Type 2 Diabetes Related Mitochondrial Defects in Peripheral Mononucleated Blood Cells from Overweight Postmenopausal Women

Abstract

Type 2 diabetes (T2D) is a multisystem disease that is the subject of many studies, but the earliest cause of the disease has yet to be elucidated. Mitochondrial impairment has been associated with diabetes in several tissues. To extend the association between T2D and mitochondrial impairment to blood cells, we investigated T2D-related changes in peripheral mononucleated blood cells’ (PBMCs) mitochondrial function in two groups of women (CTRL vs. T2D; mean age: 54.1 ± 3.8 vs. 60.9 ± 4.8; mean BMI 25.6 ± 5.2 vs. 30.0 ± 5), together with a panel of blood biomarkers, anthropometric measurements and physiological parameters (VO2max and strength tests). Dual-energy X-ray absorptiometry (DXA) scan analysis, cardio-pulmonary exercise test and blood biomarkers confirmed hallmarks of diabetes in the T2D group. Mitochondrial function assays performed with high resolution respirometry highlighted a significant reduction of mitochondrial respiration in the ADP-stimulated state (OXPHOS; −30%, p = 0.006) and maximal non-coupled respiration (ET; −30%, p = 0.004) in PBMCs samples from the T2D group. The total glutathione antioxidant pool (GSHt) was significantly reduced (−38%: p = 0.04) in plasma samples from the T2D group. The fraction of glycated hemoglobin (Hb1Ac) was positively associated with markers of inflammation (C-reactive protein-CRP r = 0.618; p = 0.006) and of dyslipidemia (triglycerides-TG r = 0.815; p < 0.0001). The same marker (Hb1Ac) was negatively associated with mitochondrial activity levels (OXPHOS r = −0.502; p = 0.034; ET r = −0.529; p = 0.024). The results obtained in overweight postmenopausal women from analysis of PBMCs mitochondrial respiration and their association with anthropometric and physiological parameters indicate that PBMC could represent a reliable model for studying T2D-related metabolic impairment and could be useful for testing the effectiveness of interventions targeting mitochondria.