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Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle
Open accessAbstract
Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.
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“Lipid accumulation in skeletal muscle (7) or metabolic overload in mitochondria (8) have also been shown to occur with IR”
From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [7]
In the citing paper
“Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [64]
In the citing paper
“It is well established that chronically elevated plasma FFA levels cause insulin resistance in skeletal muscle [1, 12, 14, 62–65].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [64]
In the citing paper
“Rodent and human studies have suggested increased serine phosphorylation of IRS-1 in insulin resistant states [111, 171–173].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [173]
In the citing paper
“GLUT4, the insulin regulatable transporter, is found in skeletal muscle, has a Km of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [173, 174].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [173]
In the citing paper
“While increased levels of fatty acyl-CoA in general are associated with IR and in C18:2-CoA accumulation is a potential indicator of IR [115,117].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [117]
In the citing paper
“In particular, an overabundance of SFA (e.g., Palmitate) can induce IR through the accumulation of lipid derivatives including DAGs, ceramides and long chain acyl-CoAs in the cytosol, which in turn can interfere with IRS1-PKB signalling [113,114,115,116,117,118].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [117]
In the citing paper
“In contrast, decreasing fatty acid flux in humans via pharmacological inhibition of lipolysis (49) or by discontinuing a lipid-plus-heparin infusion in rats (58) decreases IMTG concentration and/or the accumulation of fatty acid intermediates.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [58]
In the citing paper
“Accordingly, increasing fatty acid flux via a lipid-plus-heparin infusion in humans (23,46) or rodents (58) results in a corresponding increase in the concentration of IMTG and/or fatty acid intermediates.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [58]
In the citing paper
“Adipose tissue in obese people is insulin resistant, which raises nonesterified fatty acid levels, worsening insulin resistance in muscle 29,33 and altering hepatic metabolism 31 ;”
From Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (2005) · cites this paper as [33]
In the citing paper
“This disconnection between intramyocellular triglyceride and peripheral insulin action confirms that intra myocellular triglyceride is only a crude marker for the active metabolite (putatively diacylglycerol) that causes fat-induced insulin resistance.38”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [38]
In the citing paper
“Increased tissue lipid load, as with obesity, and/or sustained inactivity, may lead to the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action (96 -102).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [100]
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Citations
Cites
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963) · The Lancet · doi:10.1016/s0140-6736(63)91500-9 · Cited by 5,093
Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F., & Spiegelman, B. M. (1996) · Science · doi:10.1126/science.271.5249.665 · Cited by 2,630
Self-citationMechanism of free fatty acid-induced insulin resistance in humans.
Roden, M., Price, T. B., Perseghin, G., Petersen, K. F., Rothman, D. L., Cline, G. W., & Shulman, G. I. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118742 · Cited by 1,539
Self-citationAguirre, V., Uchida, T., Yenush, L., Davis, R., & White, M. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.9047 · Cited by 1,487
Self-citationDresner, A., Laurent, D., Marcucci, M., Griffin, M. E., Dufour, S., Cline, G. W., Slezak, L. A., Andersen, D. K., Hundal, R. S., Rothman, D. L., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5001 · Cited by 1,311
Self-citationGriffin, M. E., Marcucci, M. J., Cline, G. W., Bell, K., Barucci, N., Lee, D., Goodyear, L. J., Kraegen, E. W., White, M. F., & Shulman, G. I. (1999) · Diabetes · doi:10.2337/diabetes.48.6.1270 · Cited by 1,267
Self-citationKrssak, M., Falk Petersen, K., Dresner, A., DiPietro, L., Vogel, S. M., Rothman, D. L., Shulman, G. I., & Roden, M. (1999) · Diabetologia · doi:10.1007/s001250051123 · Cited by 1,264
Self-citationSkeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diab.46.6.983 · Cited by 1,179
Skeletal muscle triglyceride levels are inversely related to insulin action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diabetes.46.6.983 · Cited by 1,179
Storlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe, W. S., Khouri, S., & Kraegen, E. W. (1991) · Diabetes · doi:10.2337/diab.40.2.280 · Cited by 967
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Laybutt, 1999, Am. J. Physiol., 277, E1070
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Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., Gordon, D. J., Krauss, R. M., Savage, P. J., Smith, S. C., et al. (2005) · Circulation · doi:10.1161/circulationaha.105.169404 · Cited by 11,961
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199
Xu, H., Barnes, G. T., Yang, Q., Tan, G., Yang, D., Chou, C. J., Sole, J., Nichols, A., Ross, J. S., Tartaglia, L. A., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319451 · Cited by 6,760
Inflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143
DeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
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
Self-citationDeFronzo, 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
Self-citationInflammation, metaflammation and immunometabolic disorders
Hotamisligil, G. S. (2017) · Nature · doi:10.1038/nature21363 · Cited by 2,570
Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.
