Mechanisms of insulin resistance in obesity
Open accessAbstract
Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.
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Obesity induces insulin resistance, mediated by chronic low-grade inflammation including ER stress, mitochondrial dysfunction, and hyperinsulinemia.
“Obesity induces insulin resistance, mediated by chronic low-grade inflammation including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and hyperinsulinemia secondary to diminished insulin excretion via the kidney and the liver along with increased insulin production resulting from the increased number of pancreatic beta-cells”
Weight loss attenuates or reverses obesity-induced insulin resistance.
“weight loss is reported to attenuate or reverse obesity-induced insulin resistance [48,49]”
Dysfunctional adipose tissue in obesity is associated with hypertrophy and hyperplasia of adipocytes, chronic inflammatory cell infiltration, and activation of the cytokine network, representing the main determinant of insulin resistance and the major risk factor for type 2 diabetes and its complications.
“Dysfunctional adipose tissue in obesity is associated with hypertrophy and hyperplasia of adipocytes, chronic inflammatory cell infiltration, and activation of the cytokine network, representing the main determinant of IR and the major risk factor for the development of T2D and its complications [28].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [28]
Experimental evidence relates lipid metabolism to the pathogenesis of type 2 diabetes via challenged mitochondrial metabolism, altered cellular signaling at the membrane, and modulation of gene expression.
“In the literature, several lines of experimental evidence relate lipid metabolism to the pathogenesis of type 2 diabetes, among them a challenged mitochondrial metabolism, altered cellular signaling processes at the membrane, and modulation of gene expression (34,35).”
From Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes (2015) · cites this paper as [34]
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1 retracted
Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade
Suzawa, M., Takada, I., Yanagisawa, J., Ohtake, F., Ogawa, S., Yamauchi, T., Kadowaki, T., Takeuchi, Y., Shibuyà, H., Gotoh, Y., et al. (2003) · Nature Cell Biology · doi:10.1038/ncb942 · Cited by 292 · see citing works
RetractedObesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
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 · see citing works
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 · see citing works
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
Adipose Tissue as an Endocrine Organ
Kershaw, E. E., & Flier, J. S. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0395 · Cited by 5,522 · see citing works
Increased oxidative stress in obesity and its impact on metabolic syndrome
Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., Nakayama, O., Makishima, M., Matsuda, M., & Shimomura, I. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21625 · Cited by 5,508 · see citing works
Inflammation and insulin resistance
Shoelson, S. E. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29069 · Cited by 4,769 · see citing works
Phosphorylation meets ubiquitination: the control of NF-κB activity
Karin, M., & Ben-Neriah, Y. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.621 · Cited by 4,766 · see citing works
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29881 · Cited by 4,664 · see citing works
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · see citing works
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359 · see citing works
Diet, lifestyle, and the risk of type 2 diabetes mellitus in women.
Hu, F. B., Manson, J. E., Stampfer, M. J., Colditz, G., Liu, S., Solomon, C. G., & Willett, W. C. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010492 · Cited by 2,901 · see citing works
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799 · see citing works
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714 · see citing works
Cinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., Wang, S., Fortier, M., Greenberg, A. S., & Obin, M. S. (2005) · Journal of Lipid Research · doi:10.1194/jlr.m500294-jlr200 · Cited by 2,529 · see citing works
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · see citing works
Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.
Baynes, J. W., & Thorpe, S. R. (1999) · Diabetes · doi:10.2337/diabetes.48.1.1 · Cited by 2,441 · see citing works
Özcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413 · see citing works
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005) · Nature Medicine · doi:10.1038/nm1166 · Cited by 2,245 · see citing works
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157 · see citing works
Mitochondrial 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 · see citing works
Macrophage-specific PPARγ controls alternative activation and improves insulin resistance
Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., et al. (2007) · Nature · doi:10.1038/nature05894 · Cited by 2,107 · cited 3× · see citing works
“An increase in M1 and decrease in M2 were found in adipose tissue of obese mice [34,36].”
