Mecanismos moleculares de regulación de la via mtorc1/p70s6k, autofagia y mitofagiapapel de tsc2

Résumé

Type 2 Diabetes Mellitus (T2DM) is characterised by a first phase in which the principal event is the defect in the insulin’s action, called insulin resistance, accompanied with normoglycemia. During this phase, pancreatic β cells increased its cell number (hyperplasia) and its cell size (hypertrophy), along with an increase in insulin secretion in order to compensate hyperglycemia (Prentky, M et al. 2006). The duration of this phase is different in each patient, and finally, β cells begin to fail, and hypoinsulinemia appears. During T2DM progression, it was observed a hyperactivation of the complex 1 of the mammalian target of rapamycin (mTORC1), which is beneficial in the first phase due to an increase in β cell proliferation. However, the chronic mTORC1 hyperactivation drives to an increase in endoplasmic reticulum (ER) stress, and βcell failure. Recently, our group is focused on the study of mTORC1 pathway. Tuberous sclerosis complex, formed by two proteins called hamartin (TSC1) and tuberin (TSC2), acts an integrator of energetic signals and growth factors. TSC2 protein presents a GAP domain, which activates Rheb intrisic GTPase activity, promoting its inhibition, and as a consequence, mTORC1 inhibition. The mTORC1 signaling regulates numerous biological processes, such as proliferation, protein synthesis and autophagy inhibition. Autophagy is a physiological mechanism of cytoplasmic quality control, which its main function is the elimination of damaged proteins and organelles, diminishing ER-stress. Autophagy plays an important role in the maintaining β cells homeostasis (Jung H.S. et al., 2008; Ebato, C. et al. 2008)...