Guilherme, A., Virbasius, J. V., Puri, V., & Czech, M. P. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2391 · Cited by 2,292
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
Self-citationImpaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193
Self-citationMitochondrial dysfunction in the elderly: possible role in insulin resistance
Petersen, K. F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D. L., DiPietro, L., Cline, G. W., & Shulman, G. I. (2003) · Science · doi:10.1126/science.1082889 · Cited by 2,107
Self-citationMitochondrial dysfunction and type 2 diabetes
Lowell, B. B., & Shulman, G. I. (2005) · Science · doi:10.1126/science.1104343 · Cited by 2,070
Self-citationKoves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990
Stanhope, K. L., Schwarz, J. M., Keim, N. L., Griffen, S. C., Bremer, A. A., Graham, J. L., Hatcher, B., Cox, C. L., Dyachenko, A., Zhang, W., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37385 · Cited by 1,765
Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation
Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., & Staels, B. (2009) · Physiological Reviews · doi:10.1152/physrev.00010.2008 · Cited by 1,678
PPARs and the complex journey to obesity
Evans, R. M., Barish, G. D., & Wang, Y.-X. (2004) · Nature Medicine · doi:10.1038/nm1025 · Cited by 1,650
Self-citationAdipose 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
Chait, A., & den Hartigh, L. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00022 · Cited by 1,529
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484
Self-citationvan der Veen, J. N., Kennelly, J. P., Wan, S., Vance, J. E., Vance, D. E., & Jacobs, R. L. (2017) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2017.04.006 · Cited by 1,514
Insulin Receptor Signaling in Normal and Insulin-Resistant StatesPreprint
Boucher, J., Kleinridders, A., & Kahn, C. R. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009191 · Cited by 1,550
Pathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationObesity-associated improvements in metabolic profile through expansion of adipose tissue
Kim, J.-Y., van de Wall, E., Laplante, M., Azzara, A., Trujillo, M. E., Hofmann, S. M., Schraw, T., Durand, J. L., Li, H., Li, G., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31021 · Cited by 1,310
Self-citationWymann, M. P., & Schneiter, R. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2335 · Cited by 1,314
The nuts and bolts of AGC protein kinases
Pearce, L. R., Komander, D., & Alessi, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2822 · Cited by 1,294
Holland, W. L., Brozinick, J. T., Wang, L.-P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., Siesky, A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.002 · Cited by 1,232
Insulin sensitivity: Modulation by nutrients and inflammation
Schenk, S., Saberi, M., & Olefsky, J. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34260 · Cited by 1,191
Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis
Rajala, M. W., & Scherer, P. E. (2003) · Endocrinology · doi:10.1210/en.2003-0580 · Cited by 1,204
Lipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189
Self-citationInflammation and insulin resistance
de Luca, C., & Olefsky, J. M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2007.11.057 · Cited by 1,161
Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism
Cao, H., Gerhold, K. A., Mayers, J. R., Wiest, M. M., Watkins, S. M., & Hotamışlıgil, G. S. (2008) · Cell · doi:10.1016/j.cell.2008.07.048 · Cited by 1,174
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease
Shulman, G. I. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1011035 · Cited by 1,126
Self-citationDisordered lipid metabolism and the pathogenesis of insulin resistance.
