Gliclazide enhances exercise performance and recovery of muscle strength in healthy trained individuals: a randomized controlled trial

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Schaan, Alexandre Machado Lehnen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4450743/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract To examine the acute effect of gliclazide on exercise performance and recovery of muscle strength in healthy participants. We conducted a randomized, double-blind, placebo-controlled crossover clinical trial in 44 strength-trained men. They were allocated to gliclazide modified release (MR) (90mg, 8h before exercise sessions) or placebo, undergo three consecutive sessions of strength exercise (four sets, 80% of one-repetition maximum [1-RM] of bench press and free squat exercise). We evaluated total volume-load (VL) (#repetitions x 80%1-RM), range of motion (ROM), insulin and glucose levels, creatine kinase MM (CK-MM), lactate dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), hemodynamic parameters, perceived pain and recovery scores. Gliclazide enhanced strength exercise performance with improvements in total VL (bench press 23.3%, p < 0.001; squats 23.2%, p < 0.001), and improved muscle recovery 24-48h post-exercise: ROM (shoulder 1.1%, p < 0.001; knee 1.6%, p = 0.004), CK-MM (–13.2%, p < 0.001), LDH (–12.8%, p < 0.001), TNF-α (–17.4%, p < 0.001), IL-6 (–5.3%, p < 0.001), pain (–17.7%, p < 0.001) and recovery scores (32.5%, p = 0.001). However, hypoglycemia events were observed in 3 participants in the gliclazide group. In conclusion, Gliclazide MR 90mg, 8h before strength exercise, produced ergogenic effects (exercise performance and muscle recovery), although hypoglycemia was observed in 7% of subjects. Registration: “www.clinicaltrials.gov”, “NCT04443777” (Primary Completion: 01/08/2020; Study Completion: 31/10/2023). muscle strength doping in sports muscle recovery insulin glucose Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Sulfonylureas are a class of drugs that has been used in the treatment of type 2 diabetes mellitus (T2DM) [ 1 ]. They act by binding to a specific receptor for sulfonylureas (SUR) in pancreatic β-cells, blocking ATP-dependent potassium channels (K + -ATP) and stimulating the secretion of insulin [ 2 ]. The World Health Organization (WHO) list of medications includes gliclazide as the safest and most effective drug in the sulfonylurea class and is indicated for the treatment of T2DM [ 3 ]. Due to its pharmacodynamic properties, gliclazide is highly selective and binds to receptors on pancreatic β-cells (SUR1) and at the same time shows low affinity for receptors on cardiac muscle (SUR2A) and vascular muscle cells (SUR2B) [ 4 ]. Numerous athletes use substances and/or methods for performance enhancement which is against the spirit of sports and may be harmful to their health. One of these substances is insulin, an anabolic hormone that can artificially increase muscle mass and enhance athletic performance. Because of its use for doping in sports, the World Anti-Doping Agency (WADA) has put insulin in the list of prohibited substances [ 5 ]. Yet, there are reports of the use of sulfonylureas as an insulinotropic drug in amateur and professional athletes since they are not included in this list of doping agents. Sulfonylureas increase endogenous insulin secretion and enhance glucose and amino acid uptake in skeletal muscle cells [ 6 , 7 ]. The supply and uptake of nutrients especially glucose and amino acids would be increased in muscle cells, resulting in increased protein synthesis and, in the short-term, enhancing sports performance. In addition, sulfonylureas can increase resynthesis of glycogen stores in muscle cells over time and accelerate post-exercise muscle recovery in repeated exercise sessions [ 8 , 9 ]. As they may artificially enhance sports performance and potentially harm athlete’s health, they can be considered doping agents. In a pilot study conducted by our research group, we found that the acute use of gliclazide 60 mg as a modified-release tablet (gliclazide MR) before a single session of strength exercise did not directly enhance athletic performance, although it accelerated muscle recovery in later sessions (unpublished data). The hypothetical effect of gliclazide as a potential ergogenic substance has not yet been tested, neither as an acute nor as a chronic response to exercise. The closest approach involved studies that acutely evaluated healthy participants taking gliclazide for its bioequivalence [ 10 , 11 ] and pharmacokinetic and pharmacodynamic properties [ 12 , 13 ], studies that investigated gliclazide metabolism and polymorphic hepatic enzymes involved [ 14 , 15 ], and one study that evaluated relatively prolonged use (seven days) of gliclazide [ 16 ]. However, none of them examined athletic performance or post-exercise muscle recovery as an outcome. Hence, the objective of the present study was to examine the acute effect of gliclazide MR on strength performance and markers of muscle recovery following three strength exercise sessions in healthy trained participants. We hypothesize that gliclazide MR 90 mg once daily enhances strength performance and improves (accelerates) muscle recovery. METHODS This a randomized, double-blind, placebo-controlled crossover clinical trial. The study was approved by the research ethics committee at Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (protocol number 3,771,137). It followed the principles of the Declaration of Helsinki, is registered in www.clinicaltrials.gov (ID NCT04443777, Primary Completion: 01/08/2020; Study Completion: 31/10/2023) [ 17 ] and is reported following the CONSORT guidelines. Study participants The sample size was estimated based on a pilot crossover randomized clinical trial of our research group involving 10 healthy strength trained participants that evaluated strength performance (total volume-load [VL] in kg) as the primary outcome [ 18 ]. For the expected effect size of the study (d = 0.25), a power of 90%, a significance level of 5% and an additional 20% of sample loss, we calculated it was necessary a sample of 44 participants. We used GPower v3.1 for sample calculation. The inclusion criteria were healthy men aged 20–35 years, minimum of two years of strength training (average training frequency of three times a week), and uninterrupted training in the preceding six months. We excluded those who self-reported use of anabolic androgenic steroids or exogenous insulin in the preceding 24 months, any musculoskeletal injuries during data collection, and acute or chronic use of drugs that could affect strength performance during exercise sessions. The volunteers were strongly advised to avoid drinking alcohol for 72 hours before the study exercise sessions. One-repetition maximum test The participants were asked to get familiar with exercise sets (48 hours before the experimental session). Following a 5-minute warm-up on a cycle ergometer, they were asked to perform the specific movements for each type of exercise (bench press and free squats) at a workload of 15–20% of total body mass. Maximum load for free squats and bench press (TUTECH fitness equipment, 3-inch model) was determined in five attempts with 5% load increments. The load was determined for a full range of motion (ROM) [ 19 ]. A 5-minute rest was allowed between attempts. An electronic metronome (KORG, Melville, NY, USA) was used to control each repetition with two seconds for each contraction (concentric and eccentric) phase. The intraclass correlation coefficients (ICCs) of one-repetition maximum (1-RM) tests for bench press and squats during the familiarization and pre-session evaluation sessions were 0.96 and 0.97, respectively. At the end of this session the participants were given guidance for the next visits. Strength exercise protocol The strength exercise protocol started with dynamic warm-up involving sequential bench press and squat exercises with individualized loads of 50% of 1-RM. The participants were allowed a 2-minute rest before the main part of the session: four sets of exercise at 80% of 1-RM. An electronic metronome was used to control each repetition (2:2) until they were no longer able to complete the repetition cycle (concentric failure). The number of complete repetitions was counted. They were asked to perform a set of bench press followed by free squats with no rest between exercises and then a 3-minute rest was allowed. Volume-load We used VL as a parameter of strength performance. The absolute load lifted (80% of 1-RM), total number of repetitions up to failure for each type of exercise (bench press and free squats) and the number of sets (4 sets) were recorded on Visits 3, 4 and 5. VL was calculated as the load lifted (kg) x total number of repetitions per set x number of sets for each type of exercise [ 20 ]. Range of motion assessment We assessed ROM using an extensible goniometer (Gonnext, Brazil). Horizontal abduction ROM of the shoulder was measured with the participants lying prone on the examination table, their shoulder positioned at 90 degrees of abduction keeping the elbow extended and palm down. The axis of the goniometer was positioned on the superior-lateral aspect of the acromion. The stationary arm was positioned over the humerus. The movable arm was parallel to the humerus using the radial styloid process for reference following the horizontal abduction motion [ 21 ]. Knee flexion ROM was measured with the participants lying prone with their knees extended. The axis of the goniometer was positioned on the lateral epicondyle of the femur. The stationary arm was on the lateral midline of the femur using the greater trochanter for reference. The movable arm was in the lateral midline of the fibula using the lateral malleolus for reference [ 21 ]. ROM was measured in degrees from the range of the device’s stationary and moving arms. Intervention with gliclazide and placebo The participants were randomly allocated to receive gliclazide 90 mg as a modified-release tablet (Diamicron® MR) or placebo (starch) and then crossed over. Randomization of the study intervention sequence was carried out using a computer program ( www.randomizer.org ). An external researcher managed the randomized list and the tablets (gliclazide or placebo) for the study. We used a potentially safe gliclazide dose of 75% of the maximum clinically recommended dose (120 mg) [ 12 , 13 ]. A blinded investigator provided the calculated number of tablets required for each volunteer after their initial assessment (see Visit 2 section). Tablets containing gliclazide or placebo were matched by color, size, flavor and smell. The participants were instructed to take one tablet orally 8 hours before each exercise session (see Visits 3, 4 and 5 section). On the days between visits (interval of 