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El receptor de inositol-1,4,5-trisfosfato regula la gluconeogénesis hepática en ayunas y en la diabetes
Yiguo Wang1, Gang Li, Jason Goode
1Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|April 13, 2012
Resumen
El glucagón estimula la producción de glucosa hepática mediante la activación de la señalización del calcio, que desfosforila el CRTC2. Esta vía está desregulada en la diabetes, pero dirigirse a ella puede mejorar los niveles de glucosa.
Área de la Ciencia:
- Biología celular Biología celular.
- Regulación del metabolismo.
- La señalización hormonal.
Sus antecedentes:
- El glucagón promueve la producción de glucosa hepática a través de la vía AMP cíclica (cAMP), que involucra la desfosforilación CRTC2.
- Los mecanismos precisos que vinculan las señales hormonales a la desfosforilación del CRTC2 por las fosfatasas Ser/Thr no se comprenden completamente.
Objetivo del estudio:
- Para aclarar el papel de las reservas intracelulares de calcio y calcineurina en la desfosforilación CRTC2 mediada por glucagón en hepatocitos.
- Investigar la regulación de esta vía por la señalización de la insulina y sus implicaciones en la diabetes.
Principales métodos:
- Estudios en hepatocitos de ratón para examinar los efectos del glucagón en la movilización del calcio y la fosforilación del CRTC2.
- Se investigó la interacción entre los receptores de inositol-1,4,5-trisfosfato (InsP(3) Rs), CRTC2 y la calcineurina.
- Se evaluó el impacto de la señalización de la insulina y la diabetes en la actividad InsP(3) R y la gluconeogénesis.
Principales resultados:
- El glucagón estimula la desfosforilación del CRTC2 en los hepatocitos mediante la movilización del calcio intracelular y la activación de la calcineurina.
- Este proceso implica la fosforilación mediada por PKA de InsP(3)Rs asociados al CRTC2, mejorando la expresión génica gluconeogénica.
- La señalización de la insulina inactiva InsP(3) Rs, reduciendo la actividad de CRTC2 durante la alimentación; La actividad de InsP(3) R es elevada en la diabetes.
Conclusiones:
- El glucagón utiliza un eje de señalización de cAMP y calcio, que involucra InsP(3) Rs y calcineurina, para regular la producción de glucosa hepática.
- La actividad de InsP(3)R desregulada contribuye a la regulación al alza de la gluconeogénesis en la diabetes.
- Dirigirse a las InsP3Rs hepáticas y a la calcineurina ofrece una estrategia terapéutica potencial para la resistencia a la insulina y la diabetes.
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