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Le diabete de type 2 se caracterise par une alteration de la reponse a l’insuline dans les tissus, tels que le foie et le muscle, et par un dysfonctionnement des cellules β pancreatiques produisant l’insuline. Cette deregulation dans l’action et la secretion de l’insuline entraine une hyperglycemie chronique. Les principales causes evoquees pour expliquer la pathogenese du diabete de type 2 sont principalement la lipotoxicite, la glucotoxicite, le stress oxydant et l’inflammation. Ces differentes alterations convergent toutes vers l’activation d’une voie cellulaire appelee UPR (unfolded protein response ) qui se met en place dans la cellule β et dans les tissus sensibles a l’insuline. Cette voie cellulaire, au centre de la pathogenese du diabete de type 2, constitue une cible therapeutique pertinente dans le traitement de cette maladie.

The endoplasmic reticulum (ER) is the first compartment in the secretory pathway. In the ER, proteins fold into their native configuration and are modified by post-translational modifications. Perturbations that alter ER homeostasis therefore disrupt folding and lead to the accumulation of unfolded proteins. These perturbations include modifications of Ca2+ homeostasis, increased demand for protein folding due to elevated synthesis of proteins in specialized cells or expression of a mutant misfolded protein. To limit accumulation of unfolded proteins, the cells have developed a specialized pathway : the unfolded protein response (UPR). UPR involves the activation of three transmembrane proteins of the ER : the PKR-like ER protein kinase (PERK), the activating transcription factor 6 (ATF6) and the inositol requiring enzyme 1 (IRE-1). The activation of all three components of the UPR depends on the dissociation of the luminal chaperone BiP/GRP78 from the luminal part of these proteins. Once activated, these pathways down-regulate protein synthesis through the phosphorylation of eiF2 (eucaryotic translation initiation factor 2) and up-regulate the transcription of genes which encode ER chaperones, protein folding enzymes and components of the ER-associated degradation system (ERAD). Growing evidences indicate that UPR signaling plays critical roles in nutrient sensing, differentiation of secretory cells such as pancreatic b cell and antibody producing plasma cells, glucose homeostasis and in the development of pathologies linked to accumulation of aggregated proteins.

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