48 hours), the tablets were to be taken with breakfast. The timing of tablet administration on the day of the study session was set so that peak plasma concentration of the drug would coincide with exercise, as gliclazide MR have linear pharmacokinetic properties with increasing plasma levels within 6 hours after administration, reaching a plateau after 12 hours and lasting effect up to 24 hours [ 22 ]. We allowed a washout period of one week when we switched between the two periods of the study (gliclazide or placebo before exercise) as recommended due to gliclazide’s half-life of 16 hours (metabolized by the liver) and clearance of 0.9 L/h [ 23 ]. Nutritional management Gliclazide affects plasma insulin levels and consequently insulin-dependent glucose uptake. The participants were asked to follow a personalized diet plan prescribed by a nutritionist during the study. The diet plan consisted of an intake of 1.4 g protein/kg (~ 20% of the total energy value), 4.2 g carbohydrate/kg (~ 55%) and 0.85 g lipid/kg (~ 25%) [ 24 ]. To prevent potential hypoglycemic events after exercise, participants were offered a snack before and after the sessions including a cheese and turkey breast sandwich made with whole grain bread and a cup of fruit yogurt consisting of 0.5 g/kg proteins and 0.88 g/kg carbohydrates [ 24 ]. Description of study visits All participants completed a total of 12 visits at the study site. On visits 1 and 2, they underwent general assessment and maximal dynamic strength tests. They performed three exercise sessions on visits 3, 4 and 5 with an interval of 48 hours between them. Visits 6 and 7 were for blood collection for the assessment of muscle recovery (24 and 48 hours after the last exercise session). Following a one-week washout period, the participants completed three other strength exercise sessions and two additional visits with new blood collection for muscle recovery assessment (24 and 48 hours) (Fig. 1 ). All volunteers were instructed not to engage in any other type of exercise throughout the study. Insert Fig. 1 Visit 1: evaluation session The participants were first explained the study procedures, risks and benefits and those who agreed to participate signed an informed consent form. They underwent a medical interview (medical, family and exercise information were collected). Resting heart rate (HR) (Polar RS300) and blood pressure (BP) (Omron 7122 digital sphygmomanometer) were measured. They were also instructed to fast for 8 hours before venous blood collection (10 mL) for plasma insulin and glucose determination. We also conducted an anthropometric evaluation. Body mass (Fillizola scale; precision of 0.05 kg) and height were measured. Skinfold thickness measurements were taken in the right hemibody (chest, mid-axillary, triceps, subscapular, abdominal, supra-iliac and mid-thigh) in triplicate non-consecutively with a scientific skinfold caliper (Cescorf; precision of 0.1 mm) to estimate body density from the Jackson and Pollock equation [ 25 ]. Body composition parameters, including absolute and relative fat and fat-free mass, were evaluated using the Siri equation [ 26 ]. At the end of visit 1, the participants had an opportunity to get familiar with bench press and free squat exercises for the 1-RM test. They were instructed to return two days later to perform this test. Visit 2: one-repetition maximum test On visit 2, the participants underwent the 1-RM test to determine the appropriate loads for strength exercises. They were asked to perform the test with a load equal to or greater than their body mass [ 19 , 20 ]. Visits 3, 4 and 5: strength exercise sessions The participants completed three strength exercise sessions 48 hours apart. Upon arrival at the study site, they rested for 10 minutes before HR and BP measurements and fasting blood collection (10 mL) were done. They were offered a snack before exercise. ROM for shoulder horizontal abduction and knee flexion was assessed before warm-up (on visit 3 only). HR and BP were measured and pain was rated using the visual analog scale (VAS) [ 27 ] pre-exercise before warm-up, between sets of exercise and at the end of the session (post-exercise). A 10-mL sample of venous blood was collected immediately after exercise. Capillary blood glucose was measured using a meter (AccuChek glucometer) before and after the exercise sessions. The volunteers were offered a snack after the exercise session to prevent hypoglycemic events. In addition, they were also strongly advised not to engage in any form of physical exertion beyond that of the study and to follow the prescribed diet plan. Visits 6 and 7: assessment of muscle recovery (24 hours and 48 hours post-exercise) Muscle recovery assessments were carried out 24 and 48 hours after the exercise session on visit 5. The participants were asked to rest for 10 minutes before measuring HR, BP, VAS and perceived recovery scores (PRS) [ 28 ]. They also underwent blood collection (10 mL sample), ROM assessment and 1-RM test in a row. After visit 7, the volunteers underwent a washout period of one week. They were advised not to perform any physical exercise and keep a standard diet. On day 8 they returned to the study site for the period 2 of crossing over. They received new tablets and repeated the procedures of visits 3 to 5, totaling 12 visits per participant (Fig. 1 ). Analysis of blood markers Blood samples were collected through vacuum venipuncture in the antecubital area of the arm using an aseptic technique. Blood tubes were centrifuged and the supernatant (plasma or serum) was aliquoted and frozen at − 80ºC for subsequent analysis. Plasma insulin concentration was determined through a chemiluminescent immunoassay (COBAS® 6000, Roche Brazil) according to the manufacturer's guidelines (Insulin Elecsys Reagent, Roche Diagnostics, Germany). Creatine kinase MM (muscle-muscle) isoform (CK-MM) and lactate dehydrogenase (LDH) are indirect markers of exercise-induced muscle damage [ 29 ]. The enzymatic activity of CK-MM and LDH levels were determined in duplicate using a colorimetric enzymatic assay (Roche, Analysis 7096) according to the manufacturer's guidelines (Creatina Kit ECPK-100, 340 nm and Lactato Desidrogenase Kit LDH, 450 nm, LEAC, Brazil). CK-MM is most abundant in skeletal muscle (95% of total CK) and therefore is the most specific marker of exercise-induced muscle damage [ 30 ]. To eliminate inter-assay variance, all samples were analyzed within the same assay batch (intra-assay variances ≤ 5.9%). ICCs were 0.96 for CK-MM and 0.94 for LDH. As the muscle recovery process involves mechanisms associated with the inflammatory state, we evaluated interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Thus, plasma IL-6 and TNF-α levels were assayed in duplicate using ELISA (MB-580 model, Heales Heales) according to the manufacturer's guidelines (R&D Systems, Minneapolis, US). Statistical analysis The data are presented as mean ± standard deviation (SD). We used the Shapiro-Wilk test to assess the assumption of normality and the Levene test to assess homogeneity of variance. We performed paired Student's t-test for exercise type and set to compare total VL of exercise sessions between the gliclazide and placebo groups. We used repeated measures two-factor ANOVA and Bonferroni post-hoc tests to compare variables pre-exercise, during the three exercise sessions and in the recovery period (24 hours and 48 hours post-exercise) between the gliclazide and placebo groups. When the condition of sphericity was not met, the Greenhouse-Geisser correction was used to adjust for the significance level of the test. Cohen's d was used to determine the effect size and classified as non-relevant ( 0.80). All data were analyzed using SPSS v23.0 at an alpha level of 5% (p < 0.05). RESULTS A total of 56 volunteers were recruited at Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia and eligible to participate in the study from August 01, 2020 and study completion October 10, 2023 (including period of the COVID-19 pandemic). Of fifty-six volunteers, eight were excluded and 48 were included in the study. Four individuals did not complete the study protocol—one had a hypoglycemic event, two experienced muscle discomfort, and one gave up because of personal reasons. Our final sample comprised 44 participants, which matched the estimated sample size. Table 1 shows physical and clinical characteristics of the participants. They met all the inclusion/exclusion criteria. Table 1 – Physical and physiological characteristics of the study sample (n = 44) Variables Mean ± SD Age (years) 28.4 ± 3.24 Total body mass (kg) 83.9 ± 8.9 Height (cm) 178.0 ± 4.8 Relative fat mass (%) 22.8 ± 3.1 Absolute fat mass (kg) 19.3 ± 4.2 Relative fat-free mass (%) 77.2 ± 3.1 Absolute fat-free mass (kg) 64.7 ± 5.8 Sum of seven skinfolds (mm) 85.0 ± 19.5 Strength training experience (years) 3.8 ± 1.2 1-RM bench press (kg) 100.5 ± 17.2 1-RM squat (kg) 113.1 ± 17.9 Fasting blood glucose (mg/dL) 92.7 ± 7.3 Fasting insulin (µU/mL) 5.6 ± 1.0 HOMA-IR 1.3 ± 0.1 HOMA II (%) 0.74 ± 0.2 Insulin sensitivity 135.9 ± 5.9 b-cell function 72.4 ± 3.6 HOMA-IR was calculated using the homeostatic model assessment (HOMA) II calculator; insulin sensitivity and β-cell function were determined using an application designed by University of Oxford [ 49 ]. Insert Table 1 Strength performance Total VL in all strength exercise sessions (Fig. 2 ) was greater in the gliclazide group when compared to the placebo group (p < 0.001; d = 0.88). We found similar results for both upper limb (bench press, p < 0.001; d = 0.81) and lower limb exercises (free squats, p < 0.001; d = 0.76). Insert Fig. 2 Table 2 describes differences in performance by session and set. Overall, the gliclazide group showed better performance than the placebo group (Table 2 ). The mean difference in total VL between the gliclazide and placebo groups was 23.3% (Gliclazide: 2383.9 ± 643.3 kg; Placebo: 1721.0 ± 410.9 kg) for bench press and 23.2% for squat exercises (Gliclazide: 2470.8 ± 641.2 kg; Placebo: 1705.0 ± 428.5 kg). Table 2 – Comparison of strength exercise performance (volume-load) by type, session and set Bench press Free squats Placebo (n = 44) Gliclazide (n = 44) Placebo (n = 44) Gliclazide (n = 44) Session 1 # reps Load (kg) # reps Load (kg) p-value # reps Load (kg) # reps Load (kg) p-value 1st set 9.9 ± 1.1 805.6 ± 180.8 9.9 ± 1.2 800.1 ± 182.5 0.654 8.9 ± 1.3 807.4 ± 199.8 8.9 ± 1.5 812.4 ± 184.1 0.641 2nd set 7.4 ± 1.0 600.8 ± 143.1 8.3 ± 1.2 672.0 ± 165.2 0.001 7.4 ± 1.2 666.9 ± 166.1 7.3 ± 1.3 675.0 ± 160.8 0.204 3rd set 5.5 ± 0.9 447.3 ± 109.8 6.8 ± 1.2 550.3 ± 155.6 0.001 5.9 ± 1.0 522.3 ± 137.4 5.7 ± 1.1 535.1 ± 136.6 0.023 4th set 4.2 ± 0.9 343.1 ± 94.3 4.9 ± 1.0 400.5 ± 119.7 0.001 4.4 ± 0.8 384.6 ± 120.0 4.2 ± 1.0 398.6 ± 107.1 0.040 Total 27.1 ± 3.4 2196.8 ± 504.0 29.8 ± 4.4 2422.9 ± 609.6 