervous System Regulation of Food Intake
Schwartz, M. W. (2006) · Obesity · doi:10.1038/oby.2006.275 · Cited by 146 · see citing works
“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 141 · see citing works
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 139 · see citing works
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 · see citing works
“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 137 · see citing works
Insulin receptor substrate proteins and diabetes
Lee, Y. H., & White, M. F. (2004) · Archives of Pharmacal Research · doi:10.1007/bf02980074 · Cited by 135 · see citing works
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 131 · see citing works
“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 131 · see citing works
Solomon, S. S., Majumdar, G., Martinez-Hernandez, A., & Raghow, R. (2008) · Life Sciences · doi:10.1016/j.lfs.2008.06.024 · Cited by 128 · see citing works
MicroRNAs in metabolism and metabolic diseasesPreprint
Rottiers, V., Najafi-Shoushtari, S. H., Kristo, F., Gurumurthy, S., Zhong, L., Li, Y.-X., Cohen, D. E., Gerszten, R. E., Bardeesy, N., Mostoslavsky, R., et al. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.011049 · Cited by 130 · see citing works
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 124 · see citing works
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 123 · see citing works
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 · see citing works
“candidate for augmenting insulin action in type 2 diabetes (59).”
Background
- 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 › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › 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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