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Type 2 diabetes (T2D) is associated with oxidative stress, and metformin seems to protect against it. We hypothesised that metformin would modulate endoplasmic reticulum (ER) stress and autophagy in leukocytes of T2D patients. The study population included 53 T2D patients (37 were treated with metformin) and 30 controls. PBMCs were isolated and parameters of ER stress, autophagy and oxidative stress assessed by RT-qPCR, WB and cytometry. Whereas both T2D groups exhibited increased levels of GRP78, ATF6 was enhanced specifically in non-metformin-treated patients, and s-xbp1 and p-eIF2α were increased only in the metformin-treated group. The autophagy markers becn1 and atg7 and the LC3II/I ratio increased in non-metformin-treated T2D patients. Metformin reduced mitochondrial superoxide and increased GSH levels. Our data suggest that metformin modulates the ER stress induced by T2D (manifested by enhanced GRP78 levels); an adaptive response is activated (s-xbp1 and p-eIF2α) in treated patients, whereas the response in non-metformin-treated patients is driven by the ATF6-dependent pro-apoptotic pathway. We hypothesize an autophagy-dependent clearance of misfolded proteins that is modulated by metformin treatment.

Diabetes is associated with oxidative stress. This study evaluated the rates of oxidative stress and mitochondrial impairment in type 2 diabetes patients. The study population consisted of 182 diabetic patients and 50 body-composition- and age-matched controls. We assessed anthropometric and metabolic parameters and mitochondrial function by evaluating mitochondrial oxygen (O2) consumption, reactive oxygen species (ROS) production, glutathione (GSH) levels, GSH/GSSG ratio, mitochondrial membrane potential, and mitochondrial complex I activity in polymorphonuclear cells from diabetes type 2 patients. We found an increase in waist circumference and augmented serum levels of triglycerides, proinflammatory cytokines (IL-6 and TNF-α), homocysteine, glycated hemoglobin, ultrasensitive C-reactive protein, glucose, insulin, and homeostasis model assessment of insulin resistance score in diabetic patients versus controls. There was an impairment of mitochondrial function in diabetic patients, evidenced by a decrease in mitochondrial O2 consumption, an increase in ROS production, decreased GSH/GSSG ratio, a drop in GSH levels, and an undermining of the mitochondrial membrane potential. Furthermore, an impairment of mitochondrial complex I was detected. This study supports the hypothesis of an association of type 2 diabetes and the rate of impaired mitochondrial function. We also propose that one of the targets of oxidative stress responsible for diabetes is mitochondrial complex I.