Inflammation as a factor of the pathogenesis of insulin resistance and type 2 diabetes

Cite item

Full Text


Insulin resistance (IR) is a leading factor of type 2 diabetes (T2D), the central and governing component of the metabolic syndrome (MS), that also appears as obesity, glucose intolerance, dyslipidemia, and essential hypertension.
Recent experimental studies have indicated that proinflammatory cytokines, adipocytokines, and transcription factors are implicated in the pathogenesis of IR, as evidenced by a number of clinical observations in patients with MS and T2D, in whom IR correlates with the status of chronic mild inflammation. Based on the results of these studies, a search for methods for exposure of IR has been initiated, by controlling inflammation. The first results encourage and suggest that anti-inflammatory agents improve tissue susceptibility to insulin and they are promising for the treatment of MS and T2D.

About the authors

Viktor Shvarts


V Schwarz


  1. Shoelson S. E., Lee J., Goldfine A. B. Inflammation and insulin resistance. J. Clin. Invest. 2006; 116: 1793-1801.
  2. Tilg H., Moschen A. R. Inflammatory mechanisms in the regulation of insulin resistance. Mol. Med. 2008; 14 (3-4): 222- 231.
  3. Cave M. C., Hurt R. T., Frazier T. H. et al. Obesity, inflammation, and the potential application of pharmaconutrition. Nutr. Clin. Pract. 2008; 23 (1): 16-34.
  4. Ebstein W. Zur therapie des Diabetes mellitus, insbesondere uber die Anwendung des salicylsauren Natron bei demselben. Berliner Klinische Wochenschrift. 1876; 13: 337-340.
  5. Williamson R. T. On the treatment of glucosuria and diabetes mellitus with sodium salicylate. Br. Med. J. 1901; 1: 760-762.
  6. Reid J., Macdougall A. I., Andrews M. M. On the efficacy of salicylate in treating diabetes mellitus. Br. Med. J. 1957; 2: 1071-1074.
  7. Baron S. H. Salicylates as hypoglycemic agents. Diabet. Care 1982; 5: 64-71.
  8. Yuan M. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 2001; 293: 1673-1677.
  9. Hotamisligil G. S., Shargill N. S., Spiegelman B. M. Adipose expression of tumor necrosis factor-: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
  10. Cavalot F., Massucco P., Perna P. et al. White blood cell counts is positively correlated with albumin excretion rate in subjects with type 2 diabetes. Diabet. Care 2002; 25 (12): 2354-2355.
  11. Veronelli A., Laneri M., Ranieri R. et al. White blood cells in obesity and diabetes: effects ofr weight loss and normalisation of glucose metabolism. Diabet. Care 2004; 27 (10): 2501-2502.
  12. Chen L. K., Lin M. H., Chen Z. J. et al. Association of insulin resistance and hematologic parameters: study of a middle-aged and elderly Chinese population in Taiwan. J. Chin. Med. Assoc. 2006; 69 (6): 248-253.
  13. Zulet M. A., Puchau B., Navarro C. et al. Inflammatory biomarkers: the link between obesity and associated pathologies. Nutr. Hosp. 2007; 22 (5): 511-527.
  14. Han T. S., Sattar N., Williams K. et al. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City diabetes study. Diabet. Care 2002; 25: 2016-2021.
  15. Takebayashi K., Suetsugu M., Matsutomo R. et al. Correlation of high-sensitivity C-reactive protein and plasma fibrinogen with individual complications in patients with type 2 diabetes. South. Med. J. 2006; 99: 23-27.
  16. Steensberg A. The role of IL-6 in exercise-induced immune changes and metabolism. Exerc. Immunol. Rev. 2003; 9: 40- 47.
  17. Pang S., Le Y. Role of resistin in inflammation and inflammation-related diseases. Cell. Mol. Immunol. 2006; 3: 29-34.
  18. Xu W., Yu L., Zhou W., Luo M. Resistin increases lipid accumulation and CD36 expression in human macrophages. Biochem. Biophys. Res. Commun. 2006; 351: 376-382.
  19. Jung H. S., Park K. H., Cho Y. M. et al. Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc. Res. 2006; 69: 76-85.
