medigraphic.com
ISSN 0016-3813 (Print)

2017, Number 2

<< Back Next >>

Gac Med Mex 2017; 153 (2)

Molecular Mechanisms of Insulin Resistance: An Update

Gutiérrez-Rodelo C, Roura-Guiberna A, Olivares-Reyes JA

Language: Spanish
References: 116
Page: 214-228
PDF size: 305.04 Kb.


ABSTRACT

The biological actions of insulin are initiated by activating its membrane receptor, which triggers multiple signaling pathways to mediate their biological actions. Due to the importance of metabolic regulation and promoting functions of cell growth and proliferation, insulin actions are highly regulated to promote proper metabolic functioning and energy balance. If these mechanisms are altered, this can lead to a condition known as insulin resistance, which is the consequence of a deficient insulin signaling caused by mutations or post-translational modifications of the receptor or effector molecules located downstream. Insulin resistance is one of the main characteristics of pathological manifestations associated with type 2 diabetes mellitus, one of the leading causes of death in Mexico and worldwide. In recent years, it has been found that as inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction promote insulin resistance. The aim of this review is to elucidate the molecular aspects of insulin resistance and the mechanisms involved in regulating its effects, with particular emphasis on the role of inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction.


REFERENCES

  1. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171-6.

  2. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7(2):95-6.

  3. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473-81.

  4. Olivares-Reyes JA, Arellano-Plancarte A. Bases moleculares de las acciones de la insulina. Rev Edu Bioq. 2008;27:9-18.

  5. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;339(6116):172-7.

  6. Gribble FM. Metabolism: a higher power for insulin. Nature. 2005;434 (7036):965-6.

  7. Heesom KJ, Harbeck M, Kahn CR, Denton RM. Insulin action on metabolism. Diabetologia. 1997;40 Suppl 3:B3-9.

  8. Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res. 2008;79(2):238-48.

  9. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev. 2007;28(5):463-91.

  10. Kahn AM, Husid A, Odebunmi T, Allen JC, Seidel CL, Song T. Insulin inhibits vascular smooth muscle contraction at a site distal to intracellular Ca2+ concentration. Am J Physiol. 1998;274(5 Pt 1):E885-92.

  11. Zeng G, Nystrom FH, Ravichandran LV, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000; 101(13):1539-45.

  12. Havrankova J, Roth J, Brownstein MJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest. 1979;64(2):636-42.

  13. Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol. 2014;5:161.

  14. Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63(7):2232-43.

  15. Davis SN, Granner DK. Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas. En: Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10.a ed. Nueva York: McGraw-Hill; 2001. p. 1679-714.

  16. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105.

  17. Hubbard SR. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5(3):a008946.

  18. Hubbard SR. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 1997;16(18):5572-81.

  19. Myers MG Jr, White MF. The Molecular Basis of Insulin Action. En: Gruenberg G, Zick Y, eds. Insulin Signaling: From cultured cells to animal models. Nueva York: Taylor & Francis; 2002. p. 55-87.

  20. Jensen M, De Meyts P. Molecular mechanisms of differential intracellular signaling from the insulin receptor. Vitam Horm. 2009;80:51-75.

  21. White MF. Insulin signaling in health and disease. Science. 2003;302 (5651):1710-11.

  22. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74.

  23. Patel N, Huang C, Klip A. Cellular location of insulin-triggered signals and implications for glucose uptake. Pflugers Arch. 2006;451(4): 499-510.

  24. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85-96.

  25. Olivares-Reyes JA. Bases moleculares del síndrome metabólico y resistencia a la insulina. En: Garibay Nieto GN, García Velasco S, eds. Obesidad en la edad pediátrica: prevención y tratamiento. Ciudad de México: Corinter; 2012. p. 185-214.

  26. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806.

  27. Boulton TG, Nye SH, Robbins DJ, et al. ERKs: A family of protein-serine/ threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65(4):663-75.

  28. Lazar DF, Wiese RJ, Brady MJ, et al. Mitogen-activated Protein Kinase Kinase Inhibition Does Not Block the Stimulation of Glucose Utilization by Insulin. J Biol Chem. 1995;270(35):20801-7.

  29. Bost F, Aouadi M, Caron L, et al. The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes. 2005;54(2):402-11.

  30. Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab. 2009;296(4):E581-91.

  31. Zick Y. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol. 2001;11:437-441.

  32. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1). pii: a009191.

  33. Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase- 1B gene. Science. 1999;283(5407):1544-8.

