Skip to main content

Mechanisms of insulin resistance in obesity

Abstract

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.

This is a preview of subscription content, access via your institution.

References

  1. Ye J. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocr Metab Immune Disord Drug Targets 2007; 7(1): 65–74

    PubMed  Article  CAS  Google Scholar 

  2. He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab 2011; 300(5): E877–E885

    PubMed  Article  CAS  Google Scholar 

  3. Ye J, McGuinness OP. Inflammation during obesity is not all bad: Evidence from animal and human studies. Am J Physiol Endocrinol Metab 2012 Dec 26. [Epub ahead of print] doi: 10.1152/ajpendo.00266.2012

    Google Scholar 

  4. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116(7): 1793–1801

    PubMed  Article  CAS  Google Scholar 

  5. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87–91

    PubMed  Article  CAS  Google Scholar 

  6. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89(6): 2548–2556

    PubMed  Article  CAS  Google Scholar 

  7. Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am 2008; 37(3): 753–768, x–xi

    PubMed  Article  CAS  Google Scholar 

  8. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293(5535): 1673–1677

    PubMed  Article  CAS  Google Scholar 

  9. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420(6913): 333–336

    PubMed  Article  CAS  Google Scholar 

  10. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond) 2009; 33(1): 54–66

    Article  CAS  Google Scholar 

  11. Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor necrosis factor (TNF)-α inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem 1996; 271(22): 13018–13022

    PubMed  Article  CAS  Google Scholar 

  12. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002; 277(50): 48115–48121

    PubMed  Article  CAS  Google Scholar 

  13. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser (307). J Biol Chem 2000; 275(12): 9047–9054

    PubMed  Article  CAS  Google Scholar 

  14. Gao Z, He Q, Peng B, Chiao PJ, Ye J. Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J Biol Chem 2006; 281(7): 4540–4547

    PubMed  Article  Google Scholar 

  15. Ye J. Regulation of PPARγ function by TNF-α. Biochem Biophys Res Commun 2008; 374(3): 405–408

    PubMed  Article  CAS  Google Scholar 

  16. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18(1): 621–663

    PubMed  Article  CAS  Google Scholar 

  17. Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(α) signaling through IKK2. J Biol Chem 2008; 283(51): 35375–35382

    PubMed  Article  CAS  Google Scholar 

  18. Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF. Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 2001; 107(2): 181–189

    PubMed  Article  CAS  Google Scholar 

  19. White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 2002; 283(3): E413–E422

    PubMed  CAS  Google Scholar 

  20. Ye J, Gimble JM. Regulation of stem cell differentiation in adipose tissue by chronic inflammation. Clin Exp Pharmacol Physiol 2011; 38(12): 872–878

    PubMed  Article  CAS  Google Scholar 

  21. Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL, Ringold GM. TNF α-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARγ without effects on Pref-1 expression. Endocrinology 1997; 138(7): 2776–2783

    PubMed  Article  CAS  Google Scholar 

  22. Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-α is obligatory. Diabetes 2002; 51(5): 1319–1336

    PubMed  Article  CAS  Google Scholar 

  23. Suzawa M, Takada I, Yanagisawa J, Ohtake F, Ogawa S, Yamauchi T, Kadowaki T, Takeuchi Y, Shibuya H, Gotoh Y, Matsumoto K, Kato S. Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 2 2003; 5(3): 224–230

    Article  CAS  Google Scholar 

  24. Anforth HR, Bluthe RM, Bristow A, Hopkins S, Lenczowski MJ, Luheshi G, Lundkvist J, Michaud B, Mistry Y, Van Dam AM, Zhen C, Dantzer R, Poole S, Rothwell NJ, Tilders FJ, Wollman EE. Biological activity and brain actions of recombinant rat interleukin-1α and interleukin-1β. Eur Cytokine Netw 1998; 9(3): 279–288

    PubMed  CAS  Google Scholar 

  25. Garc’Ia MC, Wernstedt I, Berndtsson A, Enge M, Bell M, Hultgren O, Horn M, Ahr’en B, Enerback S, Ohlsson C, Wallenius V, Jansson JO. Mature-onset obesity in interleukin-1 receptor I knockout mice. Diabetes 2006; 55(5): 1205–1213

    Article  CAS  Google Scholar 

  26. Wallenius V, Wallenius K, Ahr’en B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 8(1): 75–79

    PubMed  Article  CAS  Google Scholar 

  27. Xu H, Hirosumi J, Uysal KT, Guler AD, Hotamisligil GS. Exclusive action of transmembrane TNFα in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. Endocrinology 2002; 143(4): 1502–1511