  20. Weisberg S. P., McCann D., Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 2003; 112: 1796-1808.
  21. Curat C. A., Wegner V., Sengenes C. et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006; 49: 744-747.
  22. Arkan M. C., Hevener A. L., Greten F. R. et al. IKK-beta links inflammation of obesity-related insulin resistance. Nat. Med. 2005; 11: 191-198.
  23. Weisberg S. P., Hunter D., Huber R. et al. CCR2 modulates inflammatory and metabolic effects of high fat feeding. J. Clin. Invest. 2006; 116: 115-124.
  24. Fernandez-Real J. M., Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr. Rev. 2003; 24: 278-301.
  25. Hirosumi J. et al. A central role for JNK in obesity and insuline resistance. Nature 2002; 420: 333-336.
  26. Cai D. et al. Local and systemic insulin resistance resulting from hepatic activation of LKK and NF-κB. Nat. Med. 2005; 11: 183-190.
  27. Fantuzzi G., Mazzone T. Adipose tissue and atherosclerosis: Exploring the connection. Arterioscler. Thromb. Vasc. Biol. 2007; 27: 996-1003.
  28. Ouchi N., Kihara S., Arita Y. et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signalling through a cAMP-dependent pathway. Circulation 2006; 120: 1296-1301.
  29. Griffin М. Е. et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase С theta and alterations in the insulin signalling cascade. Diabetes 1999; 48: 1270-1274.
  30. Itani S. I., Ruderman N. B., Schmieder F. et al. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005-2011.
  31. De Alvaro C., Teruel T., Hernandez R., Lorenzo M. Tumor necrosis factor alpha produced insulin resistance in sceletal muscle by activation of inhibitor kappaBkinase in ap38 MARK-deppendent manner. J. Biol. Chem. 2004; 279: 17070-17078.
  32. Granner D. K., O'Brien R. M. Molecular physiology and genetics of NIDDM. Diabet. Care 1992; 15: 369-395.
  33. Ruan H., Lodisch H. F. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis faktor. Cytokine Growth Factor Rev. 2003; 14: 447-455.
  34. Ruan H., Miles P. D., Ladd C. M. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistence. Diabetes, 2002; 51: 3176-3188.
  35. Judkin J. S. Inflammation, obesity, and the metabolic syndrome. Horm. Metab. Res. 2007; 39 (10): 707-709.
  36. Boden G., Cheung P., Stein T. P. et al. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am. J. Physiol. Endocrinol. Metab. 2002; 283 (1): E12-E19.
  37. Kim J. K., Fillmore J. J., Sunshine M. J. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 2004; 114 (6): 823-827.
  38. Gao Z., Zhang X., Zuberi A. et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol. Endocrinol. 2004; 18 (8): 2024-2034.
  39. Weisberg S. P. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 2006; 116: 115-124.
  40. Geffken D. F., Gushman M., Burke G. L. et al. Association between physical activity and markers of inflammation in a healthy elderly population. Am. J. Epidemiol. 2001; 153: 242-250.
  41. Abramson J. L., Vaccarino V. Relationship between physical activity and inflammation among apparently healthy middle-aged older US adults. Arch. Intern. Med. 2002; 162: 1286-1292.
  42. Fallon K. E., Fallon S. K., Boston T. The acute phase response and exercise: court and field sports. Br. J. Sports Med. 2001; 35: 170-173.
  43. Starkie R., Ostrowski S. R., Jauffred S. et al. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003; 17: 884-886.
  44. Tsukui S., Kanda T., Nara M. et al. Moderate-intensity regular exercise decrease serum tumor necrose factor-alpha and HdF1c levels in healthy women. Int. J. Obes. Relat. Metab. Disord. 2000; 24: 1207-1211.
  45. Nicklas B. J., Ambrosius W., Messier S. P. et al. Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial. Am. J. Clin. Nutr. 2004; 79: 544-551.
  46. Esposito K., Pontillo A., Di Palo C. et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. J. A. M. A. 2003; 289: 1799-1804.
