Molecular Mechanisms of Insulin Resistance Development

Insulin resistance (IR) is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM) and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.
IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell). Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.
This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

insulin resistance, type 2 diabetes mellitus, insulin-dependent intracellular signaling, feedback, IRS protein, phosphor?ylation

1. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. The Lancet 2010;375(9733):2267-2277. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673610604084 doi: 10.1016/S0140-6736(10)60408-4.

2. Isganaitis E, Lustig RH. Fast Food, Central Nervous System Insulin Resistance, and Obesity. Arteriosclerosis, Thrombosis, and Vascular Biology 2005;25(12):2451-2462. Available from: http://atvb.ahajournals.org/cgi/doi/10.1161/01.ATV.0000186208.06964.91 PubMed PMID: 16166564. doi: 10.1161/01.ATV.0000186208.06964.91.

3. Grayson BE, Seeley RJ, Sandoval DA. Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nat Rev Neurosci 2013;14(1):24-37. Available from: http://www.nature.com/doifinder/10.1038/nrn3409 PubMed PMID: 23232606. doi: 10.1038/nrn3409.

4. Flier J. Obesity WarsMolecular Progress Confronts an Expanding Epidemic. Cell 2004;116(2):337-350. Available from: http://linkinghub.elsevier.com/retrieve/pii/S009286740301081X PubMed PMID: 14744442. doi: 10.1016/S0092-8674(03)01081-X.

5. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444(7121):860-867. Available from: http://www.nature.com/doifinder/10.1038/nature05485 PubMed PMID: 17167474. doi: 10.1038/nature05485.

6. Schwartz MW, Seeley RJ, Tschöp MH, Woods SC, Morton GJ, Myers MG, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 2013;503(7474):59-66. Available from: http://www.nature.com/doifinder/10.1038/nature12709 PubMed PMID: 24201279. doi: 10.1038/nature12709.

7. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012;13(4):251-262. Available from: http://www.nature.com/doifinder/10.1038/nrm3311 PubMed PMID: 22436748. doi: 10.1038/nrm3311.

8. Ghillebert R, Swinnen E, Wen J, Vandesteene L, Ramon M, Norga K, et al. The AMPK/SNF1/SnRK1 fuel gauge and energy regulator: structure, function and regulation. FEBS Journal 2011;278(21):3978-3990. Available from: http://doi.wiley.com/10.1111/j.1742-4658.2011.08315.x PubMed PMID: 21883929. doi: 10.1111/j.1742-4658.2011.08315.x.

9. Wullschleger S, Loewith R, Hall MN. TOR Signaling in Growth and Metabolism. Cell 2006;124(3):471-484. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0092867406001085 PubMed PMID: 16469695. doi: 10.1016/j.cell.2006.01.016.

10. Watson RT, Pessin JE. Bridging the GAP between insulin signaling and GLUT4 translocation. Trends in Biochemical Sciences 2006;31(4):215-222. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0968000406000612 PubMed PMID: 16540333. doi: 10.1016/j.tibs.2006.02.007.

11. Kadowaki T, Yamauchi T. Adiponectin Receptor Signaling: A New Layer to the Current Model. Cell Metabolism 2011;13(2):123-124. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1550413111000131 PubMed PMID: 21284979. doi: 10.1016/j.cmet.2011.01.012.

12. Goldfine AB, Kahn CR. Adiponectin: linking the fat cell to insulin sensitivity. The Lancet 2003;362(9394):1431-1432. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673603147277 doi: 10.1016/S0140-6736(03)14727-7.

13. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2010;17(1):55-63. Available from: http://www.nature.com/doifinder/10.1038/nm.2277 PubMed PMID: 21186369. doi: 10.1038/nm.2277.