0.001 26.6 ± 4.0 2381.2 ± 600.3 26.1 ± 4.5 2421.1 ± 571.0 0.042 Session 2 # reps Load (kg) # reps Load (kg) p-value # reps Load (kg) # reps Load (kg) p-value 1st set 9.2 ± 0.8 744.7 ± 151.0 9.6 ± 1.3 778.8 ± 188.4 0.017 7.6 ± 1.2 684.1 ± 143.2 9.1 ± 1.2 826.8 ± 177.9 0.001 2nd set 6.3 ± 0.9 507.1 ± 123.5 7.9 ± 1.3 642.9 ± 168.1 0.001 6.2 ± 1.1 566.7 ± 138.8 7.3 ± 1.3 662.5 ± 162.5 0.001 3rd set 4.8 ± 0.8 386.3 ± 100.1 6.3 ± 1.2 510.1 ± 139.2 0.001 4.5 ± 1.0 409.0 ± 111.0 5.9 ± 1.0 534.6 ± 130.6 0.001 4th set 3.4 ± 0.8 277.7 ± 85.0 4.8 ± 1.0 390.3 ± 116.0 0.001 3.3 ± 0.9 297.0 ± 100.3 4.6 ± 0.9 420.0 ± 108.8 0.001 Total 23.6 ± 2.9 1915.8 ± 436.8 28.6 ± 4.6 2322.0 ± 598.2 0.001 21.5 ± 3.9 1956.9 ± 477.5 26.8 ± 4.0 2443.8 ± 561.3 0.001 Session 3 # reps Load (kg) # reps Load (kg) p-value # reps Load (kg) # reps Load (kg) p-value 1st set 8.5 ± 1.0 689.1 ± 153.1 9.5 ± 1.7 769.7 ± 202.4 0.001 6.5 ± 1.2 592.7 ± 140.4 8.6 ± 1.8 779.8 ± 214.7 0.001 2nd set 5.4 ± 1.0 439.1 ± 113.0 8.1 ± 1.5 658.7 ± 183.5 0.001 5.3 ± 1.0 482.5 ± 113.3 7.0 ± 1.6 638.1 ± 179.8 0.001 3rd set 4.2 ± 0.7 340.5 ± 90.8 6.6 ± 1.2 534.1 ± 145.4 0.001 4.0 ± 0.9 362.2 ± 98.7 6.2 ± 1.3 566.3 ± 149.8 0.001 4th set 3.1 ± 0.7 252.3 ± 78.2 5.2 ± 1.2 421.4 ± 128.7 0.001 2.9 ± 0.9 267.6 ± 91.5 5.3 ± 0.9 486.7 ± 119.4 0.001 Total 21.2 ± 2.9 1721.0 ± 410.9 29.3 ± 5.4 2383.9 ± 643.3 0.001 18.8 ± 3.6 1705.0 ± 428.5 27.2 ± 5.3 2470.8 ± 641.2 0.001 The values indicate total volume-load (VL) calculated by multiplying VL in kg (80% 1-RM) x number of repetitions per set. 1-RM: one-repetition maximum. Data are presented as mean ± standard deviation (SD). Differences were tested using Student’s t-test for paired samples for each exercise type (bench press and free squat) and considered significant at p < 0.05. Insert Table 2 Muscle strength recovery 1-RM measures were lower 24 hours and 48 hours after exercise during recovery compared to baseline (pre-intervention). However, recovery was more accelerated in the gliclazide group in all comparisons (exercise x time) for bench press (24h: p < 0.001, d = 0.26; 48h: p < 0.001, d = 0.28) and free squats (24h: p < 0.001, d = 0.30; 48h: p < 0.001, d = 0.41). These data show that gliclazide improved recovery of muscle strength (Fig. 3 ). Insert Fig. 3 Similar to 1-RM results, shoulder and knee ROM measures were lower 24 hours and 48 hours of recovery when compared to baseline (pre-intervention) – Fig. 4 . However, the gliclazide group showed faster recovery compared to placebo 24 hours (knee ROM p < 0.001, d = 0.22; shoulder ROM p = 0.004, d = 0.13) and 48 hours after the last exercise session (knee ROM p < 0.001, d = 0.20, shoulder ROM p = 0.048, d = 0.09) – Fig. 4 . Insert Fig. 4 The activity of CK-MM increased immediately post-exercise session in response to strength exercise in both the gliclazide and placebo groups in within-group comparisons (p < 0.001 for all comparisons) (Fig. 5 A). Starting from session 2, and considering the cumulative effect of strength exercise (pre- and post-session assessments), CK-MM was consistently lower in the gliclazide group compared to placebo. The same pattern of response was seen 24 and 48 hours of recovery with CK-MM being lower in the gliclazide group. Interestingly, LDH levels were also consistently lower in the gliclazide group (Fig. 5 B). As expected, our results point to intentional muscle damage in response to the exercise protocol and show that the use of gliclazide MR appears to be associated with enhanced muscle recovery despite the cumulative effect of exercise sessions. Insert Fig. 5 Inflammatory markers were measured before exercise sessions and 24 and 48 hours of recovery (Fig. 6 A). IL-6 levels increased successively over exercise sessions as well as 24 and 48 hours of recovery (p < 0.001 for all comparisons) when compared to baseline. In addition, we found no differences between the groups, except 48 hours after exercise where IL-6 levels were lower in the gliclazide group compared to placebo (p < 0.001, d = 0.31). In turn, TNF-α levels increased continuously from baseline in both groups (p < 0.001 for all comparisons) – Fig. 6 B. However, TNF-α levels were lower in the gliclazide group compared to placebo in all times evaluated as follows: session 1 (baseline), p = 0.669; session 2, p < 0.001 and d = 1.37; session 3, p < 0.001 and d = 1.33; 24 hours of recovery, p < 0.001 and d = 1.70; and 48 hours of recovery, p < 0.001 and d = 1.70 – Fig. 6 B. Pain intensity scores increased progressively with exercise in both the gliclazide and placebo groups (p < 0.001). However, from session 2, mean pain ratings were lower in the gliclazide group than placebo (Table S1 , supplementary material). Overall, during the recovery period (24 hours and 48 hours post-exercise), pain ratings decreased by 38% in both groups though they were lower in the gliclazide group compared to placebo (Table S1 , supplementary material). Finally, compared to placebo, the gliclazide group showed higher scores of perceived recovery pre-exercise in all sessions and during recovery (Table S1 , supplementary material). Insulin and glucose levels and adverse events As expected, plasma insulin levels were higher with the administration of gliclazide (pre-session and during recovery), which indicates that at this dose gliclazide exerts an insulinotropic effect (Table 3 ). We found an acute reduction in blood glucose levels in all exercise sessions in both groups. However, the magnitude of reduction was greater in the gliclazide group: in session 1, blood glucose reduced by 23.1% in the gliclazide group compared to 9.3% with placebo (p < 0.001; d = 1.32), in session 2, it reduced by 23.5% vs. 11.8% (p < 0.001; d = 1.09), and in session 3, 24.8% vs. 9.2% (p < 0.001; d = 1.21). Table 3 – Comparison of plasma glucose and insulin levels before and after the exercise sessions Placebo (n = 44) Gliclazide (n = 44) Glucose (mg/dL) 0.001 (p-interaction) Pre-exercise Post-exercise ∆ p-value Pre-exercise Post-exercise ∆ p-value (post-hoc) Session 1 115.0 ± 18.5 104.3 ± 15.3 10.6 ± 16.7 0.034 113.1 ± 9.5 86.9 ± 10.2 26.2 ± 8.8 < 0.001 Session 2 115.2 ± 17.3 106.1 ± 16.5 13.8 ± 15.2 0.039 114.8 ± 9.5 87.8 ± 11.4 27.0 ± 8.5 < 0.001 Session 3 117.1 ± 15.8 105.3 ± 14.4 11.8 ± 16.8 0.019 116.6 ± 9.8 87.6 ± 13.4 28.9 ± 10.4 < 0.001 Insulin (µm.ml − 1 ) 0.005 (p-interaction) Pre-exercise Post-exercise ∆ p-value Pre-exercise Post-exercise ∆ p-value (post-hoc) Session 1 5.7 ± 0.8 --- --- --- 7.8 ± 1.2 --- --- < 0.001 Session 2 5.7 ± 0.9 --- --- --- 7.9 ± 1.2 --- --- < 0.001 Session 3 5.7 ± 0.8 --- --- --- 7.9 ± 1.0 --- --- < 0.001 Post-24h 5.8 ± 0.8 --- --- --- 8.0 ± 0.9 --- --- < 0.001 Post-48h 5.9 ± 0.8 --- --- --- 8.0 ± 0.9 --- --- < 0.001 Post-24h, 24 hours of recovery; post-48h, 48 hours of recovery. Pre-exercise, immediately before exercise session; post-exercise, immediately after the exercise session. Data are presented as mean ± standard deviation (SD). Differences were tested using two-way ANOVA with Bonferroni post-hoc test and considered significant at p < 0.05. Three participants in the gliclazide group (7%) experienced adverse hypoglycemic events post-exercise (blood glucose levels of 46, 49 and 51 mg/dL) as dizziness, pale skin and sweating were common signs. This effect was reversed immediately with the consumption of 30g of quickly absorbed carbohydrate—maltodextrin (Integralmedica®) containing ~ 27g carbohydrates. Insert Table 3 Hemodynamic measures (HR, BP and double product) did not change significantly before, during or after strength exercise sessions (Table S2 , supplementary material). DISCUSSION To the best of our knowledge, this is the first study that primarily aimed to examine whether the use of gliclazide MR 90 mg enhances performance and/or muscle recovery in strength-trained healthy volunteers following three strength exercise sessions. Based on our main findings, we accept the hypothesis that gliclazide MR 90 mg enhances strength performance (assessed by VL) and muscle recovery (assessed by CK-MM, LDH, TNF-α and IL-6 levels and 1-RM and ROM recovery) and improves perceived pain and recovery. However, the use of gliclazide MR at a dose of 90 mg can cause adverse effects, especially associated with reduced blood glucose levels leading to hypoglycemic events. The rationale for the use of gliclazide in amateur and professional athletes is that it stimulates endogenous insulin secretion [ 3 ] and optimizes nutrient uptake (mostly glucose and amino acids) in skeletal muscle [ 6 , 7 ] during and after exercise, thus possibly enhancing performance and muscle recovery. In fact, oral administration of gliclazide MR 90 mg in a single daily dose increased insulin levels across all exercise sessions and during recovery (24 hours and 48 hours post-exercise) compared to placebo in our study, which demonstrates that our intervention protocol was effective. Change in exercise capacity has been used as a parameter of strength performance [ 19 , 20 ]. We tested a high-intensity exercise protocol (80% of 1-RM), which is characterized by predominantly lactic anaerobic activity [ 31 ]. There is a consensus in the literature that moderate-high intensity exercise performance is dependent on greater availability of nutrients especially carbohydrate in the form of glucose/glycogen stores [ 32 ]. During exercise, the secretion of endogenous insulin is reduced. Insulin-independent mechanisms promote glucose uptake by muscle cells in response to muscle contraction which is possibly a compensatory effect to reduced insulin levels during exercise [ 7 ]. The insulinotropic action of gliclazide is not a response to exercise. So, there is “twice the effect” on glucose uptake in muscle cells during exercise: through insulin-independent mechanisms triggered by muscle contraction and increased circulating levels of insulin due to pharmacological stimulation. This could explain enhanced performance seen as early as the first exercise session of our study. In contrast, we reported previously that a single-dose administration of gliclazide MR 60 mg did not improve performance in a single session of strength exercise at 65% of 1-RM (unpublished data). The ergogenic effect of this drug may be dose-dependent, requiring a higher dose and may involve exercise at greater intensity to elicit a metabolic response. The assumption of increased glucose uptake during strength exercise is further supported by the fact that three participants in the gliclazide group experienced hypoglycemic events during exercise. In addition, the participants in the placebo group probably experienced residual fatigue as a result of consecutive exercise sessions as their performance dropped by 8% from session 1 to session 2 and by 11.5% from session 2 to session 3. This decline in performance was not seen in the gliclazide group (Fig. 2 ). It could be that more rapid muscle glycogen restoration