Abstract

Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFκB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low-grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance.

References

• 1. Adams J.M. II, Pratipanawatr T., Berria R., Wang E., DeFronzoR.A., Sullards M.C., Mandarino L.J.: Ceramide content is increasedin skeletal muscle from obese insulin-resistant humans. Diabetes,2004; 53: 25-31
  Google Scholar
• 2. Aguirre V., Uchida T., Yenush L., Davis R., White M.F.: The c-JunNH(2)-terminal kinase promotes insulin resistance during associationwith insulin receptor substrate-1 and phosphorylation of Ser(307). J. Biol. Chem., 2000; 275: 9047-9054
  Google Scholar
• 3. Aguirre V., Werner E.D., Giraud J., Lee Y.H., Shoelson S.E., WhiteM.F.: Phosphorylation of Ser307 in insulin receptor substrate-1blocks interactions with the insulin receptor and inhibits insulinaction. J. Biol. Chem., 2002; 277: 1531-1537
  Google Scholar
• 4. Aljada A., Ghanim H., Saadeh R., Dandona P.: Insulin inhibits NFκBand MCP- 1 expression in human aortic endothelial cells. J. Clin. Endocrinol.Metab., 2001; 86: 450-453
  Google Scholar
• 5. Aljada A., Saadeh R., Assian E., Ghanim H., Dandona P.: Insulininhibits the expression of intercellular adhesion molecule-1 by humanaortic endothelial cells through stimulation of nitric oxide. J.Clin. Endocrinol. Metab., 2000; 85: 2572-2575
  Google Scholar
• 6. Arkan M.C., Hevener A.L., Greten F.R., Maeda S., Li Z.W., LongJ.M., Wynshaw-Boris A., Poli G., Olefsky J., Karin M.: IKK-β links inflammationto obesity-induced insulin resistance. Nat. Med., 2005;11: 191-198
  Google Scholar
• 7. Arner E., Westermark P.O., Spalding K.L., Britton T., Rydén M., FrisénJ., Bernard S., Arner P.: Adipocyte turnover: relevance to humanadipose tissue morphology. Diabetes, 2010; 59: 105-109
  Google Scholar
• 8. Artwohl M., Roden M., Waldhäusl W., Freudenthaler A., Baumgartner-ParzerS.M.: Free fatty acids trigger apoptosis and inhibitcell cycle progression in human vascular endothelial cells. FASEBJ., 2004; 18: 146-148
  Google Scholar
• 9. Banfi C., Eriksson P., Giandomenico G., Mussoni L., Sironi L., HamstenA., Tremoli E.: Transcriptional regulation of plasminogen activatorinhibitor type 1 gene by insulin: insights into the signalingpathway. Diabetes, 2001; 50: 1522-1530
  Google Scholar
• 10. Barthel A., Schmoll D.: Novel concepts in insulin regulation ofhepatic gluconeogenesis. Am. J. Physiol. Endocrinol. Metab., 2003;285: E685-E692
  Google Scholar
• 11. Bilkovski R., Schulte D.M., Oberhauser F., Mauer J., Hampel B.,Gutschow C., Krone W., Laudes M.: Adipose tissue macrophages inhibitadipogenesis of mesenchymal precursor cells via wnt-5a inhumans. Int. J. Obes., 2011; 35: 1450-1454
  Google Scholar
• 12. Blüher M., Fasshauer M., Tönjes A., Kratzsch J., Schön M.R.,Paschke R.: Association of interleukin-6, C-reactive protein, interleukin-10and adiponectin plasma concentrations with measuresof obesity, insulin sensitivity and glucose metabolism. Exp. Clin.Endocrinol. Diabetes, 2005; 113: 534-537
  Google Scholar
• 13. Boden G., She P., Mozzoli M., Cheung P., Gumireddy K., ReddyP., Xiang X., Luo Z., Ruderman N.: Free fatty acids produce insulinresistance and activate the proinflammatory nuclear factor-κB pathwayin rat liver. Diabetes, 2005; 54: 3458-3465
  Google Scholar
• 14. Bray G.A., Champagne C.M.: Obesity and the metabolic syndrome:implications for dietetics practitioners. J. Am. Diet. Assoc.,2004; 104: 86-89
  Google Scholar
• 15. Cai D., Yuan M., Frantz D.F., Melendez P.A., Hansen L., Lee J.,Shelson S.E.: Local and systemic insulin resistance resulting fromhepatic activation of IKK-β and NF-κB. Nat. Med., 2005; 11: 183-190