  47. De Mello V. D., Kolehmainen M., Schwab U. et al. Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome. Metabolism 2008; 57 (2): 192-199.
  48. Vendrell J., Broch M., Vilarassa N. et al. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationship in obesity. Obes. Res. 2004; 12: 962-971.
  49. Laimer M., Ebenbichler C. F., Kaser S. et al. Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention. Int. J. Obest. Relat. Metab. Disord. 2002; 26: 659-662.
  50. Klein S., Fontana L., Young V. L. et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N. Engl. J. Med. 2004; 350: 2549-2557.
  51. Simpson R. W., Shaw J. E., Zimmer P. Z. The prevention of type diabetes - lifestyle change or pharmacotherapy? A challenge for the 21st century. Diabet. Res. Clin. Pract. 2003; 59 (3): 165-180.
  52. Storlien L. H., Kraegen E. W., Chisholm D. J. et al. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987; 237: 885-888.
  53. Geusens P., Wouters C., Nijs J. et al. Long term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis. A 12 month, double blind, controlled study. Arthr. and Rheum. 1994; 37: 824-829.
  54. Beluzzi A., Brignola C., Campieri M. et al. Effect on enteric-coated fish-oil preparation on relapses in Crohn's disease. N. Engl. J. Med. 1996; 334: 1557-1560.
  55. Rallidis L. S., Paschos G., Liakos G. K. et al. Dietary a-linolenic acid and decreases C-reactive protein, serum amyloid A and interleukin 6 in dyslipidaemic patients. Atherosclerosis 2003; 167: 237-242.
  56. Trebble T., Arden N. K., Stroud M. A. et al. Inhibition of tumor necrosis factor alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br. J. Nutr. 2003; 90: 405-412.
  57. Todoric J., Loffler M., Huber J. et al. Adipose tissue inflammation induced by high-fat diet in obese diabetic moce is prevented by n-3 polyunsaturated fatty acids. Diabetologia 2006; 112: 239-254.
  58. Coreyy E. J., Shih C., Cashman J. R. Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc. Natl. Acad. Sci. USA 1983; 80: 3581-3584.
  59. Lee T. H., Mencia-Huerta J. M., Shih C. et al. Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils. J. Clin. Invest. 1984; 74: 1922-1933.
  60. Hughes D. A. In vitro and in vivo effects of n-3 polyunsaturated fatty acids on human monocyte function. Proc. Nutr. Soc. 1998; 57: 521-525.
  61. Bannenberg G. L., Chiang N., Ariel A. et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 2005; 174: 4345-4355.
  62. Xu H. E., Lambert M. H., Montana V. G. et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 1999; 3: 397-403.
  63. Lee C. H., Chawla A., Urbiztondo N. et al. Transcriptional repression of atherogenic inflammation: modulation by PPAR. Science 2003; 302: 453-457.
  64. Neschen S., Morino K., Rossbacher J. C. et al. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-dependent mechanism in mice. Diabetes 2006; 55: 924-928.
  65. Yki-Jarvinen H. Thiazolidinediones. N. Engl. J. Med. 2004; 351: 1106-1118.
  66. Ialenti A. et al. Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway. Mol. Pharmacol. 2005; 67: 1620-1628.
  67. Glass C. K., Ogawa S. Combinatorial roles of nuclear receptors in inflammational immunity. Nat. Rev. Immunol. 2006; 6: 44-55.
  68. Castrillo A., Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu. Rev. Cell. Dev. Biol. 2004; 20: 455-480.
  69. Goldstein B. J., Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular function. J. Clin. Endocrinol. 2004; 89: 2563-2568.
  70. Xiang A. H. et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes 2006; 55: 517-522.
  71. Meisner F. et al. Effect of pioglitazone treatment on plaque inflammation and collagen content in nondiabetic patients: date from randomized placebo-controlled trial. Arterioscler. Thromb. Vasc. Biol. 2006; 26: 845-850.