    PubMed  Article  CAS  Google Scholar 

  28. Pamir N, McMillen TS, Kaiyala KJ, Schwartz MW, LeBoeuf RC. Receptors for tumor necrosis factor-α play a protective role against obesity and alter adipose tissue macrophage status. Endocrinology 2009; 150(9): 4124–4134

    PubMed  Article  CAS  Google Scholar 

  29. Chida D, Osaka T, Hashimoto O, Iwakura Y. Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice. Diabetes 2006; 55(4): 971–977

    PubMed  Article  CAS  Google Scholar 

  30. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112(12): 1821–1830

    PubMed  CAS  Google Scholar 

  31. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112(12): 1796–1808

    PubMed  CAS  Google Scholar 

  32. Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, Ranganathan G, Peterson CA, McGehee RE, Kern PA. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 2005; 54(8): 2305–2313

    PubMed  Article  Google Scholar 

  33. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006; 74: 443–477

    PubMed  Article  CAS  Google Scholar 

  34. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 2 2007; 447(7148): 1116–1120

    Article  CAS  Google Scholar 

  35. Hevener AL, Olefsky JM, Reichart D, Nguyen MTA, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 2 2007; 117(6): 1658–1669

    Article  CAS  Google Scholar 

  36. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117(1): 175–184

    PubMed  Article  CAS  Google Scholar 

  37. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3(1): 23–35

    PubMed  Article  CAS  Google Scholar 

  38. Mosser DM. The many faces of macrophage activation. J Leukoc Biol 2003; 73(2): 209–212

    PubMed  Article  CAS  Google Scholar 

  39. Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 2007; 56(6): 1517–1526

    PubMed  Article  CAS  Google Scholar 

  40. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 2007; 100(4): e47–e57

    PubMed  Article  CAS  Google Scholar 

  41. Lijnen HR. Angiogenesis and obesity. Cardiovasc Res 2008; 78(2): 286–293

    PubMed  Article  CAS  Google Scholar 

  42. Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab 2008; 295(2): E313–E322

    PubMed  Article  CAS  Google Scholar 

  43. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46(11): 2347–2355

    PubMed  Article  CAS  Google Scholar 

  44. Clavien PA. IL-6, a key cytokine in liver regeneration. Hepatology 1997; 25(5): 1294–1296

    PubMed  Article  CAS  Google Scholar 

  45. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-κB. Nat Med 2005; 11(2): 183–190

    PubMed  Article  CAS  Google Scholar 

  46. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11(2): 191–198

    PubMed  Article  CAS  Google Scholar 

  47. Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, Ko HJ, Ong H, Kim JK, Mynatt R, Martin RJ, Keenan M, Gao Z, Ye J. Uncoupling of inflammation and insulin resistance by NF-κB in transgenic mice through elevated energy expenditure. J Biol Chem 2010; 285(7): 4637–4644

    PubMed  Article  CAS  Google Scholar 

  48. Jiao P, Feng B, Ma J, Nie Y, Paul E, Li Y, Xu H. Constitutive activation of IKKβ in adipose tissue prevents diet-induced obesity in mice. Endocrinology 2012; 153(1): 154–165

    PubMed  Article  CAS  Google Scholar 

  49. Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc Trans 2007; 35(5): 1295–1297

    PubMed  Article  CAS  Google Scholar 

  50. Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 2012; 16(2): 153–166

    PubMed  Article  CAS  Google Scholar 

  51. Straub RH, Cutolo M, Buttgereit F, Pongratz G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 2010; 267(6): 543–560

    PubMed  Article  CAS  Google Scholar 

  52. Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging (Albany NY) 2010; 2(6): 361–368

    CAS  Google Scholar 

  53. Holloszy JO. Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol 2005; 99(1): 338–343

    PubMed  Article  CAS  Google Scholar 

  54. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307(5708): 384–387

    PubMed  Article  CAS  Google Scholar 

  55. Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8(2): 92–103

    Article  CAS  Google Scholar 

  56. Holloszy JO. Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance. Am J Clin Nutr 2009; 89(1): 463S–466S

    PubMed  Article  CAS  Google Scholar 

  57. Pagel-Langenickel I, Bao J, Pang L, Sack MN. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr Rev 2010; 31(1): 25–51

    PubMed  Article  CAS  Google Scholar 

  58. Muoio DM. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim Biophys Acta 2010; 1801(3): 281–288

    PubMed  Article  CAS  Google Scholar 

  59. Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005; 115(12): 3587–3593

    PubMed  Article  CAS  Google Scholar 

  60. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 2003; 100(13): 7996–8001