  Google Scholar
• 16. Cancello R., Tordjman J., Poitou C., Guilhem G., Bouillot J.L., HugolD., Coussieu, C., Basdevant A., Hen A.B., Bedossa P., Guerre-MilloM., Clement K.: Increased infiltration of macrophages in omentaladipose tissue is associated with marked hepatic lesions in morbidhuman obesity. Diabetes, 2006; 55: 1554-1561
  Google Scholar
• 17. Cantley L.C.: The phosphoinositide 3-kinase pathway. Science,2002; 296: 1655-1657
  Google Scholar
• 18. Cinti S., Mitchell G., Barbatelli G., Murano I., Ceresi E., FaloiaE., Wang S., Fortier M., Greenberg A.S., Obin M.S.: Adipocyte deathdefines macrophage localization and function in adipose tissue ofobese mice and humans. J. Lipid. Res., 2005; 46: 2347-2355
  Google Scholar
• 19. Clément K., Viguerie N., Poitou C., Carette C., Pelloux V., CuratC.A., Sicard A., Rome S., Benis A., Zucker J.D., Vidal H., Laville M.,Barsh G.S., Basdevant A., Stich V., Cancello R., Langin D.: Weightloss regulates inflammation-related genes in white adipose tissueof obese subjects. FASEB J., 2004; 18: 1657-1669
  Google Scholar
• 20. Coll T., Eyre E., Rodríguez-Calvo R., Palomer X., Sánchez R.M.,Merlos M., Laguna J.C., Vázquez-Carrera M.: Oleate reverses palmitate-inducedinsulin resistance and inflammation in skeletal musclecells. J. Biol. Chem., 2008; 283: 11107-11116
  Google Scholar
• 21. Correia M.L., Haynes W.G.: A role for plasminogen activatorinhibitor-1 in obesity: from pie to PAI? Arterioscler. Thromb. Vasc.Biol., 2006; 26: 2183-2185
  Google Scholar
• 22. Cushing S.D., Berliner J.A., Valente A.J., Territo M.C., Navab M.,Parhami F., Gerrity R., Schwartz C.J., Fogelman A.M.: Minimally modifiedlow density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl.Acad. Sci. USA, 1990; 87: 5134-5138
  Google Scholar
• 23. Cusi K., Maezono K., Osman A., Pendergrass M., Patti M.E., PratipanawatrT., DeFronzo R.A., Kahn C.R., Mandarino L.J.: Insulin resistancedifferentially affects the PI 3-kinase- and MAP kinase-mediatedsignaling in human muscle. J. Clin. Invest., 2000; 105: 311-320
  Google Scholar
• 24. Dandona P., Aljada A., Dhindsa S., Garg R.: Insulin as an anti-inflammatoryand antiatherosclerotic hormone. Clin. Cornerstone,2003; 4: S13-S20
  Google Scholar
• 25. Dandona P., Aljada A., Mohanty P.: The anti-inflammatory andpotential anti-atherogenic effect of insulin: a new paradigm. Diabetologia,2002; 45: 924-930
  Google Scholar
• 26. Dandona P., Aljada A., Mohanty P., Ghanim H., Hamouda W.,Assian E., Ahmad S.: Insulin inhibits intranuclear nuclear factorκB and stimulates IκB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J. Clin. Endocrinol. Metab.,2001; 86: 3257-3265
  Google Scholar
• 27. Davda R.K., Stepniakowski K.T., Lu G., Ullian M.E., GoodfriendT.L., Egan B.M.: Oleic acid inhibits endothelial nitric oxide synthaseby a protein kinase C-independent mechanism. Hypertension,1995; 26: 764-770
  Google Scholar
• 28. Davis R.J.: Signal transduction by the JNK group of MAP kinases.Cell, 2000; 103: 239-252
  Google Scholar
• 29. De Meyts P.: Insulin and its receptor: structure, function andevolution. Bioessays, 2004; 26: 1351-1362
  Google Scholar
• 30. Defronzo R.A.: Banting Lecture. From the triumvirate to theominous octet: a new paradigm for the treatment of type 2 diabetesmellitus. Diabetes, 2009; 58: 773-795
  Google Scholar
• 31. DeFronzo R.A.: Insulin resistance, lipotoxicity, type 2 diabetesand atherosclerosis: the missing links. The Claude Bernard Lecture 2009 Diabetologia, 2010; 53: 1270-1287
  Google Scholar