Mitochondrial dysfunction and type 2 diabetes
Lowell, B. B., & Shulman, G. I. (2005) · Science · doi:10.1126/science.1104343 · Cited by 2,070 · see citing works
The many faces of macrophage activation
Mosser, D. M. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0602325 · Cited by 1,902 · see citing works
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884 · see citing works
IKK-β links inflammation to obesity-induced insulin resistance
Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z.-W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., & Karin, M. (2005) · Nature Medicine · doi:10.1038/nm1185 · Cited by 1,773 · see citing works
ER stress and the unfolded protein response
Schröder, M., & Kaufman, R. J. (2004) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2004.06.056 · Cited by 1,750 · see citing works
Mechanism 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 · see citing works
Aguirre, 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 · see citing works
Evans, J. L., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M. (2003) · Diabetes · doi:10.2337/diabetes.52.1.1 · Cited by 1,482 · see citing works
Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E., Frosch, M., Eckman, C., Tanzi, R., Selkoe, D., & Guénette, S. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0230450100 · Cited by 1,361 · see citing works
Obstructive Sleep Apnea Is Independently Associated with Insulin Resistance
Ip, M. S. M., Lam, B., Ng, M. M. T., Lam, W. K., Tsang, K. W. T., & Lam, K. S. L. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.165.5.2103001 · Cited by 1,300 · see citing works
Michael, M. D., Kulkarni, R. N., Postic, C., Previs, S. F., Shulman, G. I., Magnuson, M. A., & Kahn, C. R. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00015-8 · Cited by 1,296 · see citing works
Interleukin-6-deficient mice develop mature-onset obesity
Wallenius, V., Wallenius, K., Ahrén, B., Rudling, M., Carlsten, H., Dickson, S. L., Ohlsson, C., & Jansson, J.-O. (2002) · Nature Medicine · doi:10.1038/nm0102-75 · Cited by 1,213 · see citing works
Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways
Fearon, K. C. H., Glass, D. J., & D, D. C. G. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.011 · Cited by 1,203 · see citing works
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012) · Nature · doi:10.1038/nature10758 · Cited by 1,136 · see citing works
Robertson, R. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.r400019200 · Cited by 1,078 · see citing works
Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., & Goldstein, J. L. (1999) · Nature · doi:10.1038/43448 · Cited by 1,038 · see citing works
AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome
Zhang, B. B., Zhou, G., & Li, C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.012 · Cited by 1,028 · see citing works
IRS proteins and the common path to diabetes
White, M. F. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00514.2001 · Cited by 925 · see citing works
Endoplasmic Reticulum Stress Plays a Central Role in Development of Leptin Resistance
Ozcan, L., Ergin, A. S., Lu, A., Chung, J., Sarkar, S., Nie, D., Myers, M. G., & Ozcan, U. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.004 · Cited by 875 · see citing works
Ye, J., Gao, Z., Yin, J., & He, Q. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00435.2007 · Cited by 840 · see citing works
Self-citationMorino, K. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25151 · Cited by 811 · see citing works
Insulin Resistance and Hyperinsulinemia
Shanik, M. H., Xu, Y., Škrha, J., Dankner, R., Zick, Y., & Roth, J. (2008) · Diabetes Care · doi:10.2337/dc08-s264 · Cited by 791 · see citing works
Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., & Brown, M. S. (1998) · Genes & Development · doi:10.1101/gad.12.20.3182 · Cited by 790 · see citing works
Serine Phosphorylation of Insulin Receptor Substrate 1 by Inhibitor κB Kinase Complex
Gao, Z., Hwang, D. H., Bataille, F., Lefevre, M., York, D. A., Quon, M. J., & Ye, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209459200 · Cited by 777 · see citing works
Self-citationUse of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation
Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.04.001 · Cited by 773 · see citing works
Protection from obesity and diabetes by blockade of TGF-β/smad3 signaling
Yadav, H., Quijano, C., Kamaraju, A. K., Gavrilova, O., Malek, R., Chen, W., Zerfas, P., Zhigang, D., Wright, E. C., Stuelten, C., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.04.013 · Cited by 709 · see citing works
Fain, J. N. (2006) · Vitamins and hormones · doi:10.1016/s0083-6729(06)74018-3 · Cited by 679 · see citing works
Free Fatty Acids and Pathogenesis of Type 2 Diabetes Mellitus
Bergman, R. N., & Ader, M. (2000) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(00)00323-4 · Cited by 622 · see citing works
Rui, L., Aguirre, V., Kim, J. K., Shulman, G. I., Lee, A., Corbould, A. M., Dunaif, A. E., & White, M. F. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10934 · Cited by 600 · see citing works
The role of mitochondria in insulin resistance and type 2 diabetes mellitus
Szendroedi, J., Phielix, E., & Roden, M. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.138 · Cited by 600 · cited 1× · see citing works
“Although the hypothesis explains the association of improved mitochondrial function and insulin sensitivity in the models of physical exercise in humans and rodents [55], most exiting evidence suggests that mitochondrial dysfunction is a result of insulin resistance [56–58], instead of a cause of insulin resistance [5…”
Removal of Visceral Fat Prevents Insulin Resistance and Glucose Intolerance of Aging
Gabriely, I., Ma, X. H., Yang, X. M., Atzmon, G., Rajala, M. W., Berg, A. H., Scherer, P., Rossetti, L., & Barzilai, N. (2002) · Diabetes · doi:10.2337/diabetes.51.10.2951 · Cited by 563 · see citing works
Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis
Reznick, R. M., Zong, H., Li, J., Morino, K., Moore, I. K., Yu, H. J., Liu, Z.-X., Dong, J., Mustard, K. J., Hawley, S. A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.008 · Cited by 555 · see citing works
Oxidative stress and glycemic regulation
Ceriello, A. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80082-7 · Cited by 550 · see citing works
Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species
Bashan, N., Kovsan, J., Kachko, I., Ovadia, H., & Rudich, A. (2009) · Physiological Reviews · doi:10.1152/physrev.00014.2008 · Cited by 542 · see citing works
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 539 · see citing works
Self-citationRuan, H., Hacohen, N., Golub, T. R., Parijs, L. V., & Lodish, H. F. (2002) · Diabetes · doi:10.2337/diabetes.51.5.1319 · Cited by 531 · see citing works
Lee, J. Y., Ye, J., Gao, Z., Youn, H. S., Lee, W. H., Zhao, L., Sizemore, N., & Hwang, D. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305213200 · Cited by 524 · see citing works
Self-citationThiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1052 · Cited by 521 · see citing works
Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.
Boden, G., Jadali, F., White, J. V., Liang, Y. T., Mozzoli, M. A., Chen, X., Coleman, E., & Smith, C. R. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115399 · Cited by 500 · see citing works
Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production
Mehran, A. E., Templeman, N. M., Brigidi, G. S., Lim, G. E., Chu, K.-Y., Hu, X., Botezelli, J. D., Asadi, A., Hoffman, B. G., Kieffer, T. J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.10.019 · Cited by 498 · see citing works
The Hyperglycemia-induced Inflammatory Response in Adipocytes
Lin, Y., Berg, A. H., Iyengar, P., Lam, T. K. T., Giacca, A., Combs, T. P., Rajala, M. W., Du, X., Rollman, B., Li, W., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m411863200 · Cited by 497 · see citing works
Exercise-induced increase in muscle insulin sensitivity
Holloszy, J. O. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00123.2005 · Cited by 494 · see citing works
Stump, C. S., Short, K. R., Bigelow, M. L., Schimke, J. M., & Nair, K. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1332551100 · Cited by 477 · see citing works
Hevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T. A., Bandyopadyhay, G., Leung, H.-Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A.-K., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31561 · Cited by 459 · see citing works