occurred between sessions in the gliclazide group, though we did not measure glycogen in the present study. We evaluated 1-RM and ROM as functional parameters of muscle recovery. Exercise-induced muscle damage has been associated with the ability to generate maximum dynamic strength following an exercise session [ 33 ]. In our study, maximum [ 33 ]assessed by 1-RM decreased by 9.8% (bench press) and 13.3% (squats) in the gliclazide group and by 16.6% (bench press) and 18.6% (squats) in the placebo group 24 hours post-exercise. Then the participants recovered 96.1% (bench press) and 95.6% (squats) of their strength in the gliclazide group and 92.1% (bench press) and 90.3% (squats) in the placebo group 48 hours post-exercise. Though these values are small, they may indicate potential ergogenic effects of gliclazide on recovery of muscle strength. Similar effects have been shown for other interventions, such as nutritional supplements ingestion such as creatine, carbohydrates and proteins [ 34 , 35 ]. We did not find in the literature data of these effects with the use of gliclazide. ROM for shoulder horizontal abduction and knee extension is another parameter of muscle recovery [ 29 , 36 ] assessed in this study. Our findings were similar to those for 1-RM. Reduced ROM seen in the placebo group during recovery (24 and 48 hours post-exercise) is consistent with that reported for control groups in other studies testing nutritional interventions [ 34 , 35 ]. Mean ROM reduction was 9% with nearly 95% recovery 48 hours after exercise. It suggests that our sample was comparable to those used in other studies, which further supports our findings of the effects of gliclazide MR on muscle recovery. Indirect markers of exercise-induced muscle damage, mainly CK-MM and LDH, are widely used to quantitatively assess the effects of exercise on muscle recovery [ 29 , 37 ]. The activities of CK-MM and LDH showed the same pattern in our study, which is consistent with that reported by Bernat-Adell et al. [ 38 ]. In this study, the exercise protocol produced an acute increase in the levels of both markers—CK-MM and LDH—across all sessions. From session 2, CK-MM and LDH levels pre-exercise were lower in the gliclazide group compared to placebo, which suggests improved muscle damage recovery from previous sessions. Peak levels of CK-MM and LDH occurred 24 hours after the last exercise session. This finding corroborates that reported in other studies [ 36 , 39 ] although they occurred at later times after exercise session [ 40 ]. Our research group, while examining the effect of gliclazide 60 mg in a single dose on the levels of CK-MM and LDH in response to a strength exercise session, reported similar changes, but they were lower in the gliclazide group compared to placebo. Some studies [ 41 , 42 ] have shown a moderate positive correlation (r = 0.44) between CK-MM levels and VL. Nosaka and Clarkson [ 43 ] measured muscle volume involved in (unilateral or bilateral) strength exercise with the same VL and found similar increase in CK levels. We would expect that exercise requiring larger muscle groups would also result in greater muscle damage and thus higher CK levels, but this was not seen. Probably, several factors may be involved and will determine the extent of muscle damage. Indirect blood markers of damage should be evaluated together with other measures. Changes in IL-6 and TNF-α concentration levels are often used as markers of the inflammatory response [ 44 , 45 ]. The mechanical overload of concentric and eccentric contractions during strength exercises primarily induces functional adaptations in skeletal muscles due to transient desired structural changes in sarcomeres. During recovery, exercise-induced damage results in muscle inflammation and, consequently, sarcomere repair [ 45 ]. Here, the protocol of strength exercises caused a continuous increase in IL-6 levels across all sessions, as well as during recovery 24 hours after exercise. These findings corroborate that reported in other studies [ 46 , 47 ] suggesting that IL-6 levels increase in response to metabolic and mechanical stress that occur with exercise. Bartolomei study [ 48 ] showed that, after a single session of strength exercise at high intensity or with high VL, IL-6 concentration returned to pre-exercise levels 24 hours and 48 hours of recovery. Interestingly, muscle damage markers (CK-MM and LDH) showed similar response in our study. IL-6 levels were increased in the placebo group and reduced in the gliclazide group 48 hours of recovery. This finding suggests that gliclazide has an ergogenic effect, accelerating muscle recovery and reducing inflammation. We also evaluated plasma TNF-α concentration, which clearly increased across the three exercise sessions of the study and then it remained high over a 24-hour period. Concentration levels were then reduced twice 48 hours of recovery in both the gliclazide and placebo groups. Yet, this increase was of small magnitude in the gliclazide group at all times. Considering that TNF-α is essentially a pro-inflammatory cytokine, this finding reinforces its action to reduce exercise-induced inflammation. Collectively, markers of muscle damage and post-exercise recovery—CK-MM, LDH, IL-6 and TNF-α—were lower in the gliclazide group than placebo. Perceived pain and recovery scores were also lower in the gliclazide group, which further supports that gliclazide enhances recovery after strength exercise. Our study has some limitations. The main limitation lies in the unfeasibility to evaluate the effects of gliclazide for longer periods of time, which is related to ethical aspects. A second limitation is that only plasma glucose levels, but not insulin, were measured at different times. Concurrent plasma glucose and insulin measurements would have allowed a more in-depth discussion of their association with exercise. Another important point is that we did not examine counter-regulatory effects of anti-inflammatory cytokines on IL-6 and TNF-α. Still, we believe that these limitations do not weaken our results. In conclusion, this randomized, placebo-controlled, double-blind crossover randomized clinical trial showed that gliclazide MR 90 mg at single daily dose taken 8 hours before strength exercise sessions had an ergogenic effect, enhancing strength performance and accelerating muscle recovery. However, these beneficial effects were counterbalanced by blood glucose reductions during and/or immediately after exercise, including three episodes of symptomatic hypoglycemia, which is a cause for concern. Declarations Acknowledgements We also thank Mara Lane Zardin at the biochemistry laboratory of Grupo Hospitalar Conceição (GHC) and Ricardo Benitez at the laboratory of clinical analysis for their assistance. Authors' contributions J.B.M. and A.M.L. designed the study. J.B.M. collected and analyzed the data. J.B.M., T.D., B.D.S. and A.M.L. carried out the interpretation of data. J.B.M. drafted the manuscript. T.D., B.D.S and A.M.L. helped prepare the manuscript and revised it critically. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4450743","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":313316227,"identity":"ba237a79-6bfc-489e-865b-312a728d19c4","order_by":0,"name":"Jocelito Bijoldo Martins","email":"","orcid":"","institution":"Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia","correspondingAuthor":false,"prefix":"","firstName":"Jocelito","middleName":"Bijoldo","lastName":"Martins","suffix":""},{"id":313316230,"identity":"54163a02-8a55-4d96-b4f5-4acaf99f12af","order_by":1,"name":"Thiago Dipp","email":"","orcid":"","institution":"Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia","correspondingAuthor":false,"prefix":"","firstName":"Thiago","middleName":"","lastName":"Dipp","suffix":""},{"id":313316232,"identity":"2fa6eccb-d641-4569-9089-a7445bf8631a","order_by":2,"name":"Beatriz D. 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Total volume-load is the sum of values for bench press and squat exercise. Data are presented as mean ± standard deviation (SD). Differences were tested using Student’s t-test\u003cem\u003e \u003c/em\u003efor paired samples for each exercise type (bench press and free squat) and for total; * p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003eplacebo.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/2d0b5b0c0d9740cc39cb1baa.png"},{"id":58308204,"identity":"564f7c78-c75c-4bd1-8268-fa1ad3efcc1f","added_by":"auto","created_at":"2024-06-13 18:47:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":29490,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of one-repetition maximum (1-RM) between the gliclazide (n = 44) and placebo groups (n = 44). Data are presented as mean ± standard deviation (SD). Differences were tested by two-way ANOVA with repeated measures by exercise type (bench press and free squat) and time and Bonferroni post-hoc test; * p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003eplacebo; † p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003ebaseline within the group.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/05af838cb4e7c1c8bcb464e0.png"},{"id":58308206,"identity":"9701f24c-d85a-4007-bbe3-f7ace3d7dee5","added_by":"auto","created_at":"2024-06-13 18:47:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":28581,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of range of motion (ROM) between the gliclazide (n = 44) and placebo groups (n = 44). Data are presented as mean ± standard deviation (SD). Differences were tested by two-way ANOVA with repeated measures for paired samples by joint (shoulder and knee) and time and Bonferroni post\u003cem\u003e-\u003c/em\u003ehoc test; * p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003eplacebo; † p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003ebaseline within the group.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/7e715ed9087dfbf2fe17b44a.png"},{"id":58308202,"identity":"006c045c-8c2e-41a1-bdc6-e5b9051d050d","added_by":"auto","created_at":"2024-06-13 18:47:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":58356,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of muscle damage markers between the gliclazide (n = 44) and the placebo groups (n = 44). Panel A: enzymatic activity of creatine kinase MM isoform (CK-MM). Panel B: serum levels of lactate dehydrogenase (LDH). Data are presented as mean ± standard deviation (SD). Differences were tested by two-way ANOVA with repeated measures and Bonferroni post\u003cem\u003e-\u003c/em\u003ehoc test; \u003csup\u003e#\u003c/sup\u003e p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003eplacebo at the same time and * p\u0026lt;0.05 versus pre-session within the group.