The present study analyzes the oxidative stress situation in the skeletal muscle of overweight/obese men suffering from non-insulin-dependent type 2 diabetes mellitus [T2DM, n=16, years=61±7, body mass index (BMI)=31±4 kg/m(2) ] and BMI-matched non-diabetic male control subjects (CON, n=7, years=53±6, BMI=30±4 kg/m(2) ). Furthermore, it investigates whether physical training can alter the skeletal muscle antioxidative capacity of T2DM patients at rest. Molecule content analyses (immunohistochemical stainings) of 8-iso-prostaglandin-F2α (8-Iso-PGF), superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (GPX1), peroxiredoxin isoforms (PRDX 1-6) and heat-shock-protein-70 (HSP70) were performed in biopsies taken from the vastus lateralis muscle. Under basal conditions, 8-Iso-PGF was significantly decreased in T2DM patients (-35.7%), whereas PRDX2 and PRDX6 were significantly increased relative to CON (+82.6%; +82.3%). Differences were neither observed in SOD2 nor in GPX1 or PRDX1, 3, 4, 5 density. Regular physical activity (moderate endurance or resistance training twice a week for 3 months) did not alter PRDX1, 2, 3, 4, 6 in the skeletal muscle of T2DM patients, but significantly increased SOD2 (+65.9%), GPX1 (+62.4%), PRDX5 (+37.5%), and HSP70 (+48.5%). Overweight/obese men with non-insulin-dependent T2DM exhibit up-regulated cytosolic peroxiredoxin contents relative to BMI-matched controls. Regular training further up-regulates cytosolic and mitochondrial antioxidative enzymes in T2DM patients and improves their cellular protection systems. This may contribute to a retardation of the disease's progression.

Chronic elevated lactate levels are associated with insulin resistance in patients with type 2 diabetes mellitus (T2DM). Furthermore, lactacidosis plays a role in limiting physical performance. Erythrocytes, which take up lactate via monocarboxylate transporter (MCT) proteins, may help transport lactate within the blood from lactate-producing to lactate-consuming organs. This study investigates whether cycling endurance training (3 times/week for 3 months) alters the basal erythrocyte content of MCT-1, and whether it affects lactate distribution kinetics in the blood of T2DM men (n = 10, years = 61 ± 9, body mass index = 31 ± 3 kg/m(2)) following maximal exercise (WHO step-incremental cycle ergometer test). Immunohistochemical staining indicated that basal erythrocyte contents of MCT-1 protein were up-regulated (+90%, P = 0.011) post-training. Erythrocyte and plasma lactate increased from before acute exercise (= resting values) to physical exhaustion pre- as well as post-training (pre-training: +309%, P = 0.004; +360%, P < 0.001; post-training: +318%, P = 0.008; +300%, P < 0.001), and did not significantly decrease during 5 min recovery. The lactate ratio (erythrocytes:plasma) remained unchanged after acute exercise pre-training, but was significantly increased after 5 min recovery post-training (compared with the resting value) (+22%, P = 0.022). The results suggest an increased time-delayed influx of lactate into erythrocytes following an acute bout of exercise in endurance-trained diabetic men.

NOS-activation in erythrocytes (eryNOS) is impaired in patients suffering from type 2 diabetes. We investigated the effect of physical exercise on eryNOS activation and whether 6 week hypoxia interval training may alter this process. Male patients with diabetes mellitus type 2 (NIDDM, n = 12; age, 61.3 ± 8.4 years; BMI, 29.8 ± 3.7 kg/m(2)) underwent physical exercise training before and after 6 week hypoxia interval training. Training was conducted 4 times per week for 90 min at 15.4-12.7 Vol% of inspired oxygen. Vital parameters were recorded. Before hypoxia intervention, eryNOS phosphorylation at serine(1177) decreased significantly during exercise (basal 17.4 ± 12.0 compared with exercise 8.4 ± 9.2 arbitrary grey values (arGV); P < 0.05). After 6 weeks of hypoxia intervention, eryNOS-pSer(1177) (2.2 ± 2.5 arGV) was significantly lower at baseline. Ergometry showed an increase (7.6 ± 3.0 arGV; P < 0.05) followed by a decrease to almost baseline levels after 30 min (3.8 ± 1.5 arGV). Maximal exercise capacity and O(2)-uptake ([Formula: see text]  max) increased significantly. The effects were independent from exercise-induced elevation of blood pressure. Exercise-dependent eryNOS phosphorylation at serine(1177) was increased similar to that described for the endothelium in diabetic patients. EryNOS dysregulation was partially restored after intermittent hypoxia training.

Type 2 diabetes mellitus (T2DM) is associated with an increased release of free radicals which play an important role in the manifestation of diabetes and in the progression of diabetic complications. Peroxiredoxins are thought to be essential components of the erythrocyte antioxidative defense. Therefore, we compared peroxiredoxin isoform contents (PRDX1-6 immuno-histochemial stainings) in the erythrocytes of overweight/obese T2DM men (n = 6) and of BMI-matched non-diabetic male control subjects (n = 6). Only erythrocyte PRDX1 and PRDX2 proteins were detectable using immunohistochemical methods. PRDX1 was significantly increased in T2DM men relative to control subjects (+95.9%, P ≤ 0.05). Furthermore, we studied the influence of a 3-month endurance training program (3 times a week, cycling at 75% maximal heart rate) on erythrocyte PRDX1 and PRDX2 contents in overweight/obese T2DM men (n = 11). Training significantly increased PRDX2 at rest (+96%, P ≤ 0.05). The up-regulation of the peroxiredoxin system may help counteract free radicals in the erythrocytes of T2DM patients.

Patients suffering from type 2 diabetes mellitus (T2DM) often exhibit chronic elevated lactate levels which can promote peripheral insulin resistance by disturbing skeletal muscle insulin-signaling. Monocarboxylate transporter (MCT) proteins transfer lactate molecules through cellular membranes. MCT-1 and MCT-4 are the main protein isoforms expressed in human skeletal muscle, with MCT-1 showing a higher affinity (lower Km) for lactate than MCT-4. T2DM patients have reduced membranous MCT-1 proteins. Consequently, the lactate transport between muscle cells and the circulation as well as within an intracellular lactate shuttle, involving mitochondria (where lactate can be further metabolized), can be negatively affected. This study investigates whether moderate cycling endurance training (3 times per week for 3 months) can change skele-tal muscle MCT contents in T2DM men (n=8, years=56±9, body mass index (BMI)=32±4 kg/m(2)). Protein content analyses (immuno-histochemical stainings) were performed in bio-psies taken from the vastus lateralis muscle. Intracellular MCT-1 proteins were up-regulated (relative increase+89%), while intracellular MCT-4 contents were down-regulated (relative decrease - 41%) following endurance training. Sarcolemmal MCT-1 and MCT-4 did not change. The question of whether the training-induced up-regulation of intracellular MCT-1 leads to an improved lactate transport (and clearance) in T2DM patients requires further research.