The Adipocyte as an Endocrine Cell
Halberg, N., Asterholm, I. W., & Scherer, P. E. (2008) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2008.07.002 · Cited by 444 · see citing works
Nishimura, S., Manabe, I., Nagasaki, M., Hosoya, Y., Yamashita, H., Fujita, H., Ohsugi, M., Tobe, K., Kadowaki, T., Nagai, R., et al. (2007) · Diabetes · doi:10.2337/db06-1749 · Cited by 440 · see citing works
Peraldi, P., Hotamisligil, G. S., Buurman, W. A., White, M. F., & Spiegelman, B. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.13018 · Cited by 412 · see citing works
Heilbronn, L. K., Smith, S. R., & Ravussin, É. (2004) · International Journal of Obesity · doi:10.1038/sj.ijo.0802853 · Cited by 411 · see citing works
Berberine improves glucose metabolism through induction of glycolysis
Yin, J., Gao, Z., Liu, D., Liu, Z., & Ye, J. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00211.2007 · Cited by 411 · see citing works
Self-citationSchenk, S., & Horowitz, J. F. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30566 · Cited by 407 · see citing works
Energy regulation and neuroendocrine–immune control in chronic inflammatory diseases
Straub, R. H., Cutolo, M., Buttgereit, F., & Pongratz, G. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02218.x · Cited by 382 · see citing works
Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity
Iiyori, N., Alonso, L. C., Li, J., Sanders, M. H., Garcia-Ocana, A., O'Doherty, R. M., Polotsky, V. Y., & O'Donnell, C. P. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200610-1527oc · Cited by 373 · see citing works
Paolisso, G., Tataranni, P. A., Foley, J. E., BOGARDUS, C., Howard, B. V., & Ravussin, É. (1995) · Diabetologia · doi:10.1007/bf00422371 · Cited by 366 · see citing works
Di Gregorio, G. B., Yao-Borengasser, A., Rasouli, N., Varma, V., Lu, T., Miles, L. M., Ranganathan, G., Peterson, C. A., McGehee, R. E., & Kern, P. A. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2305 · Cited by 362 · see citing works
Brose, N., & Rosenmund, C. (2002) · Journal of Cell Science · doi:10.1242/jcs.00122 · Cited by 347 · see citing works
Gao, Z., Zhang, X., Zuberi, A. R., Hwang, D. H., Quon, M. J., Lefevre, M., & Ye, J. (2004) · Molecular Endocrinology · doi:10.1210/me.2003-0383 · Cited by 335 · see citing works
Self-citationTHORPE SR ROLE OF OXIDATIVE STRESS IN DIABETIC COMPLICATIONS: A NEW PERSPECTIVE ON AN OLD PARADIGM
Baynes, J. (1999) · Cited by 326 · see citing works
Angiogenic Role of LYVE-1–Positive Macrophages in Adipose Tissue
Cho, C.-H., Jun Koh, Y., Han, J., Sung, H.-K., Jong Lee, H., Morisada, T., Schwendener, R. A., Brekken, R. A., Kang, G., Oike, Y., et al. (2007) · Circulation Research · doi:10.1161/01.res.0000259564.92792.93 · Cited by 309 · see citing works
Zhang, J., Gao, Z., Yin, J., Quon, M. J., & Ye, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806480200 · Cited by 297 · see citing works
Self-citationOxygen Sensors at the Crossroad of Metabolism
Aragonés, J., Fraisl, P., Baes, M. I., & Carmeliet, P. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.001 · Cited by 290 · see citing works
Corkey, B. E. (2011) · Diabetes · doi:10.2337/db11-1483 · Cited by 285 · see citing works
Farris, W., Mansourian, S., Leissring, M. A., Eckman, E. A., Bertram, L., Eckman, C. B., Tanzi, R. E., & Selkoe, D. J. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63229-4 · Cited by 269 · see citing works
Weigert, C., Brodbeck, K., Staiger, H., Kausch, C., Machicao, F., Häring, H. U., & Schleicher, E. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312692200 · Cited by 269 · see citing works
Ceramide signalling and the immune response
Ballou, L. R., Laulederkind, S. J. F., Rosloniec, E. F., & Raghow, R. (1996) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(96)00004-5 · Cited by 259 · see citing works
Gene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment
Sreekumar, R., Halvatsiotis, P., Schimke, J. C., & Nair, K. S. (2002) · Diabetes · doi:10.2337/diabetes.51.6.1913 · Cited by 257 · see citing works
He, Q., Gao, Z., Yin, J., Zhang, J., Yun, Z., & Ye, J. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00626.2010 · Cited by 245 · see citing works
Self-citationLeptin inhibits insulin secretion by activation of phosphodiesterase 3B.