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/cf792861fc06fd7fd586f981.png"},{"id":58308208,"identity":"1065d759-46c5-4ec9-a56c-45ca556d6982","added_by":"auto","created_at":"2024-06-13 18:47:09","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":41389,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of inflammatory markers between the gliclazide (n=44) and the placebo groups (n=44). Panel A: interleukin 6 (IL-6). Panel B: tumor necrosis factor alpha (TNF-α). Data are presented as mean ± standard deviation (SD) pre-session and 24 hours and 48 hours of recovery. Differences were tested by two-way ANOVA with repeated measures and Bonferroni post-hoc test; * p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003esession 1 within the group; \u003csup\u003e#\u003c/sup\u003e p\u0026lt;0.05 versus\u003cem\u003e \u003c/em\u003eplacebo at the same time.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/e025cfcbfc07989a9ca24ecb.png"},{"id":59829132,"identity":"a93ddef6-66d6-460a-8ea2-18bc13c984dc","added_by":"auto","created_at":"2024-07-08 06:57:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1207624,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/19453e86-77a0-4263-b3ad-b97647ae1664.pdf"},{"id":58308201,"identity":"fdac66b1-9ab5-452e-a6ed-1474a0f24c5f","added_by":"auto","created_at":"2024-06-13 18:47:08","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":179223,"visible":true,"origin":"","legend":"","description":"","filename":"Dataset.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/f0bddaa4e76421aa7860bdd4.xlsx"},{"id":58308207,"identity":"3b530c62-d2f9-4f9a-bda2-67c484fe9c74","added_by":"auto","created_at":"2024-06-13 18:47:09","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19619,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4450743/v1/26437dbfdd8c74d47a05899e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Gliclazide enhances exercise performance and recovery of muscle strength in healthy trained individuals: a randomized controlled trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSulfonylureas are a class of drugs that has been used in the treatment of type 2 diabetes mellitus (T2DM) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They act by binding to a specific receptor for sulfonylureas (SUR) in pancreatic β-cells, blocking ATP-dependent potassium channels (K\u003csup\u003e+\u003c/sup\u003e-ATP) and stimulating the secretion of insulin [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The World Health Organization (WHO) list of medications includes gliclazide as the safest and most effective drug in the sulfonylurea class and is indicated for the treatment of T2DM [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Due to its pharmacodynamic properties, gliclazide is highly selective and binds to receptors on pancreatic β-cells (SUR1) and at the same time shows low affinity for receptors on cardiac muscle (SUR2A) and vascular muscle cells (SUR2B) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNumerous athletes use substances and/or methods for performance enhancement which is against the spirit of sports and may be harmful to their health. One of these substances is insulin, an anabolic hormone that can artificially increase muscle mass and enhance athletic performance. Because of its use for doping in sports, the World Anti-Doping Agency (WADA) has put insulin in the list of prohibited substances [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Yet, there are reports of the use of sulfonylureas as an insulinotropic drug in amateur and professional athletes since they are not included in this list of doping agents.\u003c/p\u003e \u003cp\u003eSulfonylureas increase endogenous insulin secretion and enhance glucose and amino acid uptake in skeletal muscle cells [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The supply and uptake of nutrients especially glucose and amino acids would be increased in muscle cells, resulting in increased protein synthesis and, in the short-term, enhancing sports performance. In addition, sulfonylureas can increase resynthesis of glycogen stores in muscle cells over time and accelerate post-exercise muscle recovery in repeated exercise sessions [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As they may artificially enhance sports performance and potentially harm athlete\u0026rsquo;s health, they can be considered doping agents. In a pilot study conducted by our research group, we found that the acute use of gliclazide 60 mg as a modified-release tablet (gliclazide MR) before a single session of strength exercise did not directly enhance athletic performance, although it accelerated muscle recovery in later sessions (unpublished data).\u003c/p\u003e \u003cp\u003eThe hypothetical effect of gliclazide as a potential ergogenic substance has not yet been tested, neither as an acute nor as a chronic response to exercise. The closest approach involved studies that acutely evaluated healthy participants taking gliclazide for its bioequivalence [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and pharmacokinetic and pharmacodynamic properties [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], studies that investigated gliclazide metabolism and polymorphic hepatic enzymes involved [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and one study that evaluated relatively prolonged use (seven days) of gliclazide [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, none of them examined athletic performance or post-exercise muscle recovery as an outcome.\u003c/p\u003e \u003cp\u003eHence, the objective of the present study was to examine the acute effect of gliclazide MR on strength performance and markers of muscle recovery following three strength exercise sessions in healthy trained participants. We hypothesize that gliclazide MR 90 mg once daily enhances strength performance and improves (accelerates) muscle recovery.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis a randomized, double-blind, placebo-controlled crossover clinical trial. The study was approved by the research ethics committee at \u003cem\u003eInstituto de Cardiologia do Rio Grande do Sul/Funda\u0026ccedil;\u0026atilde;o Universit\u0026aacute;ria de Cardiologia\u003c/em\u003e (protocol number 3,771,137). It followed the principles of the Declaration of Helsinki, is registered in \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.clinicaltrials.gov\u003c/span\u003e\u003c/span\u003e (ID NCT04443777, Primary Completion: 01/08/2020; Study Completion: 31/10/2023) [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e] and is reported following the CONSORT guidelines.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy participants\u003c/h2\u003e\n \u003cp\u003eThe sample size was estimated based on a pilot crossover randomized clinical trial of our research group involving 10 healthy strength trained participants that evaluated strength performance (total volume-load [VL] in kg) as the primary outcome [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. For the expected effect size of the study (d\u0026thinsp;=\u0026thinsp;0.25), a power of 90%, a significance level of 5% and an additional 20% of sample loss, we calculated it was necessary a sample of 44 participants. We used GPower v3.1 for sample calculation.\u003c/p\u003e\n \u003cp\u003eThe inclusion criteria were healthy men aged 20\u0026ndash;35 years, minimum of two years of strength training (average training frequency of three times a week), and uninterrupted training in the preceding six months. We excluded those who self-reported use of anabolic androgenic steroids or exogenous insulin in the preceding 24 months, any musculoskeletal injuries during data collection, and acute or chronic use of drugs that could affect strength performance during exercise sessions. The volunteers were strongly advised to avoid drinking alcohol for 72 hours before the study exercise sessions.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eOne-repetition maximum test\u003c/h2\u003e\n \u003cp\u003eThe participants were asked to get familiar with exercise sets (48 hours before the experimental session). Following a 5-minute warm-up on a cycle ergometer, they were asked to perform the specific movements for each type of exercise (bench press and free squats) at a workload of 15\u0026ndash;20% of total body mass. Maximum load for free squats and bench press (TUTECH fitness equipment, 3-inch model) was determined in five attempts with 5% load increments. The load was determined for a full range of motion (ROM) [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. A 5-minute rest was allowed between attempts. An electronic metronome (KORG, Melville, NY, USA) was used to control each repetition with two seconds for each contraction (concentric and eccentric) phase. The intraclass correlation coefficients (ICCs) of one-repetition maximum (1-RM) tests for bench press and squats during the familiarization and pre-session evaluation sessions were 0.96 and 0.97, respectively. At the end of this session the participants were given guidance for the next visits.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eStrength exercise protocol\u003c/h2\u003e\n \u003cp\u003eThe strength exercise protocol started with dynamic warm-up involving sequential bench press and squat exercises with individualized loads of 50% of 1-RM. The participants were allowed a 2-minute rest before the main part of the session: four sets of exercise at 80% of 1-RM. An electronic metronome was used to control each repetition (2:2) until they were no longer able to complete the repetition cycle (concentric failure). The number of complete repetitions was counted. They were asked to perform a set of bench press followed by free squats with no rest between exercises and then a 3-minute rest was allowed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eVolume-load\u003c/h2\u003e\n \u003cp\u003eWe used VL as a parameter of strength performance. The absolute load lifted (80% of 1-RM), total number of repetitions up to failure for each type of exercise (bench press and free squats) and the number of sets (4 sets) were recorded on Visits 3, 4 and 5. VL was calculated as the load lifted (kg) x total number of repetitions per set x number of sets for each type of exercise [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eRange of motion assessment\u003c/h2\u003e\n \u003cp\u003eWe assessed ROM using an extensible goniometer (Gonnext, Brazil). Horizontal abduction ROM of the shoulder was measured with the participants lying prone on the examination table, their shoulder positioned at 90 degrees of abduction keeping the elbow extended and palm down. The axis of the goniometer was positioned on the superior-lateral aspect of the acromion. The stationary arm was positioned over the humerus. The movable arm was parallel to the humerus using the radial styloid process for reference following the horizontal abduction motion [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Knee flexion ROM was measured with the participants lying prone with their knees extended. The axis of the goniometer was positioned on the lateral epicondyle of the femur. The stationary arm was on the lateral midline of the femur using the greater trochanter for reference. The movable arm was in the lateral midline of the fibula using the lateral malleolus for reference [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. ROM was measured in degrees from the range of the device\u0026rsquo;s stationary and moving arms.