1D). specific alterations in SEV proteome reflecting down-regulation of the phospholipase C pathway (T2D) and up-regulated antioxidant capacity (IR NDM). Thus, SEV cargo may contribute to modulating the individual metabolic responsiveness to exercise training in humans. INTRODUCTION Regular exercise training not only reduces cardiovascular risk but also helps to prevent and treat type 2 diabetes (T2D) (value), was more prevalent among the groups with insulin resistance before HIIT. This study therefore investigated next whether quantity and proteome of SEV help to differentiate between responders (T2D-R and IR-R from the T2D and IR NDM groups) and nonresponders (IS-NR from the IS NDM group). SEVs were isolated by size exclusion chromatography (SEC), allowing for subsequent downstream analysis (value reflects insulin-stimulated skeletal muscle glucose uptake (values of less than 5.5 mg kg?1 min?1 (under high insulin clamp conditions) as insulin resistance state in adult humans (values were lower in T2D and IR NDM than IS NDM ( 0.001; Fig. 1B), even after the correction for insulin achieved during the clamp procedure. Insulin-mediated suppression of endogenous glucose production (iEGP), as the measure of hepatic insulin sensitivity, was lower ( 0.001; Fig. 1C), whereas liver fat content was higher in T2D than in both NDM groups ( 0.001; Fig. 1D). As expected, T2D also had higher hemoglobin A1c and lower high-density lipoprotein cholesterol than both NDM groups (Table 1). Compared to IS NDM, Tezampanel T2D had higher body mass index (BMI), partly due to higher visceral fat mass, whereas the greater BMI of IR NDM resulted from both higher subcutaneous and visceral fat mass (Table 1). Fasting plasma glucose was higher in the T2D group compared to the NDM groups, whereas fasting plasma insulin was only different between T2D and IS NDM (Table 1). Open in a separate window Fig. 1. HIIT induces metabolic changes and stimulates maximal skeletal muscle mitochondrial capacity in humans with (T2D) and without T2D (NDM).(A) Maximal oxygen uptake (VO2max) (***= 0.00025 for T2D, ***= 6.42 10?5 for IR NDM, and **= 0.008 for IS NDM), (B) peripheral insulin sensitivity (value) (**= 0.003 for T2D and **= 0.002 for IR NDM), (C) hepatic insulin sensitivity [suppression of EGP (iEGP)] during high-insulin clamp (***= 0.0001 for T2D, **= 0.007 for IR NDM, and *= 0.02 for IS NDM; #= 0.01 T2D versus IR NDM, ###= 7.87 10?7 T2D versus IS NDM; & = 0.04 IR NDM versus Tezampanel IS NDM), (D) liver fat content (**= 0.003 for T2D and *= 0.02 for IR NDM; ###= 0.0005 T2D versus IR NDM, ###= 7.17 10?5 T2D versus IS NDM), (E) maximal uncoupled respiration (= 3.73 10?5 for T2D, ***= 0.0005 for IR NDM, and **= 0.001 for IS NDM), (F) leak control ratio (LCR), (G) citrate synthase activity (CSA) (**= 0.001 for T2D, *** 0.0001 for IR NDM, and **= 0.004 for IS NDM; = 0.004 T2D versus IR NDM, = 0.01 IS NDM versus IR NDM at 12 weeks), and (H) reduced-to-oxidized glutathione (GSH/GSSG) ratio (*** 0.0001 for T2D and Tezampanel IS NDM and ***= 0.0002 for IR NDM) at baseline and after 12-week HIIT in persons with T2D, IR SPTAN1 NDM, and IS NDM. Data are presented as means SEM. Table 1. Anthropometric and metabolic parameters at baseline and after 12 weeks of HIIT in patients with T2D, IR controls (IR NDM), and IS controls (IS NDM).BMI, body mass index; HbA1c, hemoglobin A1c; SGPT, serum glutamic-pyruvic transaminase; LDL, low-density lipoprotein; HDL, high-density lipoprotein; fasting insulin, difference between fasting insulin at 12 weeks versus baseline; insulin clamp, difference between insulin during high insulin clamp and insulin before the clamp. Data are shown as means SEM or median (q1, q3). & 0.05, && 0.01, and &&& 0.001 T2D versus IS NDM; 0.05, 0.01, and 0.001 T2D versus IR NDM; # 0.05 and ## 0.01 IS NDM versus IR NDM; * 0.05, ** 0.001, and *** 0.00001 12 weeks versus baseline. = 20) IR NDM (= 11) IS NDM (= 12) Baseline 12 weeks Baseline 12 weeks Baseline 12 weeks value per high clamp insulin value per insulin clamp = 0.06) but rose by 28 to 45% in all groups after HIIT (Fig. 1E). The leak control ratio (LCR), reflecting increased proton leak across the mitochondrial membrane, remained unchanged (Fig. 1F), whereas muscle citrate synthase activity.