• 32. Denton R.M., Tavaré J.M.: Does mitogen-activated-protein kinasehave a role in insulin action? The cases for and against. Eur. J.Biochem., 1995; 227: 597-611
  Google Scholar
• 33. Desruisseaux M.S., Nagajyothi, Trujillo M.E., Tanowitz H.B., SchererP.E.: Adipocyte, adipose tissue, and infectious disease. Infect.Immun., 2007; 75: 1066-1078
  Google Scholar
• 34. Dubé J.J., Amati F., Stefanovic-Racic M., Toledo F.G., Sauers S.E.,Goodpaster B.H.: Exercise-induced alterations in intramyocellularlipids and insulin resistance: the athlete’s paradox revisited. Am. J.Physiol. Endocrinol. Metab., 2008; 294: E882-E888
  Google Scholar
• 35. Dyson J.M., Kong A.M., Wiradjaja F., Astle M.V., Gurung R., MitchellC.A.: The SH2 domain containing inositol polyphosphate 5-phosphatase-2:SHIP2. Int. J. Biochem. Cell. Biol., 2005; 37: 2260-2265
  Google Scholar
• 36. Eisele P.S., Salatino S., Sobek J., Hottiger M.O., Handschin C.:The peroxisome proliferator-activated receptor γ coactivator 1α/β(PGC-1) coactivators repress the transcriptional activity of NF-κB inskeletal muscle cells. J. Biol. Chem., 2013; 288: 2246-2260
  Google Scholar
• 37. Engeli S., Negrel R., Sharma A.M.: Physiology and pathophysiologyof the adipose tissue renin-angiotensin system. Hypertension,2000; 35: 1270-1277
  Google Scholar
• 38. Feuerer M., Herrero L., Cipolletta D., Naaz A., Wong J., NayerA., Lee J., Goldfine A.B., Benoist C., Shoelson S., Mathis D.: Lean, butnot obese, fat is enriched for a unique population of regulatory Tcells that affect metabolic parameters. Nat. Med., 2009; 15: 930-939
  Google Scholar
• 39. Fukui K., Wada T., Kagawa S., Nagira K., Ikubo M., Ishihara H.,Kobayashi M., Sasaoka T.: Impact of the liver-specific expression ofSHIP2 (SH2-containing inositol 5’-phosphatase 2) on insulin signalingand glucose metabolism in mice. Diabetes, 2005; 54: 1958-1967
  Google Scholar
• 40. Furukawa S., Fujita T., Shimabukuro M., Iwaki M., Yamada Y.,Nakajima Y., Nakayama O., Makishima M., Matsuda M., ShimomuraI.: Increased oxidative stress in obesity and its impact on metabolicsyndrome. J. Clin. Invest., 2004; 114: 1752-1761
  Google Scholar
• 41. Fuster V., Moreno P.R., Fayad Z.A., Corti R., Badimon J.J.: Atherothrombosisand high-risk plaque: part I: evolving concepts. J. Am.Coll. Cardiol., 2005; 46: 937-954
  Google Scholar
• 42. Gao Z., Hwang D., Bataille F., Lefevre M., York D., Quon M.J., YeJ.: Serine phosphorylation of insulin receptor substrate 1 by inhibitorkappa B kinase complex. J. Biol. Chem., 2002; 277: 48115-48121
  Google Scholar
• 43. Goodpaster B.H., He J., Watkins S., Kelley D.E.: Skeletal musclelipid content and insulin resistance: evidence for a paradox inendurance-trained athletes. J. Clin. Endocrinol. Metab., 2001; 86:5755-5761
  Google Scholar
• 44. Goodpaster B.H., Katsiaras A., Kelley D.E.: Enhanced fat oxidationthrough physical activity is associated with improvements in insulinsensitivity in obesity. Diabetes, 2003; 52: 2191-2197
  Google Scholar
• 45. Gordon S.: Macrophage heterogeneity and tissue lipids. J. Clin.Invest., 2007; 117: 89-93
  Google Scholar
• 46. Gorgani-Firuzjaee S., Ahmadi S., Meshkani R.: Palmitate inducesSHIP2 expression via the ceramide-mediated activation of NF-κB,and JNK in skeletal muscle cells. Biochem. Biophys. Res. Commun.,2014; 450: 494-499
  Google Scholar
• 47. Guebre-Xabier M., Yang S., Lin H.Z., Schwenk R., Krzych U., DiehlA.M.: Altered hepatic lymphocyte subpopulations in obesity-relatedmurine fatty livers: potential mechanism for sensitization to liverdamage. Hepatology, 2000; 31: 633-640
  Google Scholar