  34. Klaman LD, Boss O, Peroni OD, et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol. 2000;20(15): 5479-89.

  35. Lu B, Gu P, Xu Y, et al. Overexpression of protein tyrosine phosphatase 1B impairs glucose-stimulated insulin secretion in INS-1 cells. Minerva Endocrinol. 2016;41(1):1-9.

  36. Youngren J. Regulation of insulin receptor function. Cell Mol Life Sci. 2007;64(7-8):873-91.

  37. Puig O, Tjian R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev. 2005;19(20):2435-46.

  38. Ciaraldi TP. Cellular Mechanisms of Insulin Action. En: Poretsky L, ed. Principles of Diabetes Mellitus. Nueva York: Springer; 2010. p. 75-87.

  39. Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012;55(10):2565-82.

  40. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E. SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling. J Biol Chem. 2000;275(21):15985-91.

  41. Lebrun P, Van Obberghen E. SOCS proteins causing trouble in insulin action. Acta Physiol. 2008;192(1):29-36.

  42. Desbuquois B, Carre N, Burnol AF. Regulation of insulin and type 1 insulin- like growth factor signaling and action by the Grb10/14 and SH2B1/ B2 adaptor proteins. FEBS J. 2013;280(3):794-816.

  43. Cariou B, Capitaine N, Le Marcis V, et al. Increased adipose tissue expression of Grb14 in several models of insulin resistance. FASEB J. 2004;18(9):965-7.

  44. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/ AKT pathway. Proc Natl Acad Sci U S A. 1999;96(8):4240-5.

  45. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27(41):5527-41.

  46. Shi Y, Wang J, Chandarlapaty S, et al. PTEN is a protein tyrosine phosphatase for IRS1. Nat Struct Mol Biol. 2014;21(6):522-27.

  47. Suwa A, Kurama T, Shimokawa T. SHIP2 and its involvement in various diseases. Expert Opin Ther Targets. 2010;14(7):727-37.

  48. Dyson JM, Fedele CG, Davies EM, Becanovic J, Mitchell CA. Phosphoinositide phosphatases: just as important as the kinases. Subcell Biochem. 2012;58:215-79.

  49. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol. 2002;16(8):1931-42.

  50. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601-5.

  51. Lee JH, Ragolia L. AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. Am J Physiol Cell Physiol. 2006;291(6):C1355-65.

  52. Zick Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE. 2005;2005(268):pe4.

  53. Kido Y, Burks DJ, Withers D, et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000;105(2):199-205.

  54. Chavez JA, Knotts TA, Wang LP, et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem. 2003;278(12):10297-303.

  55. Salinas M, López-Valdaliso R, Martín D, Alvarez A, Cuadrado A. Inhibition of PKB/Akt1 by C2-Ceramide Involves Activation of Ceramide-Activated Protein Phosphatase in PC12 Cells. Mol Cell Neurosci. 2000;15(2):156-69.

  56. Chavez Jose A, Summers Scott A. A Ceramide-Centric View of Insulin Resistance. Cell Metab. 2012;15(5):585-94.

  57. Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem. 2004;27935):36608-15.

  58. Bourbon NA, Sandirasegarane L, Kester M. Ceramide-induced Inhibition of Akt Is Mediated through Protein Kinase Cζ: IMPLICATIONS FOR GROWTH ARREST. J Biol Chem. 2002;277(5):3286-92.

  59. Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013; 7(1):14-24.

  60. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282(22):2131-5.

  61. Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract. 2005;69(1):29-35.

  62. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821-30.

  63. 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):1796-808.

  64. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92(3):347-55.

  65. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-801.

  66. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85-97.

  67. Soumaya K. Molecular Mechanisms of Insulin Resistance in Diabetes. En: Ahmad S, ed. Diabetes. Nueva York: Springer; 2013. p. 240-51.

  68. Esposito K, Pontillo A, Ciotola M, et al. Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab. 2002;87(8):3864-6.

  69. Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012;13(2):136-49.

  70. Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA. Activation of SOCS-3 by resistin. Mol Cell Biol. 2005;25(4):1569-75.

  71. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54(10):2939-45.

  72. Senn JJ, Klover PJ, Nowak IA, et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. 2003;278(16):13740-6.

  73. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne). 2013;4:71.

  74. 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):3015-25.

  75. Himes RW, Smith CW. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 2010;24(3):731-9.

  76. Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell. 2013;152(4):673-84.

  77. Suganami T, Mieda T, Itoh M, Shimoda Y, Kamei Y, Ogawa Y. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun. 2007;354(1):45-9.