14. Oppert J, Nadeau A, Tremblay A, Després J, Thériault G, Dériaz O, et al. Plasma glucose, insulin, and glucagon before and after long-term overfeeding in identical twins. Metabolism 1995;44(1):96-105. Available from: http://linkinghub.elsevier.com/retrieve/pii/0026049595902953 PubMed PMID: 7854173. doi: 10.1016/0026-0495(95)90295-3.

15. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 1999;48(4):839-847. Available from: http://diabetes.diabetesjournals.org/cgi/doi/10.2337/diabetes.48.4.839 PubMed PMID: 10102702. doi: 10.2337/diabetes.48.4.839.

16. Snel M, Jonker JT, Schoones J, Lamb H, Roos, A. de , Pijl H, et al. Ectopic Fat and Insulin Resistance: Pathophysiology and Effect of Diet and Lifestyle Interventions. International Journal of Endocrinology 2012;2012:1-18. Available from: http://www.hindawi.com/journals/ije/2012/983814 PubMed PMID: 22675355. doi: 10.1155/2012/983814.

17. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proceedings of the National Academy of Sciences 2009;106(36):15430-15435. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0904944106 PubMed PMID: 19706383. doi: 10.1073/pnas.0904944106.

18. Mizuno TM, Funabashi T, Kleopoulos SP, Mobbs CV. Specific preservation of biosynthetic responses to insulin in adipose tissue may contribute to hyperleptinemia in insulin-resistant obese mice. J Nutr 2004;134(5):1045-1050.

19. Kitamura T, Kahn CR, Accili D. Insulin receptor knockout mice.. Annu. Rev. Physiol 2003;65(1):313-332. Available from: http://www.annualreviews.org/doi/abs/10.1146/annurev.physiol.65.092101.142540 PubMed PMID: 12471165. doi: 10.1146/annurev.physiol.65.092101.142540.

20. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis 2004;8(3):521-533. Available from: http://www.scholaruniverse.com/ncbi-linkout?id=15331061 PubMed PMID: 15331061. doi: 10.1016/j.cld.2004.04.004.

21. Steinberg SF. Structural Basis of Protein Kinase C Isoform Function. Physiological Reviews 2008;88(4):1341-1378. Available from: http://physrev.physiology.org/cgi/doi/10.1152/physrev.00034.2007 PubMed PMID: 18923184. doi: 10.1152/physrev.00034.2007.

22. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proceedings of the National Academy of Sciences 2011;108(39):16381-16385. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1113359108 doi: 10.1073/pnas.1113359108.

23. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006;55(Suppl 2):9-15. doi: 10.2337/db06-S002.

24. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, et al. Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle. Journal of Biological Chemistry 2002;277(52):50230-50236. Available from: http://www.jbc.org/cgi/doi/10.1074/jbc.M200958200 PubMed PMID: 12006582. doi: 10.1074/jbc.M200958200.

25. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity. J. Clin. Invest 1999;103(2):253-259. Available from: http://www.jci.org/articles/view/5001 doi: 10.1172/JCI5001.

26. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1 H NMR spectroscopy study. Diabetologia 1999;42(1):113-116. Available from: http://link.springer.com/10.1007/s001250051123 PubMed PMID: 10027589. doi: 10.1007/s001250051123.

27. Iochida LC, Tominaga M, Matsumoto M, Sekikawa A, Sasaki H. Insulin resistance in septic rats - a study by the euglycemic clamp technique. Life Sciences 1989;45(17):1567-1573. Available from: http://linkinghub.elsevier.com/retrieve/pii/0024320589904232 PubMed PMID: 2685486. doi: 10.1016/0024-3205(89)90423-2.

28. Shangraw RE, Jahoor F, Miyoshi H, Neff WA, Stuart CA, Herndon DN, et al. Differentiation between septic and postburn insulin resistance. Metabolism 1989;38(10):983-989. Available from: http://linkinghub.elsevier.com/retrieve/pii/0026049589900103 PubMed PMID: 2677612. doi: 10.1016/0026-0495(89)90010-3.