Zhao, A. Z., Bornfeldt, K., & Beavo, J. A. (1998) · Journal of Clinical Investigation · doi:10.1172/jci3920 · Cited by 236 · see citing works
Pang, C., Gao, Z., Yin, J., Zhang, J., Jia, W., & Ye, J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90296.2008 · Cited by 229 · see citing works
Self-citationp38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis
Lee, J., Sun, C., Zhou, Y., Lee, J., Gökalp, D., Herrema, H., Park, S. W., Davis, R. J., & Özcan, U. (2011) · Nature Medicine · doi:10.1038/nm.2449 · Cited by 208 · see citing works
Lijnen, H. R. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvm007 · Cited by 206 · see citing works
Regulation of PPARγ function by TNF-α
Ye, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.07.068 · Cited by 198 · see citing works
Self-citationXing, H. Y., Northrop, J. P., Grove, J. R., Kilpatrick, K. E., Su, J., & RINGOLD, G. M. (1997) · Endocrinology · doi:10.1210/endo.138.7.5242 · Cited by 189 · see citing works
IL-6 signalling in exercise and disease
Pedersen, B. K. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351295 · Cited by 187 · see citing works
Nair, K. S., Bigelow, M. L., Asmann, Y. W., Chow, L. S., Coenen-Schimke, J. M., Klaus, K. A., Guo, Z.-K., Sreekumar, R., & Irving, B. A. (2008) · Diabetes · doi:10.2337/db07-1556 · Cited by 187 · see citing works
Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance
Holloszy, J. O. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26717c · Cited by 175 · see citing works
Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice
García, M. C., Asterholm, I. W., Berndtsson, A., Enge, M., Bell, M. I., Hultgren, O., Horn, M., Åhrén, B., Enerbäck, S., Ohlsson, C., et al. (2006) · Diabetes · doi:10.2337/db05-1304 · Cited by 174 · see citing works
Inflammation during obesity is not all bad: evidence from animal and human studies
Ye, J., & McGuinness, O. P. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00266.2012 · Cited by 173 · see citing works
Self-citationYe, J., & Keller, J. N. (2010) · Aging · doi:10.18632/aging.100155 · Cited by 171 · see citing works
Self-citationTang, T., Zhang, J., Yin, J., Staszkiewicz, J., Gawrońska‐Kozak, B., Jung, D. Y., Ko, H. J., Ong, H., Kim, J. K., Mynatt, R., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.068007 · Cited by 159 · see citing works
Self-citationThe Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance
Pagel-Langenickel, I., Bao, J., Pang, L., & Sack, M. N. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0003 · Cited by 154 · see citing works
Ogihara, T., Asano, T., Katagiri, H., Sakoda, H., Anai, M., Shojima, N., Ono, H., Fujishiro, M., Kushiyama, A., Fukushima, Y., et al. (2004) · Diabetologia · doi:10.1007/s00125-004-1391-x · Cited by 150 · see citing works
Mora, M. V., Scarfone, A., Calvani, M., Greco, A. V., & Mingrone, G. (2003) · Journal of the American College of Nutrition · doi:10.1080/07315724.2003.10719326 · Cited by 148 · see citing works
ROS Signaling in Systemic and Cellular Responses to Chronic Intermittent Hypoxia
Prabhakar, N. R., Kumar, G. K., Nanduri, J., & Semenza, G. L. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1732 · Cited by 147 · see citing works
Smad3 Deficiency in Mice Protects Against Insulin Resistance and Obesity Induced by a High-Fat Diet
Tan, C. K., Leuenberger, N., Tan, M., Yan, Y. W., Chen, Y., Kambadur, R., Wahli, W., & Tan, N. S. (2011) · Diabetes · doi:10.2337/db10-0801 · Cited by 147 · see citing works
Gao, Z., He, Q., Peng, B., Chiao, P. J., & Ye, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507784200 · Cited by 141 · see citing works
Self-citationIntramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused?
Muoio, D. M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.11.007 · Cited by 137 · see citing works
Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta.