  72. Bullkao C., Ribeiro-Filho F. F., Sanudo А. et al. Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. Am. J. Cardiovasc. Drugs 2007; 7: 219-224.
  73. Orio F., Manguso F., Di Biase S. et al. Metformin administration improves leukocyte count in women with polycystic ovary syndrome: a 6-month prospective study. Eur. J. Endjcrinol. 2007; 157: 69-73.
  74. Ersoy C., Kiyici S., Budak F. et al. The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabet. Res. Clin. Pract. 2008; 3: 256-265.
  75. Hannori Y., Suzuki K., Hattori S. et al. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006; 47: 1183-1188.
  76. Akbar D. H. Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 2003; 20: 215-218.
  77. Yin W. H., Jen H. L., Chen L. W. et al. Differential effects of peroxisome proliferator-activated receptor ligands and sulfonylurea plus statin treatment in plasma concentrations of adipokines in type 2 diabetes with dyslipidemia. Diabet. Metab. 2006; 32: 229-235.
  78. Koshiba K., Nomura M., Nakaya Y., Ito S. Efficacy of glimepiride on insulin resistance, adipocytokines, and atherosclerosis. J. Med. Invest. 2006; 53: 87-94.
  79. Hanefeld M., Marx N., Pfutzner A. et al. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J. Am. Coll. Cardiol. 2007; 49: 290- 297.
  80. Gomez-Garcia A., Martinez T. G., Ortega-Pierres L. E. et al. Rosuvastatin and metformin decrease inflammation and oxidative stress in patients with hypertension and dyslipidemia. Rev. Esp. Cardiol. 2007; 60: 1242-1249.
  81. Kastelein J. P., Akdim F., Stroes E. S. et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 2008; 358 (14): 1431-1443.
  82. Barbuio R., Milanski M., Bertolo M. B. et al. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J. Endocrinol. 2007; 194: 539-550.
  83. Bernstein L. E., Berry J., Kim S. et al. Effects of etanercept in patients with the metabolic syndrome. Arch. Intern. Med. 2006; 166: 902-908.
  84. Paquot N., Castillo M. J., Lefebvre P. J. et al. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J. Clin. Endocrinol. 2000; 85: 1316-1319.
  85. Dominguez H., Storgaard H., Rask-Madsen C. et al. Metabolic and vascular effects of tumor necrosis factor-alpha blocade with etanercept in obese patients with type 2 diabetes. J. Vasc. Res. 2005; 42: 517-525.
  86. Rosenvinge A., Krogh-Madsen R., Baslund B. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand. J. Rheumatol. 2007; 36: 91-96.
  87. Yuan M., Konstantinopoulos N., Lee J. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673-1677.
  88. Hundal R. S., Petersen K. F., Mayerson A. B. et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J. Clin. Invest. 2002; 109: 1321-1326.
  89. Yin M. J., Yamamoto Y., Gaynor R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.
  90. Somm E., Cettour-Rose P., Aensio C. et al. Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents. Diabetologia 2006; 49: 387-393.
  91. Larsen C. M., Faulenbach M., Vaag A. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 2007; 356: 1517-1526.
  92. Bogdanski P., Pupek-Musialik D., Dytfeld J. et al. Influence of insulin therapy on expression of chemokine receptor CCR5 and selected inflammatory markers in patients with type 2 diabetes mellitus. Int. J. Clin. Pharmacol. Ther. 2007; 45: 563- 567.
  93. Dandona P., Chaudhuri A., Mohanty P., Ghanim H. Anti-inflammatory effects of insulin. Curr. Opin. Clin. Nutr. Metab. Care 2007; 10: 511-517.

Copyright (c) 2009 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Address of the Editorial Office:

  • Novij Zykovskij proezd, 3, 40, Moscow, 125167

Correspondence address:

  • Alabyan Street, 13/1, Moscow, 127055, Russian Federation

Managing Editor:

  • Tel.: +7 (926) 905-41-26
  • E-mail:


© 2018-2021 "Consilium Medicum" Publishing house

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies