Bastarrachea RA, Laviada-Molina H, Machado-Domínguez I, Kent JJ, López-Alvarenga JC, Comuzzie AG

Idioma: Español
Referencias bibliográficas: 71
Paginas: 180-189
Archivo PDF: 254.89 Kb.

RESUMEN

Las acciones de la insulina inician con su acoplamiento al receptor de insulina (IR), una proteína de membrana heterotetramérica unida por disulfuros. La insulina se une a dos sitios asimétricos de las subunidades extracelulares alpha y ocasiona cambios conformacionales que dan lugar a la autofosforilación de las subunidades beta que se insertan a través de la membrana, y a la activación de la tirosina cinasa intrínseca del receptor. Los receptores de la insulina transfosforilan varios sustratos subyacentes (en los residuos Tir), incluyendo los sustratos proteicos del receptor de insulina (IRS). Estos eventos dan lugar a la activación de moléculas de señalización en el interior del citosol. La función del receptor de tirosina cinasa es esencial para los efectos biológicos de la insulina. La patogénesis de la diabetes mellitus tipo 2 es compleja e involucra el desarrollo progresivo de resistencia a la insulina así como defectos en la secreción de la insulina, la cual conduce con el tiempo hacia la hiperglucemia franca. Las bases moleculares para la aparición de resistencia a la insulina en la diabetes tipo 2 permanecen aún pobremente comprendidas. Aun con esto, el papel de la resistencia a nivel hepático y en tejidos periféricos a la insulina en la patogénesis de la diabetes es indiscutible. La resistencia a la insulina puede deberse a múltiples defectos en la transducción de las señales (como por ejemplo, la activación defectuosa del receptor insulínico de tirosina cinasa y la activación disminuida de la fosfatidilinositol-3-OH cinasa estimulada por insulina (PI-3K). Un número sustancial de objetivos moleculares están siendo investigados hoy en día como estrategia para aumentar la transducción de señales mediadas por la insulina. Los nuevos enfoques se encuentran dirigidos a inhibir las vías enzimáticas que desactivan el receptor de insulina, o a sus efectores intrasitosólicos subyacentes como las proteínas IRS. De esta manera, se han podido identificar proteínas de tirosin-fosfatasas específicas (PTPs) como objetivos genéticos, entre otras.

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