    PubMed  Article  CAS  Google Scholar 

  61. Sreekumar R, Halvatsiotis P, Schimke JC, Nair KS. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 2002; 51(6): 1913–1920

    PubMed  Article  CAS  Google Scholar 

  62. Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 1991; 88 (3): 960–966

    PubMed  Article  CAS  Google Scholar 

  63. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97(12): 2859–2865

    PubMed  Article  CAS  Google Scholar 

  64. Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhäusl W, Fürnsinn C. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 2004; 53(4): 1052–1059

    PubMed  Article  CAS  Google Scholar 

  65. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(3): 607–614

    PubMed  Article  CAS  Google Scholar 

  66. Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 2008; 294(1): E148–E156

    PubMed  Article  CAS  Google Scholar 

  67. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 2010; 11(6): 554–565

    PubMed  Article  CAS  Google Scholar 

  68. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 2008; 31(Suppl 2): S262–S268

    PubMed  Article  CAS  Google Scholar 

  69. Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 2012; 61(1): 4–13

    PubMed  Article  CAS  Google Scholar 

  70. Gray SL, Donald C, Jetha A, Covey SD, Kieffer TJ. Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic β-cell leptin signaling. Endocrinology 2010; 151(9): 4178–4186

    PubMed  Article  CAS  Google Scholar 

  71. Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 1998; 102(5): 869–873

    PubMed  Article  CAS  Google Scholar 

  72. Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, Bamji SX, Clee SM, Johnson JD. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 2012; 16(6): 723–737

    PubMed  Article  CAS  Google Scholar 

  73. Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003; 22(6): 487–493

    PubMed  Google Scholar 

  74. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 2000; 6(1): 87–97

    PubMed  CAS  Google Scholar 

  75. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100(7): 4162–4167

    PubMed  Article  CAS  Google Scholar 

  76. Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, Eckman CB, Tanzi RE, Selkoe DJ. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid β-protein. Am J Pathol 2004; 164 (4): 1425–1434

    PubMed  Article  CAS  Google Scholar 

  77. Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokinemediated process? Diabetes 2002; 51(10): 2951–2958

    PubMed  Article  CAS  Google Scholar 

  78. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300(5622): 1140–1142

    PubMed  Article  CAS  Google Scholar 

  79. Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 2007; 5(2): 151–156

    PubMed  Article  CAS  Google Scholar 

  80. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006; 440(7086): 944–948

    PubMed  Article  CAS  Google Scholar 

  81. Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 2008; 57(5): 1166–1175

    PubMed  Article  CAS  Google Scholar 

  82. Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 2000; 11(9): 351–356

    PubMed  Article  CAS  Google Scholar 

  83. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106(2): 171–176

    PubMed  Article  CAS  Google Scholar 

  84. Boden G. Free fatty acids and insulin secretion in humans. Curr Diab Rep 2005; 5(3): 167–170

    PubMed  Article  CAS  Google Scholar 

  85. Paolisso G, Tataranni PA, Foley JE, Bogardus C, Howard BV, Ravussin E. A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 1995; 38(10): 1213–1217

    PubMed  Article  CAS  Google Scholar 

  86. Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004; 28(Suppl 4): S12–S21

    PubMed  Article  CAS  Google Scholar 

  87. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998; 12(20): 3182–3194

    PubMed  Article  CAS  Google Scholar 

  88. Schenk S, Horowitz JF. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest 2007; 117(6): 1690–1698

    PubMed  Article  CAS  Google Scholar 

  89. Yadav H, Quijano C, Kamaraju AK, Gavrilova O, Malek R, Chen W, Zerfas P, Zhigang D, Wright EC, Stuelten C, Sun P, Lonning S, Skarulis M, Sumner AE, Finkel T, Rane SG. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab 2011; 14(1): 67–79

    PubMed  Article  CAS  Google Scholar 

  90. Tan CK, Leuenberger N, Tan MJ, Yan YW, Chen Y, Kambadur R, Wahli W, Tan NS. Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet. Diabetes 2011; 60(2): 464–476

    PubMed  Article  CAS  Google Scholar 

  91. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005; 1(1): 15–25

    PubMed  Article  CAS  Google Scholar 

  92. Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009; 9(5): 407–416

    PubMed  Article  CAS  Google Scholar 

  93. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 2003; 278(39): 37041–37051

