medigraphic.com
ISSN 0016-3813 (Impreso)

2017, Número 2

<< Anterior Siguiente >>

Gac Med Mex 2017; 153 (2)


Mecanismos Moleculares de la Resistencia a la Insulina: Una Actualización

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

Idioma: Español
Referencias bibliográficas: 116
Paginas: 214-228
Archivo PDF: 305.04 Kb.


RESUMEN

Las acciones biológicas de la insulina se inician al activar su receptor de membrana, el cual desencadena múltiples vías de señalización que median sus acciones biológicas. Debido a la importancia de la regulación de funciones metabólicas promotoras del crecimiento y la proliferación celulares, las acciones de la insulina son altamente reguladas para promover el adecuado funcionamiento metabólico y el balance energético. Si estos mecanismos se ven alterados, se puede producir una condición conocida como resistencia a la insulina, que es la consecuencia de una señalización deficiente de la insulina causada por mutaciones o modificaciones postraduccionales de su receptor o de moléculas efectoras localizadas río abajo del mismo. La resistencia a la insulina es una de las principales características de las manifestaciones patológicas asociadas con la diabetes mellitus tipo 2 (DM2), una de las primeras causas de muerte en México y en todo el mundo. En años recientes, se ha identificado que condiciones como la inflamación, el estrés del retículo endoplásmico (ER) y la disfunción mitocondrial promueven la resistencia a la insulina. El objetivo de la presente revisión es dilucidar los aspectos moleculares de la resistencia a la insulina, con particular énfasis en el papel que juegan la inflamación, el estrés del retículo y la disfunción mitocondrial.


REFERENCIAS (EN ESTE ARTÍCULO)

  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