Anforth, H. R., Bluthé, R.-M., Bristow, A., Hopkins, S. J., Lenczowski, M. J. P., Luheshi, G. N., Lundkvist, J., Michaud, B., Mistry, Y., van Dam, A., et al. (1998) · PubMed · Cited by 108 · see citing works
Role of Insulin in the Pathogenesis of Free Fatty Acid-Induced Insulin Resistance in Skeletal Muscle
Ye, J. (2007) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153007780059423 · Cited by 106 · see citing works
Self-citationStressed out about obesity and insulin resistance
de Luca, C., & Olefsky, J. M. (2006) · Nature Medicine · doi:10.1038/nm0106-41 · Cited by 98 · see citing works
Xu, H., Hirosumi, J., Uysal, K. T., Güler, A. D., & Hotamışlıgil, G. S. (2002) · Endocrinology · doi:10.1210/endo.143.4.8715 · Cited by 92 · see citing works
Hyperinsulinemia Precedes Insulin Resistance in Mice Lacking Pancreatic β-Cell Leptin Signaling
Gray, S. L., Donald, C., Jetha, A., Covey, S. D., & Kieffer, T. J. (2010) · Endocrinology · doi:10.1210/en.2010-0102 · Cited by 92 · see citing works
Pamir, N., McMillen, T. S., Kaiyala, K. J., Schwartz, M. W., & LeBoeuf, R. C. (2009) · Endocrinology · doi:10.1210/en.2009-0137 · Cited by 91 · see citing works
Combined Interleukin-6 and Interleukin-1 Deficiency Causes Obesity in Young Mice
Chida, D., Osaka, T., Hashimoto, O., & Iwakura, Y. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1250 · Cited by 89 · see citing works
Lü, G., Greene, E. L., Nagai, T., & Egan, B. M. (1998) · Hypertension · doi:10.1161/01.hyp.32.6.1003 · Cited by 80 · see citing works
Free fatty acids and insulin secretion in humans
Boden, G. H. (2005) · Current Diabetes Reports · doi:10.1007/s11892-005-0004-5 · Cited by 70 · see citing works
Regulation of stem cell differentiation in adipose tissue by chronic inflammation
Ye, J., & Gimble, J. M. (2011) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2011.05596.x · Cited by 70 · see citing works
Self-citationGreene, E. L., Lü, G., Zhang, D., & Egan, B. M. (2001) · Hypertension · doi:10.1161/01.hyp.37.2.308 · Cited by 65 · see citing works
Mitochondrial Inhibitor as a New Class of Insulin Sensitizer
Zhang, Y., & Ye, J. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.010 · Cited by 47 · see citing works
Constitutive Activation of IKKβ in Adipose Tissue Prevents Diet-Induced Obesity in Mice
Jiao, P., Feng, B., Ma, J., Nie, Y., Paul, E., Li, Y., & Xu, H. (2011) · Endocrinology · doi:10.1210/en.2011-1346 · Cited by 46 · see citing works
IL-6, a key cytokine in liver regeneration
Clavien, P. (1997) · Hepatology · doi:10.1002/hep.510250544 · Cited by 32 · see citing works
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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 · see citing works
Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments
Ruze, R., Liu, T., Zou, X., Song, J., Chen, Y., Xu, R., Yin, X., & Xu, Q. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1161521 · Cited by 799 · see citing works
“oxidative stress, inflammation, ER stress, and mitochondrial dysfunction, induce a negative impact on autophagy as well (99).”
BackgroundThe Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615 · see citing works
Targeting autophagy in obesity: from pathophysiology to management
Zhang, Y., Sowers, J. R., & Ren, J. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0009-1 · Cited by 338 · see citing works
Lifestyle factors, self-management and patient empowerment in diabetes care
Lambrinou, E., Hansen, T. B., & Beulens, J. W. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487319885455 · Cited by 261 · see citing works
Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases
Mirabelli, M., Chiefari, E., Arcidiacono, B., Corigliano, D. M., Brunetti, F. S., Maggisano, V., Russo, D., Foti, D. P., & Brunetti, A. (2020) · Nutrients · doi:10.3390/nu12041066 · Cited by 272 · see citing works
“and hyperplasia of adipocytes, chronic inflammatory cell infiltration, and activation of the cytokine network, representing the main determinant of IR and the major risk factor for the development of T2D and its complications [28].”
