Unfolded protein response in gastric glandulocytes of rats with the pharmacological correction of type 2 diabetes

Abstract

Background. The cellular and molecular mechanisms underlying gastrointestinal complications caused by type 2 diabetes mellitus (T2DM) may involve accumulation of misfolded proteins in the endoplasmic reticulum that disrupts protein homeostasis and activates a signaling pathway termed the unfolded protein response (UPR). The goal of the present study was to assess the state of the UPR system in gastric glandulocytes of untreated and metformin- and propionate-treated T2DM rats. Materials and methods. Rats with induced T2DM received metformin, propionate, and their combination. Analysis of the levels of 78-kDa glucose-regulated protein (GRP78), activating transcription factor 6 (ATF6), protein kinase R-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 (IRE1) was performed by Western blotting and immunohistochemical assessment of slices. Results. In T2DM rats, an increase in GRP78 vs. control (normal) group was found. Metformin and propionate treatment led to an increase in GRP78; under combination therapy, its content was registered at the level in untreated T2DM group. An increase in the ATF6 in T2DM rats was found, and all treatment regimens contributed to its growth. The PERK level in T2DM rats exceeded that in controls, and propionate treatment caused its decrease to the level observed in control group. An immunohistochemical assessment revealed a tendency to increase the intensity of immunoreaction for GRP78 in T2DM rats. With metformin treatment, an intensive immunoreaction for GRP78 was revealed. The general trend in T2DM rats was a significant increase in ATF6 expression. Conclusions. Combination treatment with metformin and propionate led to a significant decrease in GRP78, which may indicate a positive effect of such therapy. New data on propionic acid effect on UPR in the stomach have been obtained that may be beneficial for developing possible treatment strategies in complications of gastropathy caused by diabetes.