29. Pickup JC, Crook MA. Is Type II diabetes mellitus a disease of the innate immune system. Diabetologia 1998;41(10):1241-1248. Available from: http://link.springer.com/10.1007/s001250051058 PubMed PMID: 9794114. doi: 10.1007/s001250051058.

30. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link. Atherosclerosis 2000;148(2):209-214. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0021915099004633 doi: 10.1016/S0021-9150(99)00463-3.

31. Hotamisligil G, Shargill N, Spiegelman B. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259(5091):87-91. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.7678183 PubMed PMID: 7678183. doi: 10.1126/science.7678183.

32. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest 1995;95(5):2409-2415. Available from: http://www.jci.org/articles/view/117936 doi: 10.1172/JCI117936.

33. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307. Journal of Biological Chemistry 2000;275(12):9047-9054. Available from: http://www.jbc.org/cgi/doi/10.1074/jbc.275.12.9047 PubMed PMID: 10722755. doi: 10.1074/jbc.275.12.9047.

34. Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, DeFronzo RA, et al. NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions.. Am J Physiol Endocrinol Metab 2010;299(5):794-801. Available from: http://ajpendo.physiology.org/cgi/pmidlookup?view=long&pmid=20739506 PubMed PMID: 20739506. doi: 10.1152/ajpendo.00776.2009.

35. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest 2003;112(12):1796-1808. Available from: http://www.jci.org/articles/view/19246 PubMed PMID: 14679176. doi: 10.1172/JCI19246.

36. Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van_Hall . G IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab 2010;299(5):832-840. doi: 10.1152/ajpendo.00328.2010.

37. Bézaire V, Langin D. Regulation of adipose tissue lipolysis revisited. Proc. Nutr. Soc 2009;68(04):350-360. Available from: http://www.journals.cambridge.org/abstract_S0029665109990279 PubMed PMID: 19698205. doi: 10.1017/S0029665109990279.

38. Ranjit S, Boutet E, Gandhi P, Prot M, Tamori Y, Chawla A, et al. Regulation of fat specific protein 27 by isoproterenol and TNF- to control lipolysis in murine adipocytes. The Journal of Lipid Research 2011;52(2):221-236. Available from: http://www.jlr.org/cgi/doi/10.1194/jlr.M008771 doi: 10.1194/jlr.M008771.

39. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. Journal of Clinical Investigation 2006;116(6):1494-1505. Available from: http://www.jci.org/cgi/doi/10.1172/JCI26498 doi: 10.1172/JCI26498.

40. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest 2006;116(1):115-124. Available from: http://www.jci.org/articles/view/24335 PubMed PMID: 16341265. doi: 10.1172/JCI24335.

41. Hotamisligil GS. Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease. Cell 2010;140(6):900-917. Available from: http://linkinghub.elsevier.com/retrieve/pii/S009286741000187X doi: 10.1016/j.cell.2010.02.034.

42. Rutkowski DT, Hegde RS. Regulation of basal cellular physiology by the homeostatic unfolded protein response. The Journal of Cell Biology 2010;189(5):783-794. Available from: http://www.jcb.org/cgi/doi/10.1083/jcb.201003138 PubMed PMID: 20513765. doi: 10.1083/jcb.201003138.

43. Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway. The International Journal of Biochemistry & Cell Biology 2006;38(3):317-332. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1357272505003055 PubMed PMID: 16290097. doi: 10.1016/j.biocel.2005.09.018.

44. Appenzeller-Herzog C, Hall MN. Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling. Trends in Cell Biology 2012;22(5):274-282. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0962892412000359 PubMed PMID: 22444729. doi: 10.1016/j.tcb.2012.02.006.

45. Ozcan U, Cao Q, Yilmaz E, Lee A, Iwakoshi NN, Ozdelen E, et al. Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes. Science 2004;306(5695):457-461. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1103160 PubMed PMID: 15486293. doi: 10.1126/science.1103160.

46. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO. Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes. Science 2006;313(5790):1137-1140. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1128294 doi: 10.1126/science.1128294.

47. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 2006;34(Pt 5):647-662. Available from: http://ghr.nlm.nih.gov/gene=PIK3CA PubMed PMID: 17052169. doi: 10.1042/BST0340647.

48. Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010;11(1):9-22. Available from: http://www.nature.com/doifinder/10.1038/nrm2822 PubMed PMID: 20027184. doi: 10.1038/nrm2822.

49. Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell 2007;129(7):1261-1274. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0092867407007751 PubMed PMID: 17604717. doi: 10.1016/j.cell.2007.06.009.

50. Alessi DR, Pearce LR, García-Martínez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal 2009;2(67):27-10. Available from: http://www.scholaruniverse.com/ncbi-linkout?id=19383978 PubMed PMID: 19383978. doi: 10.1126/scisignal.267pe27.

51. Bhaskar PT, Hay N. The Two TORCs and Akt. Developmental Cell 2007;12(4):487-502. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1534580707001207 PubMed PMID: 17419990. doi: 10.1016/j.devcel.2007.03.020.

52. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2010;12(1):21-35. Available from: http://www.nature.com/doifinder/10.1038/nrm3025 PubMed PMID: 21157483. doi: 10.1038/nrm3025.

53. Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 2012;13(6):383-396. Available from: http://www.nature.com/doifinder/10.1038/nrm3351 PubMed PMID: 22617471. doi: 10.1038/nrm3351.

54. Penkov DN, Egorov AD, Mozgovaya MN, Tkachuk VA. Insulin resistance and adipogenesis: Role of transcription and secreted factors. Biochemistry Moscow 2013;78(1):8-18. Available from: http://link.springer.com/10.1134/S0006297913010021 PubMed PMID: 23379555. doi: 10.1134/S0006297913010021.

55. Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009;296(4):581-591. doi: 10.1152/ajpendo.90437.2008.

56. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004;431(7005):200-205. Available from: http://www.nature.com/doifinder/10.1038/nature02866 doi: 10.1038/nature02866.

57. Dann SG, Selvaraj A, Thomas G. mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends in Molecular Medicine 2007;13(6):252-259. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1471491407000664 PubMed PMID: 17452018. doi: 10.1016/j.molmed.2007.04.002.

58. Tyurin-Kuzmin PA, Morozov YI, Sukhova AA, Sagaradze GD, Zdanovskaya ND, Agaronian KM, et al. Differences in the effects of PDGF and EGF on migration and mitotic activity of NIH-3T3 fibroblasts are due to redox dependent phosphorylation of PKB/Akt, but not Erk1/2. 2014.

59. Mahadev K, Wu X, Zilbering A, Zhu L, Lawrence JT, Goldstein BJ. Hydrogen Peroxide Generated during Cellular Insulin Stimulation Is Integral to Activation of the Distal Insulin Signaling Cascade in 3T3-L1 Adipocytes. Journal of Biological Chemistry 2001;276(52):48662-48669. Available from: http://www.jbc.org/cgi/doi/10.1074/jbc.M105061200 doi: 10.1074/jbc.M105061200.

60. Ravichandran LV, Esposito DL, Chen J, Quon MJ. Protein Kinase C-zeta Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin. Journal of Biological Chemistry 2001;276(5):3543-3549. Available from: http://www.jbc.org/cgi/doi/10.1074/jbc.M007231200 doi: 10.1074/jbc.M007231200.

61. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim D, et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest 2004;114(6):823-827. Available from: http://www.jci.org/articles/view/22230 doi: 10.1172/JCI200422230.

62. Raddatz K, Turner N, Frangioudakis G, Liao BM, Pedersen DJ, Cantley J, et al. Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice. Diabetologia 2011;54(6):1447-1456. Available from: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+50-99-7 PubMed PMID: 21347625. doi: 10.1007/s00125-011-2073-0.