• 48. Hall J.P., Merithew E., Davis R.J.: c-Jun N-terminal kinase (JNK)repression during the inflammatory response? Just say NO. Proc.Natl. Acad. Sci. USA, 2000; 97: 14022-14024
  Google Scholar
• 49. Hermann C., Assmus B., Urbich C., Zeiher A.M., Dimmeler S.:Insulin-mediated stimulation of protein kinase Akt: A potent survivalsignaling cascade for endothelial cells. Arterioscler. Thromb.Vasc. Biol., 2000; 20: 402-409
  Google Scholar
• 50. Hirosumi J., Tuncman G., Chang L., Görgün C.Z., Uysal K.T., MaedaK., Karin M., Hotamisligil G.S.: A central role for JNK in obesityand insulin resistance. Nature, 2002; 420: 333-336
  Google Scholar
• 51. Hotamisligil G.S., Peraldi P., Budavari A., Ellis R., White M.F.,Spiegelman B.M.: IRS-1-mediated inhibition of insulin receptor tyrosinekinase activity in TNF-alpha- and obesity-induced insulinresistance. Science, 1996; 271: 665-668
  Google Scholar
• 52. Hotamisligil G.S., Shargill N.S., Spiegelman B.M.: Adipose expressionof tumor necrosis factor-α: direct role in obesity-linked insulinresistance. Science, 1993; 259: 87-91
  Google Scholar
• 53. Huang W., Metlakunta A., Dedousis N., Zhang P., Sipula I., DubeJ.J., Scott D.K., O’Doherty R.M.: Depletion of liver Kupffer cells preventsthe development of diet-induced hepatic steatosis and insulinresistance. Diabetes, 2010; 59: 347-357
  Google Scholar
• 54. Hube F., Hauner H.: The role of TNF-α in human adipose tissue:prevention of weight gain at the expense of insulin resistance?Horm. Metab. Res., 1999; 31: 626-631
  Google Scholar
• 55. Hussey S.E., Lum H., Alvarez A., Cipriani Y., Garduño-Garcia J.,Anaya L., Dube J., Musi N.: A sustained increase in plasma NEFA upregulatesthe Toll-like receptor network in human muscle. Diabetologia,2014; 57: 582-591
  Google Scholar
• 56. Ip Y.T., Davis R.J.: Signal transduction by the c-Jun N-terminalkinase (JNK)-from inflammation to development. Curr. Opin. Cell.Biol., 1998; 10: 205-219
  Google Scholar
• 57. Itani S.I., Ruderman N.B., Schmieder F., Boden G.: Lipid inducedinsulin resistance in human muscle is associated with changes in diacylglycerol,protein kinase C, and IκB-α. Diabetes, 2002; 51: 2005-2011
  Google Scholar
• 58. Iwasaki A., Medzhitov R.: Toll-like receptor control of the adaptiveimmune responses. Nat. Immunol., 2004; 5: 987-995
  Google Scholar
• 59. Jaeschke H., Smith C.W., Clemens M.G., Ganey P.E., Roth R.A.:Mechanisms of inflammatory liver injury: adhesion molecules andcytotoxicity of neutrophils. Toxicol. Appl. Pharmacol., 1996; 139:213-226
  Google Scholar
• 60. Jazet I.M., Schaart G., Gastaldelli A., Ferrannini E., HesselinkM.K., Schrauwen P., Romijn J.A., Maassen J.A., Pijl H., Ouwens D.M.,Meinders A.E.: Loss of 50% of excess weight using a very low energydiet improves insulin-stimulated glucose disposal and skeletalmuscle insulin signaling in obese insulin-treated type 2 diabeticpatients. Diabetologia, 2008; 51: 309-319
  Google Scholar
• 61. Jeong S., Yoon M.: 17β-Estradiol inhibition of PPARγ-inducedadipogenesis and adipocyte-specific gene expression. Acta Pharmacol.Sin., 2011; 32: 230-238
  Google Scholar
• 62. Ji Y., Sun S., Xu A., Bhargava P., Yang L., Lam K.S., Gao B., LeeC.H., Kersten S., Qi L.: Activation of natural killer T cells promotes M2macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signalingaxis in obesity. J. Biol. Chem., 2012; 287: 13561-13571
  Google Scholar
• 63. Jia L., Vianna C.R., Fukuda M., Berglund E.D., Liu C., Tao C., Sun K.,Liu T., Harper M.J., Lee C.E., Lee S., Scherer P.E., Elmquist J.K.: HepatocyteToll-like receptor 4 regulates obesity-induced inflammationand insulin resistance. Nat. Commun., 2014; 5: 3878