    PubMed  Article  CAS  Google Scholar 

  94. Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Häring HU, Schleicher ED. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB. J Biol Chem 2004; 279(23): 23942–23952

    PubMed  Article  CAS  Google Scholar 

  95. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. 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

    PubMed  Article  CAS  Google Scholar 

  96. Brose N, Rosenmund C. Move over protein kinase C, you’ve got company: alternative cellular effectors of diacylglycerol and phorbol esters. J Cell Sci 2002; 115(23): 4399–4411

    PubMed  Article  CAS  Google Scholar 

  97. Ballou LR, Laulederkind SJ, Rosloniec EF, Raghow R. Ceramide signalling and the immune response. Biochim Biophys Acta 1996; 1301(3): 273–287

    PubMed  Article  Google Scholar 

  98. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): 457–461

    PubMed  Article  CAS  Google Scholar 

  99. de Luca C, Olefsky JM. Stressed out about obesity and insulin resistance. Nat Med 2006; 12(1): 41–42, discussion 42

    PubMed  Article  CAS  Google Scholar 

  100. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 2009; 9(1): 35–51

    PubMed  Article  CAS  Google Scholar 

  101. Schröder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res 2005; 569(1–2): 29–63

    PubMed  Google Scholar 

  102. Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med 2011; 17(10): 1251–1260

    PubMed  Article  CAS  Google Scholar 

  103. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313(5790): 1137–1140

    PubMed  Article  CAS  Google Scholar 

  104. Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165(5): 670–676

    PubMed  Google Scholar 

  105. Iiyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O’Doherty RM, Polotsky VY, O’Donnell CP. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007; 175(8): 851–857

    PubMed  Article  CAS  Google Scholar 

  106. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293(4): E1118–E1128

    PubMed  Article  CAS  Google Scholar 

  107. Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 2009; 89(1): 27–71

    PubMed  Article  CAS  Google Scholar 

  108. Greene EL, Lu G, Zhang D, Egan BM. Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension 2001; 37(2): 308–312

    PubMed  Article  CAS  Google Scholar 

  109. Lu G, Greene EL, Nagai T, Egan BM. Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension 1998; 32(6): 1003–1010

    PubMed  Article  CAS  Google Scholar 

  110. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114(12): 1752–1761

    PubMed  CAS  Google Scholar 

  111. Lin Y, Berg AH, Iyengar P, Lam TKT, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 2005; 280(6): 4617–4626

    PubMed  Article  CAS  Google Scholar 

  112. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003; 52(1): 1–8

    PubMed  Article  CAS  Google Scholar 

  113. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet β cells in diabetes. J Biol Chem 2004; 279(41): 42351–42354

    PubMed  Article  CAS  Google Scholar 

  114. Aragon’es J, Fraisl P, Baes M, Carmeliet P. Oxygen sensors at the crossroad of metabolism. Cell Metab 2009; 9(1): 11–22

    Article  CAS  Google Scholar 

  115. Prabhakar NR, Kumar GK, Nanduri J, Semenza GL. ROS signaling in systemic and cellular responses to chronic intermittent hypoxia. Antioxid Redox Signal 2007; 9(9): 1397–1403

    PubMed  Article  CAS  Google Scholar 

  116. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48(1): 1–9

    PubMed  Article  CAS  Google Scholar 

  117. Ceriello A. Oxidative stress and glycemic regulation. Metabolism 2000; 49(2 Suppl 1): 27–29

    PubMed  Article  CAS  Google Scholar 

  118. Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, Ono H, Fujishiro M, Kushiyama A, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Gotoh Y, Komuro I, Fujita T. Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia 2004; 47(5): 794–6805

    PubMed  Article  CAS  Google Scholar 

  119. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med 2001; 345(11): 790–797

    PubMed  Article  CAS  Google Scholar 

  120. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012; 481(7382): 511–515

    PubMed  Article  CAS  Google Scholar 

  121. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401(6748): 73–76

    PubMed  Article  CAS  Google Scholar 

  122. Zhang Y, Ye J. Mitochondrial inhibitor as a new class of insulin sensitizer. Acta Pharmaceutica Sinica B 2012; 2(4): 341–349

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jianping Ye.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ye, J. Mechanisms of insulin resistance in obesity. Front. Med. 7, 14–24 (2013). https://doi.org/10.1007/s11684-013-0262-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-013-0262-6

Keywords

  • type 2 diabetes
  • energy expenditure
  • inflammation
  • lipotoxicity
  • mitochondria
  • hyperinsulinemia
  • adenosine monophosphate-activated protein kinase (AMPK)