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eIntervention with gliclazide and placebo\u003c/h2\u003e\n \u003cp\u003eThe participants were randomly allocated to receive gliclazide 90 mg as a modified-release tablet (Diamicron\u0026reg; MR) or placebo (starch) and then crossed over. Randomization of the study intervention sequence was carried out using a computer program (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.randomizer.org\u003c/span\u003e\u003c/span\u003e). An external researcher managed the randomized list and the tablets (gliclazide or placebo) for the study. We used a potentially safe gliclazide dose of 75% of the maximum clinically recommended dose (120 mg) [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eA blinded investigator provided the calculated number of tablets required for each volunteer after their initial assessment (see Visit 2 section). Tablets containing gliclazide or placebo were matched by color, size, flavor and smell. The participants were instructed to take one tablet orally 8 hours before each exercise session (see Visits 3, 4 and 5 section). On the days between visits (interval of 48 hours), the tablets were to be taken with breakfast. The timing of tablet administration on the day of the study session was set so that peak plasma concentration of the drug would coincide with exercise, as gliclazide MR have linear pharmacokinetic properties with increasing plasma levels within 6 hours after administration, reaching a plateau after 12 hours and lasting effect up to 24 hours [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eWe allowed a washout period of one week when we switched between the two periods of the study (gliclazide or placebo before exercise) as recommended due to gliclazide\u0026rsquo;s half-life of 16 hours (metabolized by the liver) and clearance of 0.9 L/h [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eNutritional management\u003c/h2\u003e\n \u003cp\u003eGliclazide affects plasma insulin levels and consequently insulin-dependent glucose uptake. The participants were asked to follow a personalized diet plan prescribed by a nutritionist during the study. The diet plan consisted of an intake of 1.4 g protein/kg (~\u0026thinsp;20% of the total energy value), 4.2 g carbohydrate/kg (~\u0026thinsp;55%) and 0.85 g lipid/kg (~\u0026thinsp;25%) [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. To prevent potential hypoglycemic events after exercise, participants were offered a snack before and after the sessions including a cheese and turkey breast sandwich made with whole grain bread and a cup of fruit yogurt consisting of 0.5 g/kg proteins and 0.88 g/kg carbohydrates [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eDescription of study visits\u003c/h2\u003e\n \u003cp\u003eAll participants completed a total of 12 visits at the study site. On visits 1 and 2, they underwent general assessment and maximal dynamic strength tests. They performed three exercise sessions on visits 3, 4 and 5 with an interval of 48 hours between them. Visits 6 and 7 were for blood collection for the assessment of muscle recovery (24 and 48 hours after the last exercise session). Following a one-week washout period, the participants completed three other strength exercise sessions and two additional visits with new blood collection for muscle recovery assessment (24 and 48 hours) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). All volunteers were instructed not to engage in any other type of exercise throughout the study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eInsert Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/h2\u003e\n \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\n \u003ch2\u003eVisit 1: evaluation session\u003c/h2\u003e\n \u003cp\u003eThe participants were first explained the study procedures, risks and benefits and those who agreed to participate signed an informed consent form. They underwent a medical interview (medical, family and exercise information were collected). Resting heart rate (HR) (Polar RS300) and blood pressure (BP) (Omron 7122 digital sphygmomanometer) were measured. They were also instructed to fast for 8 hours before venous blood collection (10 mL) for plasma insulin and glucose determination.\u003c/p\u003e\n \u003cp\u003eWe also conducted an anthropometric evaluation. Body mass (Fillizola scale; precision of 0.05 kg) and height were measured. Skinfold thickness measurements were taken in the right hemibody (chest, mid-axillary, triceps, subscapular, abdominal, supra-iliac and mid-thigh) in triplicate non-consecutively with a scientific skinfold caliper (Cescorf; precision of 0.1 mm) to estimate body density from the Jackson and Pollock equation [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Body composition parameters, including absolute and relative fat and fat-free mass, were evaluated using the Siri equation [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eAt the end of visit 1, the participants had an opportunity to get familiar with bench press and free squat exercises for the 1-RM test. They were instructed to return two days later to perform this test.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eVisit 2: one-repetition maximum test\u003c/h2\u003e\n \u003cp\u003eOn visit 2, the participants underwent the 1-RM test to determine the appropriate loads for strength exercises. They were asked to perform the test with a load equal to or greater than their body mass [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eVisits 3, 4 and 5: strength exercise sessions\u003c/h2\u003e\n \u003cp\u003eThe participants completed three strength exercise sessions 48 hours apart. Upon arrival at the study site, they rested for 10 minutes before HR and BP measurements and fasting blood collection (10 mL) were done. They were offered a snack before exercise. ROM for shoulder horizontal abduction and knee flexion was assessed before warm-up (on visit 3 only).\u003c/p\u003e\n \u003cp\u003eHR and BP were measured and pain was rated using the visual analog scale (VAS) [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] pre-exercise before warm-up, between sets of exercise and at the end of the session (post-exercise). A 10-mL sample of venous blood was collected immediately after exercise. Capillary blood glucose was measured using a meter (AccuChek glucometer) before and after the exercise sessions.\u003c/p\u003e\n \u003cp\u003eThe volunteers were offered a snack after the exercise session to prevent hypoglycemic events. In addition, they were also strongly advised not to engage in any form of physical exertion beyond that of the study and to follow the prescribed diet plan.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eVisits 6 and 7: assessment of muscle recovery (24 hours and 48 hours post-exercise)\u003c/h2\u003e\n \u003cp\u003eMuscle recovery assessments were carried out 24 and 48 hours after the exercise session on visit 5. The participants were asked to rest for 10 minutes before measuring HR, BP, VAS and perceived recovery scores (PRS) [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. They also underwent blood collection (10 mL sample), ROM assessment and 1-RM test in a row.\u003c/p\u003e\n \u003cp\u003eAfter visit 7, the volunteers underwent a washout period of one week. They were advised not to perform any physical exercise and keep a standard diet. On day 8 they returned to the study site for the period 2 of crossing over. They received new tablets and repeated the procedures of visits 3 to 5, totaling 12 visits per participant (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eAnalysis of blood markers\u003c/h2\u003e\n \u003cp\u003eBlood samples were collected through vacuum venipuncture in the antecubital area of the arm using an aseptic technique. Blood tubes were centrifuged and the supernatant (plasma or serum) was aliquoted and frozen at \u0026minus;\u0026thinsp;80\u0026ordm;C for subsequent analysis.\u003c/p\u003e\n \u003cp\u003ePlasma insulin concentration was determined through a chemiluminescent immunoassay (COBAS\u0026reg; 6000, Roche Brazil) according to the manufacturer\u0026apos;s guidelines (Insulin Elecsys Reagent, Roche Diagnostics, Germany).\u003c/p\u003e\n \u003cp\u003eCreatine kinase MM (muscle-muscle) isoform (CK-MM) and lactate dehydrogenase (LDH) are indirect markers of exercise-induced muscle damage [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. The enzymatic activity of CK-MM and LDH levels were determined in duplicate using a colorimetric enzymatic assay (Roche, Analysis 7096) according to the manufacturer\u0026apos;s guidelines (Creatina Kit ECPK-100, 340 nm and Lactato Desidrogenase Kit LDH, 450 nm, LEAC, Brazil). CK-MM is most abundant in skeletal muscle (95% of total CK) and therefore is the most specific marker of exercise-induced muscle damage [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. To eliminate inter-assay variance, all samples were analyzed within the same assay batch (intra-assay variances\u0026thinsp;\u0026le;\u0026thinsp;5.9%). ICCs were 0.96 for CK-MM and 0.94 for LDH.\u003c/p\u003e\n \u003cp\u003eAs the muscle recovery process involves mechanisms associated with the inflammatory state, we evaluated interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-\u0026alpha;). Thus, plasma IL-6 and TNF-\u0026alpha; levels were assayed in duplicate using ELISA (MB-580 model, Heales Heales) according to the manufacturer\u0026apos;s guidelines (R\u0026amp;D Systems, Minneapolis, US).