  Google Scholar
• 64. Kamei N., Tobe K., Suzuki R., Ohsugi M., Watanabe T., KubotaN., Ohtsuka-Kowatari N., Kumagai K., Sakamoto K., Kobayashi M.,Yamauchi T., Ueki K., Oishi Y., Nishimura S., Manabe I. i wsp.: Overexpressionof monocyte chemoattractant protein-1in adipose tissuescauses macrophage recruitment and insulin resistance. J. Biol.Chem., 2006; 281: 26602-26614
  Google Scholar
• 65. Kanety H., Hemi R., Papa M.Z., Karasik A.: Sphingomyelinaseand ceramide suppress insulin-induced tyrosine phosphorylation ofthe insulin receptor substrate-1. J. Biol. Chem., 1996; 271: 9895-9897
  Google Scholar
• 66. Karin M., Delhase M.: The IκB kinase (IKK) and NF-κB: key elementsof proinflammatory signalling. Semin. Immunol., 2000; 12:85-98
  Google Scholar
• 67. Kim F., Pham M., Maloney E., Rizzo N.O., Morton G.J., Wisse B.E.,Kirk E.A., Chait A., Schwartz M.W.: Vascular inflammation, insulinresistance, and reduced nitric oxide production precede the onsetof peripheral insulin resistance. Arterioscler. Thromb. Vasc. Biol.,2008; 28: 1982-1988
  Google Scholar
• 68. Kim F., Tysseling K.A., Rice J., Pham M., Haji L., Gallis B.M., BaasA.S., Paramsothy P., Giachelli C.M., Corson M.A., Raines E.W.: Free fattyacid impairment of nitric oxide production in endothelial cells ismediated by IKKβ. Arterioscler. Thromb. Vasc. Biol., 2005; 25: 989-994
  Google Scholar
• 69. 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., Kim J.K.: Differential effects ofinterleukin-6 and -10 on skeletal muscle and liver insulin action invivo. Diabetes, 2004; 53: 1060-1067
  Google Scholar
• 70. Kim J.K., Fillmore J.J., Sunshine M.J., Albrecht B., Higashimori T.,Kim D.W., Liu Z.X., Soos T.J., Cline G.W., O’Brien W.R., Littman D.R.,Shulman G.I.: PKC-θ knockout mice are protected from fat-inducedinsulin resistance. J. Clin. Invest., 2004; 114: 823-827
  Google Scholar
• 71. Lafontan M., Langin D.: Lipolysis and lipid mobilization in humanadipose tissue. Prog. Lipid. Res., 2009; 48: 275-297
  Google Scholar
• 72. Lanthier N., Molendi-Coste O., Horsmans Y., van Rooijen N., CaniP.D., Leclercq I.A.: Kupffer cell activation is a causal factor for hepaticinsulin resistance. Am. J. Physiol. Gastrointest. Liver. Physiol.,2010; 298: G107-G116
  Google Scholar
• 73. Lee J.Y., Hwang D.H.: The modulation of inflammatory geneexpression by lipids: mediation through Toll-like receptors. Mol.Cells, 2006; 21: 174-185
  Google Scholar
• 74. Lehner R, Kuksis A.: Biosynthesis of triacylglycerols. Prog. Lipid.Res., 1996; 35: 169-201
  Google Scholar
• 75. Lewis G.F., Vranic M., Harley P., Giacca A.: Fatty acids mediatethe acute extrahepatic effects of insulin on hepatic glucose productionin humans. Diabetes, 1997; 46: 1111-1119
  Google Scholar
• 76. Li Y., Soos T.J., Li X., Wu J., Degennaro M., Sun X., Littman D.R.,Birnbaum M.J., Polakiewicz R.D.: Protein kinase C Theta inhibits insulinsignaling by phosphorylating IRS1 at Ser(1101). J. Biol. Chem.,2004; 279: 45304-45307
  Google Scholar
• 77. Li Z., Soloski M.J., Diehl A.M.: Dietary factors alter hepatic innateimmune system in mice with nonalcoholic fatty liver disease.Hepatology, 2005; 42: 880-885
  Google Scholar
• 78. Libby P., Theroux P.: Pathophysiology of coronary artery disease.Circulation, 2005; 111: 3481-3488
  Google Scholar
• 79. Liu G., Ma H., Qiu L., Li L., Cao Y., Ma J., Zhao Y.: Phenotypic andfunctional switch of macrophages induced by regulatory CD4+CD25+T cells in mice. Immunol. Cell. Biol., 2011; 89: 130-142
  Google Scholar
• 80. Liu L., Zhang Y., Chen N., Shi X., Tsang B., Yu Y.H.: Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletalmuscle and protects against fat-induced insulin resistance. J. Clin.Invest., 2007; 117: 1679-1689