BackgroundObesity, insulin resistance and comorbidities? Mechanisms of association
Castro, A. V. B., Kolka, C. M., Kim, S. P., & Bergman, R. N. (2014) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/0004-2730000003223 · Cited by 254 · see citing works
Engin, A. B. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_8 · Cited by 260 · see citing works
Choi, Y. J., Jeon, S.-M., & Shin, S. (2020) · Nutrients · doi:10.3390/nu12072005 · Cited by 193 · see citing works
Lima, J. E. B. F., Moreira, N. C. S., & Sakamoto-Hojo, E. T. (2022) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2021.503437 · Cited by 203 · see citing works
Zhou, C., Wang, M., Liang, J., He, G., & Chen, N. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph191610429 · Cited by 151 · see citing works
Obesity, estrogens and adipose tissue dysfunction - implications for pulmonary arterial hypertension
Mair, K. M., Gaw, R., & MacLean, M. R. (2020) · Pulmonary Circulation · doi:10.1177/2045894020952023 · Cited by 129 · see citing works
Shaik Mohamed Sayed, U. F., Moshawih, S., Goh, H. P., Kifli, N., Gupta, G., Singh, S. K., Chellappan, D. K., Dua, K., Hermansyah, A., Ser, H. L., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1182937 · Cited by 136 · see citing works
Wittenbecher, C., Mühlenbruch, K., Kröger, J., Jacobs, S., Kuxhaus, O., Floegel, A., Fritsche, A., Pischon, T., Prehn, C., Adamski, J., et al. (2015) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.099150 · Cited by 120 · see citing works
Ye, J. (2015) · Frontiers of Medicine · doi:10.1007/s11684-015-0377-z · Cited by 66 · see citing works
Self-citationThe clinical and biochemical significance of 11-oxygenated androgens in human health and disease
Storbeck, K.-H., & O’Reilly, M. W. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad047 · Cited by 63 · see citing works
Persistent effects of obesity: A neuroplasticity hypothesis
Matikainen‐Ankney, B. A., & Kravitz, A. V. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13665 · Cited by 56 · see citing works
Energy regulation mechanism and therapeutic potential of asprosin
Hoffmann, J. G., Xie, W., & Chopra, A. R. (2020) · Diabetes · doi:10.2337/dbi19-0009 · Cited by 52 · see citing works
Wiss, D. A., Criscitelli, K., Gold, M., & Avena, N. (2017) · Appetite · doi:10.1016/j.appet.2016.12.019 · Cited by 53 · see citing works
Etiology of type 2 diabetes and Alzheimer’s disease: Exploring the mitochondria
Silzer, T. K., & Phillips, N. R. (2018) · Mitochondrion · doi:10.1016/j.mito.2018.04.004 · Cited by 53 · see citing works
Abu Bakar, M. H., Shariff, K. A., Tan, J. S., & Lee, L. K. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173371 · Cited by 51 · see citing works
Chen, E., Brody, G. H., Yu, T., Hoffer, L. C., Russak-Pribble, A., & Miller, G. E. (2021) · Psychological Science · doi:10.1177/0956797621998308 · Cited by 21 · see citing works
The Role of Nutrition in Addiction Recovery
Wiss, D. A. (2019) · The Assessment and Treatment of Addiction · doi:10.1016/b978-0-323-54856-4.00002-x · Cited by 20 · see citing works
Ansari, P., Khan, J. T., Choudhary, S., Reberio, A. D., Kumar, S., Seidel, V., Abdel-Wahab, Y. H. A., & Flatt, P. R. (2024) · doi:10.20944/preprints202408.1739.v1 · Cited by 89 · see citing works
- Authors
- Ye, J.
- Affiliations
- Pennington Biomedical Research Center (US)
- Corresponding author
- Ye, Jianping
- ORCID
- Ye, Jianping
- Venue
- Frontiers of Medicine
- Published
- 2013-03
- Volume
- 7
- Issue
- 1
- Pages
- 14-24
- ISSN
- 1673-7342 (ISSN-L)
- 2095-0217
- 2095-0225
- PMC
- PMC3936017
- OpenAlex
- W2081827377
- Cited by
- 699
- References
- 123
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 47 · 2023: 58 · 2022: 73 · 2021: 81 · 2020: 95 · 2019: 98 · 2018: 49 · 2017: 39 · 2016: 35 · 2015: 35 · 2014: 31 · 2013: 10
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Frontiers of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute for Health and Care Research
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-085495, R56DK068036, R01DK085495, R01DK068036, DK068036)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, obesity, type 2 diabetes, energy surplus, ATP, AMPK signaling, mitochondrial dysfunction, insulin sensitizers, weight loss, physical activity, caloric restriction, aging, lipodystrophy, oxidative stress, endoplasmic reticulum stress, lipotoxicity, hyperinsulinemia, inflammation
- MeSH terms
- Diabetes Mellitus, Type 2, Energy Metabolism, Fatty Acids, Nonesterified, Humans, Hyperinsulinism, Inflammation, Insulin, Insulin Resistance, Mitochondria, Obesity, Risk Factors, Signal Transduction, Metabolic Networks and Pathways, AMP-Activated Protein Kinases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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