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). We used the Shapiro-Wilk test to assess the assumption of normality and the Levene test to assess homogeneity of variance. We performed paired Student\u0026apos;s t-test for exercise type and set to compare total VL of exercise sessions between the gliclazide and placebo groups. We used repeated measures two-factor ANOVA and Bonferroni post-hoc tests to compare variables pre-exercise, during the three exercise sessions and in the recovery period (24 hours and 48 hours post-exercise) between the gliclazide and placebo groups. When the condition of sphericity was not met, the Greenhouse-Geisser correction was used to adjust for the significance level of the test. Cohen\u0026apos;s d was used to determine the effect size and classified as non-relevant (\u0026lt;\u0026thinsp;0.20), small (0.20 to 0.49), medium (0.50 and 0.79), and large or consistent (\u0026gt;\u0026thinsp;0.80). All data were analyzed using SPSS v23.0 at an alpha level of 5% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 56 volunteers were recruited at \u003cem\u003eInstituto de Cardiologia do Rio Grande do Sul/Funda\u0026ccedil;\u0026atilde;o Universit\u0026aacute;ria de Cardiologia\u003c/em\u003e and eligible to participate in the study from August 01, 2020 and study completion October 10, 2023 (including period of the COVID-19 pandemic). Of fifty-six volunteers, eight were excluded and 48 were included in the study. Four individuals did not complete the study protocol\u0026mdash;one had a hypoglycemic event, two experienced muscle discomfort, and one gave up because of personal reasons. Our final sample comprised 44 participants, which matched the estimated sample size.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows physical and clinical characteristics of the participants. They met all the inclusion/exclusion criteria.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Physical and physiological characteristics of the study sample (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e28.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal body mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e83.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e178.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelative fat mass (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsolute fat mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e19.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelative fat-free mass (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e77.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsolute fat-free mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e64.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSum of seven skinfolds (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e85.0\u0026thinsp;\u0026plusmn;\u0026thinsp;19.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStrength training experience (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-RM bench press (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e100.5\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-RM squat (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e113.1\u0026thinsp;\u0026plusmn;\u0026thinsp;17.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting blood glucose (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e92.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting insulin (\u0026micro;U/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOMA-IR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOMA II (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin sensitivity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e135.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eb-cell function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eHOMA-IR was calculated using the homeostatic model assessment (HOMA) II calculator; insulin sensitivity and β-cell function were determined using an application designed by University of Oxford [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e].\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eInsert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003c/h2\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003eStrength performance\u003c/h2\u003e \u003cp\u003eTotal VL in all strength exercise sessions (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) was greater in the gliclazide group when compared to the placebo group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;0.88). We found similar results for both upper limb (bench press, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;0.81) and lower limb exercises (free squats, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;0.76).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eInsert Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e describes differences in performance by session and set. Overall, the gliclazide group showed better performance than the placebo group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The mean difference in total VL between the gliclazide and placebo groups was 23.3% (Gliclazide: 2383.9\u0026thinsp;\u0026plusmn;\u0026thinsp;643.3 kg; Placebo: 1721.0\u0026thinsp;\u0026plusmn;\u0026thinsp;410.9 kg) for bench press and 23.2% for squat exercises (Gliclazide: 2470.8\u0026thinsp;\u0026plusmn;\u0026thinsp;641.2 kg; Placebo: 1705.0\u0026thinsp;\u0026plusmn;\u0026thinsp;428.5 kg).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Comparison of strength exercise performance (volume-load) by type, session and set\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eBench press\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c11\" namest=\"c7\"\u003e \u003cp\u003eFree squats\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePlacebo (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGliclazide (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003ePlacebo (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eGliclazide (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1st set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e805.6\u0026thinsp;\u0026plusmn;\u0026thinsp;180.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e800.1\u0026thinsp;\u0026plusmn;\u0026thinsp;182.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e807.4\u0026thinsp;\u0026plusmn;\u0026thinsp;199.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e812.4\u0026thinsp;\u0026plusmn;\u0026thinsp;184.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2nd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e600.8\u0026thinsp;\u0026plusmn;\u0026thinsp;143.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e672.0\u0026thinsp;\u0026plusmn;\u0026thinsp;165.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e666.9\u0026thinsp;\u0026plusmn;\u0026thinsp;166.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e675.0\u0026thinsp;\u0026plusmn;\u0026thinsp;160.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.204\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3rd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e447.3\u0026thinsp;\u0026plusmn;\u0026thinsp;109.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e550.3\u0026thinsp;\u0026plusmn;\u0026thinsp;155.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e522.3\u0026thinsp;\u0026plusmn;\u0026thinsp;137.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e535.1\u0026thinsp;\u0026plusmn;\u0026thinsp;136.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4th set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e343.1\u0026thinsp;\u0026plusmn;\u0026thinsp;94.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e400.5\u0026thinsp;\u0026plusmn;\u0026thinsp;119.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e384.6\u0026thinsp;\u0026plusmn;\u0026thinsp;120.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e398.6\u0026thinsp;\u0026plusmn;\u0026thinsp;107.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2196.8\u0026thinsp;\u0026plusmn;\u0026thinsp;504.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2422.9\u0026thinsp;\u0026plusmn;\u0026thinsp;609.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2381.2\u0026thinsp;\u0026plusmn;\u0026thinsp;600.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2421.1\u0026thinsp;\u0026plusmn;\u0026thinsp;571.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1st set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e744.7\u0026thinsp;\u0026plusmn;\u0026thinsp;151.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e778.8\u0026thinsp;\u0026plusmn;\u0026thinsp;188.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e684.1\u0026thinsp;\u0026plusmn;\u0026thinsp;143.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e826.8\u0026thinsp;\u0026plusmn;\u0026thinsp;177.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2nd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e507.1\u0026thinsp;\u0026plusmn;\u0026thinsp;123.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e642.9\u0026thinsp;\u0026plusmn;\u0026thinsp;168.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e566.7\u0026thinsp;\u0026plusmn;\u0026thinsp;138.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e662.5\u0026thinsp;\u0026plusmn;\u0026thinsp;162.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3rd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e386.3\u0026thinsp;\u0026plusmn;\u0026thinsp;100.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e510.1\u0026thinsp;\u0026plusmn;\u0026thinsp;139.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e409.0\u0026thinsp;\u0026plusmn;\u0026thinsp;111.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e534.6\u0026thinsp;\u0026plusmn;\u0026thinsp;130.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4th set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e277.7\u0026thinsp;\u0026plusmn;\u0026thinsp;85.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e390.3\u0026thinsp;\u0026plusmn;\u0026thinsp;116.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e297.0\u0026thinsp;\u0026plusmn;\u0026thinsp;100.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e420.0\u0026thinsp;\u0026plusmn;\u0026thinsp;108.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1915.8\u0026thinsp;\u0026plusmn;\u0026thinsp;436.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2322.0\u0026thinsp;\u0026plusmn;\u0026thinsp;598.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1956.9\u0026thinsp;\u0026plusmn;\u0026thinsp;477.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2443.8\u0026thinsp;\u0026plusmn;\u0026thinsp;561.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e# reps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eLoad (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1st set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e689.1\u0026thinsp;\u0026plusmn;\u0026thinsp;153.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e769.7\u0026thinsp;\u0026plusmn;\u0026thinsp;202.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e592.7\u0026thinsp;\u0026plusmn;\u0026thinsp;140.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e779.8\u0026thinsp;\u0026plusmn;\u0026thinsp;214.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2nd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e439.1\u0026thinsp;\u0026plusmn;\u0026thinsp;113.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e658.7\u0026thinsp;\u0026plusmn;\u0026thinsp;183.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e482.5\u0026thinsp;\u0026plusmn;\u0026thinsp;113.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e638.1\u0026thinsp;\u0026plusmn;\u0026thinsp;179.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3rd set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e340.5\u0026thinsp;\u0026plusmn;\u0026thinsp;90.