Does Metformin Modulate Endoplasmic Reticulum Stress and Autophagy in Type 2 Diabetic Peripheral Blood Mononuclear...

Since type 2 diabetes (T2D) is associated with oxidative stress and metformin has been shown to exert a protective role against the said stress, we wondered whether metformin treatment might also modulate endoplasmic reticulum (ER) stress and autophagy in leukocytes of T2D patients. We studied 53 T2D patients (37 of whom had been treated with metformin 1700 mg for at least 1 year) and 30 healthy volunteers. Leukocytes from both groups of T2D patients exhibited increased protein levels of 78-kDa glucose-regulated protein (GRP78) with respect to controls, whereas activating transcription factor 6 (ATF6) was enhanced specifically in nonmetformin-treated T2D, and (s-xbp1) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α) increased only in the metformin-treated group. The autophagy markers beclin1 (becn1), autophagy-related 7 (atg7), and microtubule-associated protein 1A/1B-light chain 3II/I (LC3 II/I) increased in nonmetformin-treated T2D, and metformin treatment reduced mitochondrial superoxide and increased glutathione (GSH) levels. 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. Further, our findings lead to us to form the hypothesis of an autophagy-dependent clearance of misfolded proteins in nonmetformin-treated T2D patients that could be repressed by metformin treatment.-Antioxid. Redox Signal. 28, 1562-1569.