  78. Watanabe Y, Nagai Y, Takatsu K. Activation and regulation of the pattern recognition receptors in obesity-induced adipose tissue inflammation and insulin resistance. Nutrients. 2013;5(9):3757-78.

  79. Holland WL, Bikman BT, Wang LP, 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):1858-70.

  80. Banhegyi G, Baumeister P, Benedetti A, et al. Endoplasmic reticulum stress. Ann N Y Acad Sci. 2007;1113:58-71.

  81. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29(1):42-61.

  82. Guerrero-Hernandez A, Leon-Aparicio D, Chavez-Reyes J, Olivares- Reyes JA, DeJesus S. Endoplasmic reticulum stress in insulin resistance and diabetes. Cell Calcium. 2014;56(5):311-22.

  83. Yalcin A, Hotamisligil GS. Impact of ER protein homeostasis on metabolism. Diabetes. 2013;62(3):691-93.

  84. Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 2012; 15(5):623-34.

  85. Sommerweiss D, Gorski T, Richter S, Garten A, Kiess W. Oleate rescues INS-1E β-cells from palmitate-induced apoptosis by preventing activation of the unfolded protein response. Biochem Biophys Res Commun. 2013;441(4):770-6.

  86. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900-17.

  87. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26(8):3071-84.

  88. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287(5453):664-6.

  89. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333-6.

  90. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet- induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673-7.

  91. Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S6-11.

  92. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457-61.

  93. Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 2005; 280(1):847-51.

  94. Boden G, Song W, Duan X, et al. Infusion of glucose and lipids at physiological rates causes acute endoplasmic reticulum stress in rat liver. Obesity. 2011;19(7):1366-73.

  95. Sharma NK, Das SK, Mondal AK, et al. Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J Clin Endocrinol Metab. 2008;93(11):4532-41.

  96. Gregor MF, Yang L, Fabbrini E, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes. 2009;58(3):693-700.

  97. Yoshida H. ER stress and diseases. FEBS J. 2007;274(3):630-58.

  98. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137-40.

  99. Kammoun HL, Chabanon H, Hainault I, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest. 2009;119(5):1201-15.

  100. Ozawa K, Miyazaki M, Matsuhisa M, et al. The Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes. Diabetes. 2005;54(3):657-63.

  101. Xiao C, Giacca A, Lewis GF. Sodium Phenylbutyrate, a Drug With Known Capacity to Reduce Endoplasmic Reticulum Stress, Partially Alleviates Lipid-Induced Insulin Resistance and β-Cell Dysfunction in Humans. Diabetes. 2011;60(3):918-24.

  102. Kars M, Yang L, Gregor MF, et al. Tauroursodeoxycholic Acid May Improve Liver and Muscle but Not Adipose Tissue Insulin Sensitivity in Obese Men and Women. Diabetes. 2010;59(8):1899-905.

  103. Caspersen C, Pedersen PS, Treiman M. The sarco/endoplasmic reticulum calcium-ATPase 2b is an endoplasmic reticulum stress-inducible protein. J Biol Chem. 2000;275(29):22363-72.

  104. Park SW, Zhou Y, Lee J, Ozcan U. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci U S A. 2010; 107(45):19320-5.

  105. Randriamboavonjy V, Pistrosch F, Bolck B, et al. Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation. 2008;117(1):52-60.

  106. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307(5708):384-7.

  107. 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.

  108. Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocrine Connect. 2015;4(1):R1-R15.

  109. Morino K, Petersen KF, Dufour S, et al. 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): 3587-93.

  110. Cheng Z, Guo S, Copps K, et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med. 2009;15(11):1307-11.

  111. Dong XC, Copps KD, Guo S, et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008;8(1):65-76.

  112. Long YC, Cheng Z, Copps KD, White MF. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol. 2011;31(3):430-41.

  113. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;123(7): 2764-72.

  114. Wei Y, Sowers JR, Nistala R, et al. Angiotensin II-induced NADPH Oxidase Activation Impairs Insulin Signaling in Skeletal Muscle Cells. J Biol Chem. 2006;281(46):35137-46.

  115. Wei Y, Sowers JR, Clark SE, Li W, Ferrario CM, Stump CS. Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. Am J Physiol Endocrinol Metab. 2008;294(2):E345-51.

  116. Kim JA, Wei Y, Sowers JR. Role of Mitochondrial Dysfunction in Insulin Resistance. Circ Res. 2008;102(4):401-14.




2020     |     www.medigraphic.com