  Google Scholar
• 81. Logan C.Y., Nusse R.: The Wnt signaling pathway in developmentand disease. Annu. Rev. Cell Dev. Biol., 2004; 20: 781-810
  Google Scholar
• 82. Lumeng C.N., Bodzin J.L., Saltiel A.R.: Obesity induces a phenotypicswitch in adipose tissue macrophage polarization. J. Clin.Invest., 2007; 117: 175-184
  Google Scholar
• 83. Madonna R., Massaro M., De Caterina R.: Insulin potentiatescytokine-induced VCAM-1 expression in human endothelial cells.Biochim. Biophys. Acta, 2008; 1782: 511-516
  Google Scholar
• 84. Martinez F.O., Gordon S.: The M1 and M2 paradigm of macrophageactivation: time for reassessment. F1000Prime Rep., 2014; 6: 13
  Google Scholar
• 85. Maury E., Brichard S.M.: Adipokine dysregulation, adipose tissueinflammation and metabolic syndrome. Mol. Cell Endocrinol.,2010; 314: 1-16
  Google Scholar
• 86. Mills C.D., Kincaid K., Alt J.M., Heilman M.J., Hill A.M.: M-1/M-2macrophages and the Th1/Th2 paradigm. J. Immunol., 2000; 164:6166-6173
  Google Scholar
• 87. Mooney R.A., Senn J., Cameron S., Inamdar N., Boivin L.M., ShangY., Furlanetto R.W.: Suppressors of cytokine signaling-1 and -6 associatewith and inhibit the insulin receptor. A potential mechanismfor cytokine-mediated insulin resistance. J. Biol. Chem., 2001; 276:25889-25893
  Google Scholar
• 88. Neuschwander-Tetri B.A.: Fatty liver and nonalcoholic steatohepatitis.Clin. Cornerstone, 2001; 3: 47-57
  Google Scholar
• 89. Nickenig G., Röling J., Strehlow K., Schnabel P., Böhm M.: Insulininduces upregulation of vascular AT1 receptor gene expression byposttranscriptional mechanisms. Circulation, 1998; 98: 2453-2460
  Google Scholar
• 90. Ouchi N., Higuchi A., Ohashi K., Oshima Y., Gokce N., ShibataR., Akasaki Y., Shimono A., Walsh K.: Sfrp5 is an anti-inflammatoryadipokine that modulates metabolic dysfunction in obesity. Science,2010; 329: 454-457
  Google Scholar
• 91. Pandey M., Loskutoff D.J., Samad F.: Molecular mechanismsof tumor necrosis factor-alpha-mediated plasminogen activatorinhibitor-1 expression in adipocytes. FASEB J., 2005; 19: 1317-1319
  Google Scholar
• 92. Pereira S., Park E., Mori Y., Haber C.A., Han P., Uchida T., StavarL., Oprescu A.I., Koulajian K., Ivovic A., Yu Z., Li D., Bowman T.A.,Dewald J., El-Benna J. i wsp.: FFA-induced hepatic insulin resistancein vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress.Am. J. Physiol. Endocrinol. Metab., 2014; 307: E34-E46
  Google Scholar
• 93. Reaven G.M.: Pathophysiology of insulin resistance in humandisease. Physiol. Rev., 1995; 75: 473-486
  Google Scholar
• 94. Reaven G.M.: The insulin resistance syndrome: definition anddietary approaches to treatment. Annu. Rev. Nutr., 2005; 25: 391-406
  Google Scholar
• 95. Reyna S.M., Ghosh S., Tantiwong P., Meka C.S., Eagan P., JenkinsonC.P., Cersosimo E., Defronzo R.A., Coletta D.K., Sriwijitkamol A.,Musi N.: Elevated toll-like receptor 4 expression and signaling inmuscle from insulin-resistant subjects. Diabetes, 2008; 57: 2595-2602
  Google Scholar
• 96. Rieusset J., Bouzakri K., Chevillotte E., Ricard N., Jacquet D.,Bastard J.P., Laville M., Vidal H.: Suppressor of cytokine signaling 3 expression and insulin resistance in skeletal muscle of obese andtype 2 diabetic patients. Diabetes, 2004; 53: 2232-2241
  Google Scholar
• 97. Rosen E.D., Spiegelman B.M.: Molecular regulation of adipogenesis.Annu. Rev. Cell Dev. Biol., 2000; 16: 145-171
  Google Scholar
• 98. Ross R.: Atherosclerosis is an inflammatory disease. Am. HeartJ., 1999; 138: S419-S420
  Google Scholar