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2007) · Physiological Reviews · doi:10.1152/physrev.00024.2006 · Cited by 1,107
Self-citationInsulin Resistance: From Mechanisms to Therapeutic Strategies
Lee, S.-H., Park, S., & Choi, C. S. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0280 · Cited by 1,248
Role of Mitochondrial Dysfunction in Insulin Resistance
Kim, J.-A., Wei, Y., & Sowers, J. R. (2008) · Circulation Research · doi:10.1161/circresaha.107.165472 · Cited by 1,103
Self-citationCopps, K. D., & White, M. F. (2012) · Diabetologia · doi:10.1007/s00125-012-2644-8 · Cited by 1,017
“NEFA levels causes insulin resistance in rats, accompanied by elevated muscle IRS1 S307 (hS312) phosphorylation [146].”
BackgroundSelf-citationMetabolic Flexibility in Health and Disease
Goodpaster, B. H., & Sparks, L. M. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.015 · Cited by 995
Inflammation and Lipid Signaling in the Etiology of Insulin Resistance
Glass, C. K., & Olefsky, J. M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.001 · Cited by 956
Trends in insulin resistance: insights into mechanisms and therapeutic strategy
Li, M., Chi, X., Wang, Y., Setrerrahmane, S., Xie, W., & Xu, H. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01073-0 · Cited by 939
Self-citationPositive and negative regulation of insulin signaling through IRS-1 phosphorylation
Gual, P., Le Marchand-Brustel, Y., & Tanti, J.-F. (2005) · Biochimie · doi:10.1016/j.biochi.2004.10.019 · Cited by 912
Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893
Lipotoxicity: when tissues overeat
Schaffer, J. E. (2003) · Current Opinion in Lipidology · doi:10.1097/00041433-200306000-00008 · Cited by 933
Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease
Mehlem, A., Hagberg, C. E., Muhl, L., Eriksson, U., & Falkevall, A. (2013) · Nature Protocols · doi:10.1038/nprot.2013.055 · Cited by 918
Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin
Holland, W. L., Miller, R. A., Wang, Z. V., Sun, K., Barth, B. M., Bui, H. H., Davis, K. E., Bikman, B. T., Halberg, N., Rutkowski, J. M., et al. (2011) · Nature Medicine · doi:10.1038/nm.2277 · Cited by 892
DeFronzo, R. A. (2010) · Diabetologia · doi:10.1007/s00125-010-1684-1 · Cited by 908
Morino, K., Petersen, K. F., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/db06-s002 · Cited by 853
Self-citationBoden, G. H. (2008) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2008.06.007 · Cited by 852
Obesity, insulin resistance and free fatty acids
Boden, G. (2011) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3283444b09 · Cited by 848
Ceramides in insulin resistance and lipotoxicity
Summers, S. A. (2005) · Progress in Lipid Research · doi:10.1016/j.plipres.2005.11.002 · Cited by 866
Adiels, M., Olofsson, S.-O., Taskinen, M.-R., & Borén, J. (2008) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.107.160192 · Cited by 820
Bonnard, C., Durand, A., Peyrol, S., Chanseaume, E., Chauvin, M.-A., Morio, B., Vidal, H., & Rieusset, J. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32601 · Cited by 819
Morino, K. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25151 · Cited by 811
Signaling Pathways in Skeletal Muscle Remodeling
Bassel‐Duby, R., & Olson, E. N. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142622 · Cited by 823
Ramachandran, A., Wan Ma, R. C., & Snehalatha, C. (2010) · The Lancet · doi:10.1016/s0140-6736(09)60937-5 · Cited by 782
Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745
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Self-citationDu, J., Wang, X., Miereles, C., Bailey, J. L., Debigaré, R., Zheng, B., Price, S. R., & Mitch, W. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18330 · Cited by 730
Holland, W. L., Bikman, B. T., Wang, L.-P., Yuguang, G., Sargent, K. M., Bulchand, S., Knotts, T. A., Shui, G., Clegg, D. J., Wenk, M. R., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43378 · Cited by 705
Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)
Musso, G., Gambino, R. J., & Cassader, M. (2008) · Progress in Lipid Research · doi:10.1016/j.plipres.2008.08.001 · Cited by 691
Pathogenesis of insulin resistance in skeletal muscle