63. Bezy O, Tran TT, Pihlajamäki J, Suzuki R, Emanuelli B, Winnay J, et al. PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J. Clin. Invest 2011;121(6):2504-2517. Available from: http://www.jci.org/articles/view/46045 PubMed PMID: 21576825. doi: 10.1172/JCI46045.

64. Frangioudakis G, Burchfield JG, Narasimhan S, Cooney GJ, Leitges M, Biden TJ, et al. Diverse roles for protein kinase C delta and protein kinase C epsilon in the generation of high-fat-diet-induced glucose intolerance in mice: regulation of lipogenesis by protein kinase C delta.. Diabetologia 2009;52(12):2616-2620. Available from: http://link.springer.com/10.1007/s00125-009-1543-0 PubMed PMID: 19809797. doi: 10.1007/s00125-009-1543-0.

65. Holland WL, Bikman BT, Wang L, Yuguang G, Sargent KM, Bulchand S, et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice. J. Clin. Invest 2011;121(5):1858-1870. Available from: http://www.jci.org/articles/view/43378 doi: 10.1172/JCI43378.

66. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid–induced insulin resistance. J. Clin. Invest 2006;116(11):3015-3025. Available from: http://www.jci.org/cgi/doi/10.1172/JCI28898 PubMed PMID: 17053832. doi: 10.1172/JCI28898.

67. Powell DJ, Hajduch E, Kular G, Hundal HS. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Molecular and Cellular Biology 2003;23(21):7794-7808. Available from: http://mcb.asm.org/cgi/doi/10.1128/MCB.23.21.7794-7808.2003 PubMed PMID: 14560023. doi: 10.1128/MCB.23.21.7794-7808.2003.

68. Teruel T, Hernandez R, Lorenzo M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 2001;50(11):2563-2571. Available from: http://diabetes.diabetesjournals.org/cgi/doi/10.2337/diabetes.50.11.2563 PubMed PMID: 11679435. doi: 10.2337/diabetes.50.11.2563.

69. Chiang S, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009;138(5):961-975. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0092867409007934 PubMed PMID: 19737522. doi: 10.1016/j.cell.2009.06.046.

70. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420(6913):333-336. Available from: http://www.nature.com/doifinder/10.1038/nature01137 PubMed PMID: 12447443. doi: 10.1038/nature01137.

71. Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance. Science 2008;322(5907):1539-1543. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1160794 doi: 10.1126/science.1160794.

72. Tuncman G, Hirosumi J, Solinas G, Chang L, Karin M, Hotamisligil GS. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proceedings of the National Academy of Sciences 2006;103(28):10741-10746. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0603509103 PubMed PMID: 16818881. doi: 10.1073/pnas.0603509103.

73. Liu L, Wise DR, Diehl JA, Simon MC. Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival. Journal of Biological Chemistry 2008;283(45):31153-31162. Available from: http://www.jbc.org/cgi/doi/10.1074/jbc.M805056200 doi: 10.1074/jbc.M805056200.

74. Goldstein BJ, Mahadev K, Wu X. Redox Paradox: Insulin Action Is Facilitated by Insulin-Stimulated Reactive Oxygen Species With Multiple Potential Signaling Targets. Diabetes 2005;54(2):311-321. Available from: http://diabetes.diabetesjournals.org/cgi/doi/10.2337/diabetes.54.2.311 doi: 10.2337/diabetes.54.2.311.

75. Ткачук ВА, Тюрин-Кузьмин ПА, Белоусов ВВ, Воротников АВ. Пероксид водорода как новый вторичный посредник. Биологические мембраны: журнал мембранной и клеточной биологии. (2012); 29(1-2): 21. [Tkachuk VA, Tyurin-Kuz'min PA, Belousov VV, Vorotnikov AV. Peroksid vodoroda kak novyy vtorichnyy posrednik. Biochemistry (Moscow) Supplement. Series A, Membrane and cell biology. 2012;29(1-2):21]