• 99. Ross S.E., Hemati N., Longo K.A., Bennett C.N., Lucas P.C., EricksonR.L., MacDougald O.A.: Inhibition of adipogenesis by Wnt signaling.Science, 2000; 289: 950-953
  Google Scholar
• 100. Rossi R., Nuzzo A., Origliani G., Modena M.G.: Metabolic syndromeaffects cardiovascular risk profile and response to treatmentin hypertensive postmenopausal women. Hypertension, 2008; 52:865-872
  Google Scholar
• 101. Samokhvalov V., Bilan P.J., Schertzer J.D., Antonescu C.N., KlipA.: Palmitate- and lipopolysaccharide-activated macrophages evokecontrasting insulin responses in muscle cells. Am. J. Physiol. Endocrinol.Metab., 2009; 296: E37-E46
  Google Scholar
• 102. Schenk S., Horowitz J.F.: Acute exercise increases triglyceridesynthesis in skeletal muscle and prevents fatty acid-induced insulinresistance. J. Clin. Invest., 2007; 117: 1690-1698
  Google Scholar
• 103. Schipper H.S., Prakken B., Kalkhoven E., Boes M.: Adiposetissue-resident immune cells: key players in immunometabolism.Trends Endocrinol. Metab., 2012; 23: 407-415
  Google Scholar
• 104. Seki E., Brenner D.A.: Toll-like receptors and adaptor moleculesin liver disease: update. Hepatology, 2008; 48: 322-335
  Google Scholar
• 105. Sethi J.K., Vidal-Puig A.J.: Thematic review series: adipocytebiology. Adipose tissue function and plasticity orchestrate nutritionaladaptation. J. Lipid Res., 2007; 48: 1253-1262
  Google Scholar
• 106. Shi H., Kokoeva M.V., Inouye K., Tzameli I., Yin H., Flier J.S.:TLR4 links innate immunity and fatty acid-induced insulin resistance.J. Clin. Invest., 2006; 116: 3015-3025
  Google Scholar
• 107. Siebenlist U., Franzoso G., Brown K.: Structure, regulation andfunction of NF-κB. Annu. Rev. Cell Biol., 1994; 10: 405-455
  Google Scholar
• 108. Song Y., Manson J.E., Tinker L., Rifai N., Cook N.R., Hu F.B., HotamisligilG.S., Ridker P.M., Rodriguez B.L., Margolis K.L., ObermanA., Liu S.: Circulating levels of endothelial adhesion molecules andrisk of diabetes in an ethnically diverse cohort of women. Diabetes,2007; 56: 1898-1904
  Google Scholar
• 109. Stein B., Baldwin A.S.Jr.: Distinct mechanisms for regulation ofthe interleukin-8 gene involve synergism and cooperatively betweenC/EBP and NF-κB. Mol. Cell Biol., 1993; 13: 7191-7198
  Google Scholar
• 110. Stienstra R., Duval C., Keshtkar S., van der Laak J., Kersten S.,Müller M.: Peroxisome proliferator-activated receptor γ activationpromotes infiltration of alternatively activated macrophages intoadipose tissue. J. Biol. Chem., 2008; 283: 22620-22627
  Google Scholar
• 111. Straczkowski M., Kowalska I., Baranowski M., Nikolajuk A.,Otziomek E., Zabielski P., Adamska A., Blachnio A., Gorski J., GorskaM.: Increased skeletal muscle ceramide level in men at risk of developingtype 2 diabetes. Diabetologia, 2007; 50: 2366-2373
  Google Scholar
• 112. Talior I., Tennenbaum T., Kuroki T., Eldar-Finkelman H.: PKC-δ-dependent activation of oxidative stress in adipocytes of obeseand insulin-resistant mice: role for NADPH oxidase. Am. J. Physiol.Endocrinol. Metab., 2005; 288: E405-E411
  Google Scholar
• 113. Timmers S., Schrauwen P., de Vogel J.: Muscular diacylglycerolmetabolism and insulin resistance. Physiol. Behav., 2008; 94: 242-251
  Google Scholar
• 114. Tsukumo D.M., Carvalho-Filho M.A., Carvalheira J.B., PradaP.O., Hirabara S.M., Schenka A.A., Araújo E.P., Vassallo J., Curi R., VellosoL.A., Saad M.J.: Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes,2007; 56: 1986-1998
  Google Scholar
• 115. Ueki K., Kondo T., Kahn C.R.: Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibitionof tyrosine phosphorylation of insulin receptor substrate proteinsby discrete mechanisms. Mol. Cell Biol., 2004; 24: 5434-5446