Abdul-Ghani, M. A., & DeFronzo, R. A. (2010) · Journal of Biomedicine and Biotechnology · doi:10.1155/2010/476279 · Cited by 670
Ceramide Content Is Increased in Skeletal Muscle From Obese Insulin-Resistant Humans
Adams, J. M., Pratipanawatr, T., Berria, R., Wang, E. L., DeFronzo, R. A., Sullards, M. C., & Mandarino, L. J. (2004) · Diabetes · doi:10.2337/diabetes.53.1.25 · Cited by 677
Metabolites as regulators of insulin sensitivity and metabolism
Yang, Q., Vijayakumar, A., & Kahn, B. B. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0044-8 · Cited by 698
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Goodpaster, B. H., Krishnaswami, S., Harris, T. B., Katsiaras, A., Kritchevsky, S. B., Simonsick, E. M., Nevitt, M., Holvoet, P., & Newman, A. B. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.7.777 · Cited by 637
Chavez, J. A., Knotts, T. A., Wang, L.-P., Li, G., Dobrowsky, R. T., Florant, G. L., & Summers, S. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212307200 · Cited by 617
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Chavez, J. A., & Summers, S. A. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.002 · Cited by 637
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Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615
Phosphorylation of IRS proteins, insulin action, and insulin resistance
Boura-Halfon, S., & Zick, Y. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90437.2008 · Cited by 598
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Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585
Self-citationHolland, W. L., & Summers, S. A. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0025 · Cited by 604
Posey, K. A., Clegg, D. J., Printz, R. L., Byun, J., Morton, G. J., Vivekanandan-Giri, A., Pennathur, S., Baskin, D. G., Heinecke, J. W., Woods, S. C., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90377.2008 · Cited by 586
A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila
Musselman, L. P., Fink, J. L., Narzinski, K., Ramachandran, P. V., Hathiramani, S. S., Cagan, R. L., & Baranski, T. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.007948 · Cited by 564
Adipokines as novel biomarkers and regulators of the metabolic syndrome
Deng, Y., & Scherer, P. E. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05875.x · Cited by 578
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Cariou, B., van Harmelen, K., Durán-Sandoval, D., van Dijk, T. H., Grefhorst, A., Abdelkarim, M., Caron, S., Torpier, G., Fruchart, J., Gonzalez, F. J., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510258200 · Cited by 546
Combs, T. P., Pajvani, U. B., Berg, A. H., Lin, Y., Jelicks, L. A., Laplante, M., Nawrocki, A. R., Rajala, M. W., Parlow, A. F., Cheeseboro, L., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1068 · Cited by 545
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Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551
Emerging role of adipose tissue hypoxia in obesity and insulin resistance
Ye, J. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.229 · Cited by 556
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Matsuzaka, T., Shimano, H., Yahagi, N., Kato, T., Atsumi, A., Yamamoto, T., Inoue, N., Ishikawa, M., Okada, S., Ishigaki, N., et al. (2007) · Nature Medicine · doi:10.1038/nm1662 · Cited by 557
Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α
Ruan, H., & Lodish, H. F. (2003) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(03)00052-2 · Cited by 541
Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Kim, H.-J., Higashimori, T., Park, S.-Y., Choi, H., Dong, J., Kim, Y.-J., Noh, H.-L., Cho, Y.-R., Cline, G., Kim, Y.-B., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1060 · Cited by 534
Self-citationObesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association
Bays, H. E., Toth, P. P., Kris-Etherton, P. M., Abate, N., Aronne, L. J., Brown, W. V., Gonzalez-Campoy, J. M., Jones, S. R., Kumar, R., La Forge, R., et al. (2013) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2013.04.001 · Cited by 521
Kawaguchi, T., Yoshida, T., Harada, M., Hisamoto, T., Nagao, Y., Ide, T., Taniguchi, E., Kumemura, H., Hanada, S., Maeyama, M., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63408-6 · Cited by 534
