Our observations raise the question of whether metformin treatment could reduce oxidative stress and act as an ER stress modulator in T2D patients by promoting an adaptive unfolded protein response (s-xbp1 and p-eIF2α) in their leukocytes; this was in contrast with nonmetformin-treated patients whose response could be driven by the ATF6-dependent pro-apoptotic pathway.
GRP78 and CHOP protein and gene expression were higher in the MAO and MADO groups with respect to MHO subjects, and sXBP1 gene expression was associated with the presence of diabetes.
The study supports a role for -116C/G polymorphism of the XBP1 promoter in the pathogenesis of T2D in a Chinese Han population, and more studies are needed to further evaluate our results.
Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.