  Google Scholar
• 116. Virkamäki A., Ueki K., Kahn C.R.: Protein-protein interactionin insulin signaling and the molecular mechanisms of insulin resistance.J. Clin. Invest., 1999; 103: 931-943
  Google Scholar
• 117. Wang Q., Somwar R., Bilan P.J., Liu Z., Jin J., Woodgett J.R., KlipA.: Protein kinase B/Akt participates in GLUT4 translocation by insulinin L6 myoblasts. Mol. Cell Biol., 1999; 19: 4008-4018
  Google Scholar
• 118. Weisberg S.P., Hunter D., Huber R., Lemieux J., Slaymaker S.,Vaddi K., Charo I., Leibel R.L., Ferrante A.W. Jr.: CCR2 modulates inflammatoryand metabolic effects of high-fat feeding. J. Clin. Invest.,2006; 116: 115-124
  Google Scholar
• 119. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L.,Ferrante A.W.Jr.: Obesity is associated with macrophage accumulationin adipose tissue. J. Clin. Invest., 2003; 112: 1796-1808
  Google Scholar
• 120. Williamson R.T.: On the treatment of glycosuria and diabetesmellitus with sodium salicylate. Br. Med. J., 1901; 1: 760-762
  Google Scholar
• 121. Winer D.A., Winer S., Shen L., Wadia P.P., Yantha J., Paltser G.,Tsui H., Wu P., Davidson M.G., Alonso M.N., Leong H.X., GlassfordA., Caimol M., Kenkel J.A., Tedder T.F. i wsp.: B cells promote insulinresistance through modulation of T cells and production of pathogenicIgG antibodies. Nat. Med., 2011; 17: 610-617
  Google Scholar
• 122. Winer S., Chan Y., Paltser G., Truong D., Tsui H., Bahrami J., DorfmanR., Wang Y., Zielenski J., Mastronardi F., Maezawa Y., DruckerD.J., Engleman E., Winer D., Dosch H.M.: Normalization of obesity–associated insulin resistance through immunotherapy. Nat. Med.,2009; 15: 921-929
  Google Scholar
• 123. Wright W.S., Longo K.A., Dolinsky V.W., Gerin I., Kang S., BennettC.N., Chiang S.H., Prestwich T.C., Gress C., Burant C.F., SusulicV.S., MacDougald O.A.: Wnt10b inhibits obesity in ob/ob and agoutimice. Diabetes, 2007; 56: 295-303
  Google Scholar
• 124. Wu D., Molofsky A.B., Liang H.E., Ricardo-Gonzalez R.R., JouihanH.A., Bando J.K., Chawla A., Locksley R.M.: Eosinophils sustain adiposealternatively activated macrophages associated with glucosehomeostasis. Science, 2011; 332: 243-247
  Google Scholar
• 125. Wu H., Ghosh S., Perrard X.D., Feng L., Garcia G.E., Perrard J.L,Sweeney J.F., Peterson L.E., Chan L., Smith C.W., Ballantyne C.M.: T–cell accumulation and regulated on activation, normal T cell expressedand secreted upregulation in adipose tissue in obesity. Circulation,2007; 115: 1029-1038
  Google Scholar
• 126. Xu H., Barnes G.T., Yang Q., Tan G., Yang D., Chou C.J., Sole J.,Nichols A., Ross J.S., Tartaglia L.A., Chen H.: Chronic inflammation infat plays a crucial role in the development of obesity-related insulinresistance. J. Clin. Invest., 2003; 112: 1821-1830
  Google Scholar
• 127. Zaid H., Antonescu C.N., Randhawa V.K., Klip A.: Insulin actionon glucose transporters through molecular switches, tracks and tethers.Biochem. J., 2008; 413: 201-215
  Google Scholar
• 128. Zeng G., Nystrom F.H., Ravichandran L.V., Cong L.N., KirbyM., Mostowski H., Quon M.J.: Roles for insulin receptor, PI3-kinase,and Akt in insulin-signaling pathways related to production ofnitric oxide in human vascular endothelial cells. Circulation, 2000;101: 1539-1545
  Google Scholar
• 129. Zhou M.S., Schulman I.H., Raij L.: Vascular inflammation, insulinresistance, and endothelial dysfunction in salt-sensitive hypertension:role of nuclear factor kappa B activation. J. Hypertens.,2010; 28: 527-535
  Google Scholar

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