McArdle, M. A., Finucane, O. M., Connaughton, R. M., McMorrow, A. M., & Roche, H. M. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00052 · Cited by 552
Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance
Kojta, I., Chacińska, M., & Błachnio-Zabielska, A. U. (2020) · Nutrients · doi:10.3390/nu12051305 · Cited by 558
Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., Xiang, X., Luo, Z., & Ruderman, N. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3458 · Cited by 528
Korbecki, J., & Bajdak-Rusinek, K. (2019) · Inflammation Research · doi:10.1007/s00011-019-01273-5 · Cited by 558
Foundations of Immunometabolism and Implications for Metabolic Health and Disease
Hotamışlıgil, G. S. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.009 · Cited by 534
Lipid accumulation in non-adipose tissue and lipotoxicity
van Herpen, N. A., & Schrauwen-Hinderling, V. B. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.11.049 · Cited by 500
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497
Self-citationWeiss, R., Dufour, S., Taksali, S. E., Tamborlane, W. V., Petersen, K. F., Bonadonna, R. C., Boselli, L., Barbetta, G., Allen, K., Rife, F., et al. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14364-4 · Cited by 501
Self-citationInsulin Resistance, Obesity and Lipotoxicity
Yazıcı, D., & Sezer, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_12 · Cited by 525
Diacylglycerol-mediated insulin resistance
Erion, D. M., & Shulman, G. I. (2010) · Nature Medicine · doi:10.1038/nm0410-400 · Cited by 502
Self-citationErtunc, M. E., & Hotamışlıgil, G. S. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r066514 · Cited by 500
Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle
Palacios, O. M., Carmona, J. J., Michan, S., Chen, K. Y., Manabe, Y., III, J. L. W., Goodyear, L. J., & Tong, Q. (2009) · Aging · doi:10.18632/aging.100075 · Cited by 487
Skeletal Muscle Lipid Metabolism in Exercise and Insulin Resistance
Kiens, B. (2006) · Physiological Reviews · doi:10.1152/physrev.00023.2004 · Cited by 478
Boden, G., Duan, X., Homko, C., Molina, E. J., Song, W., Perez, O., Cheung, P., & Merali, S. (2008) · Diabetes · doi:10.2337/db08-0604 · Cited by 468
An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450
Self-citationCurrent views on type 2 diabetes
Lin, Y., & Sun, Z. (2010) · Journal of Endocrinology · doi:10.1677/joe-09-0260 · Cited by 457
Hepatic insulin resistance, metabolic syndrome and cardiovascular disease
Meshkani, R., & Adeli, K. (2009) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2009.05.018 · Cited by 470
Befroy, D. E., Petersen, K. F., Dufour, S., Mason, G. F., de Graaf, R. A., Rothman, D. L., & Shulman, G. I. (2007) · Diabetes · doi:10.2337/db06-0783 · Cited by 453
Self-citation
Metadata
- Authors
- Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., Atcheson, B., White, M. F., Kraegen, E. W., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- Garvan Institute of Medical Research (AU)
- Joslin Diabetes Center (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 277
- Issue
- 52
- Pages
- 50230-50236
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2130850001
- Cited by
- 1,561
- References
- 21
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 36 · 2023: 27 · 2022: 26 · 2021: 47 · 2020: 55 · 2019: 52 · 2018: 56 · 2017: 71 · 2016: 65 · 2015: 65 · 2014: 77 · 2013: 97 · 2012: 101
- FWCI
- 22.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P30 DK, DK-45735)
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- fatty acids, insulin resistance, skeletal muscle, IRS-1, phosphatidylinositol 3-kinase, protein kinase C theta, diacylglycerol, fatty acyl-CoA, IRS-1 serine phosphorylation, IRS-1 tyrosine phosphorylation, glucose transport, lipid emulsions
- MeSH terms
- Animals, Diglycerides, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Insulin, Kinetics, Male, Phosphoproteins, Phosphorylation, Rats, Wistar, Muscle, Skeletal, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Rats, Insulin Receptor Substrate Proteins
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