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e534.1\u0026thinsp;\u0026plusmn;\u0026thinsp;145.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e362.2\u0026thinsp;\u0026plusmn;\u0026thinsp;98.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e566.3\u0026thinsp;\u0026plusmn;\u0026thinsp;149.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4th set\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e252.3\u0026thinsp;\u0026plusmn;\u0026thinsp;78.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e421.4\u0026thinsp;\u0026plusmn;\u0026thinsp;128.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e267.6\u0026thinsp;\u0026plusmn;\u0026thinsp;91.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e486.7\u0026thinsp;\u0026plusmn;\u0026thinsp;119.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1721.0\u0026thinsp;\u0026plusmn;\u0026thinsp;410.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2383.9\u0026thinsp;\u0026plusmn;\u0026thinsp;643.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1705.0\u0026thinsp;\u0026plusmn;\u0026thinsp;428.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e27.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2470.8\u0026thinsp;\u0026plusmn;\u0026thinsp;641.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eThe values indicate total volume-load (VL) calculated by multiplying VL in kg (80% 1-RM) x number of repetitions per set. 1-RM: one-repetition maximum. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Differences were tested using Student\u0026rsquo;s t-test for paired samples for each exercise type (bench press and free squat) and considered significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eInsert Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/h2\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eMuscle strength recovery\u003c/h2\u003e \u003cp\u003e1-RM measures were lower 24 hours and 48 hours after exercise during recovery compared to baseline (pre-intervention). However, recovery was more accelerated in the gliclazide group in all comparisons (exercise x time) for bench press (24h: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.26; 48h: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.28) and free squats (24h: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.30; 48h: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.41). These data show that gliclazide improved recovery of muscle strength (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eInsert Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eSimilar to 1-RM results, shoulder and knee ROM measures were lower 24 hours and 48 hours of recovery when compared to baseline (pre-intervention) \u0026ndash; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. However, the gliclazide group showed faster recovery compared to placebo 24 hours (knee ROM p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.22; shoulder ROM p\u0026thinsp;=\u0026thinsp;0.004, d\u0026thinsp;=\u0026thinsp;0.13) and 48 hours after the last exercise session (knee ROM p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.20, shoulder ROM p\u0026thinsp;=\u0026thinsp;0.048, d\u0026thinsp;=\u0026thinsp;0.09) \u0026ndash; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eInsert Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eThe activity of CK-MM increased immediately post-exercise session in response to strength exercise in both the gliclazide and placebo groups in within-group comparisons (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all comparisons) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Starting from session 2, and considering the cumulative effect of strength exercise (pre- and post-session assessments), CK-MM was consistently lower in the gliclazide group compared to placebo. The same pattern of response was seen 24 and 48 hours of recovery with CK-MM being lower in the gliclazide group. Interestingly, LDH levels were also consistently lower in the gliclazide group (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB). As expected, our results point to intentional muscle damage in response to the exercise protocol and show that the use of gliclazide MR appears to be associated with enhanced muscle recovery despite the cumulative effect of exercise sessions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eInsert Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eInflammatory markers were measured before exercise sessions and 24 and 48 hours of recovery (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). IL-6 levels increased successively over exercise sessions as well as 24 and 48 hours of recovery (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all comparisons) when compared to baseline. In addition, we found no differences between the groups, except 48 hours after exercise where IL-6 levels were lower in the gliclazide group compared to placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, d\u0026thinsp;=\u0026thinsp;0.31). In turn, TNF-α levels increased continuously from baseline in both groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all comparisons) \u0026ndash; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB. However, TNF-α levels were lower in the gliclazide group compared to placebo in all times evaluated as follows: session 1 (baseline), p\u0026thinsp;=\u0026thinsp;0.669; session 2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and d\u0026thinsp;=\u0026thinsp;1.37; session 3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and d\u0026thinsp;=\u0026thinsp;1.33; 24 hours of recovery, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and d\u0026thinsp;=\u0026thinsp;1.70; and 48 hours of recovery, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and d\u0026thinsp;=\u0026thinsp;1.70 \u0026ndash; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePain intensity scores increased progressively with exercise in both the gliclazide and placebo groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, from session 2, mean pain ratings were lower in the gliclazide group than placebo (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, supplementary material). Overall, during the recovery period (24 hours and 48 hours post-exercise), pain ratings decreased by 38% in both groups though they were lower in the gliclazide group compared to placebo (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, supplementary material). Finally, compared to placebo, the gliclazide group showed higher scores of perceived recovery pre-exercise in all sessions and during recovery (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, supplementary material).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eInsulin and glucose levels and adverse events\u003c/h2\u003e \u003cp\u003eAs expected, plasma insulin levels were higher with the administration of gliclazide (pre-session and during recovery), which indicates that at this dose gliclazide exerts an insulinotropic effect (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We found an acute reduction in blood glucose levels in all exercise sessions in both groups. However, the magnitude of reduction was greater in the gliclazide group: in session 1, blood glucose reduced by 23.1% in the gliclazide group compared to 9.3% with placebo (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;1.32), in session 2, it reduced by 23.5% vs. 11.8% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;1.09), and in session 3, 24.8% vs. 9.2% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; d\u0026thinsp;=\u0026thinsp;1.21).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026ndash; Comparison of plasma glucose and insulin levels before and after the exercise sessions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003ePlacebo (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eGliclazide (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.001 (p-interaction)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e∆\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePre-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePost-exercise\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e∆\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep-value (post-hoc)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e113.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e86.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115.2\u0026thinsp;\u0026plusmn;\u0026thinsp;17.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e114.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117.1\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e116.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInsulin (\u0026micro;m.ml\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026minus;\u0026thinsp;1\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.005 (p-interaction)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePre-exercise\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ePost-exercise\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e∆\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003ePre-exercise\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003ePost-exercise\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e∆\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003ep-value (post-hoc)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSession 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-24h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-48h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003ePost-24h, 24 hours of recovery; post-48h, 48 hours of recovery. Pre-exercise, immediately before exercise session; post-exercise, immediately after the exercise session. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Differences were tested using two-way ANOVA with Bonferroni post-hoc test and considered significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThree participants in the gliclazide group (7%) experienced adverse hypoglycemic events post-exercise (blood glucose levels of 46, 49 and 51 mg/dL) as dizziness, pale skin and sweating were common signs. This effect was reversed immediately with the consumption of 30g of quickly absorbed carbohydrate\u0026mdash;maltodextrin (Integralmedica\u0026reg;) containing\u0026thinsp;~\u0026thinsp;27g carbohydrates.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eInsert Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eHemodynamic measures (HR, BP and double product) did not change significantly before, during or after strength exercise sessions (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e, supplementary material).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this is the first study that primarily aimed to examine whether the use of gliclazide MR 90 mg enhances performance and/or muscle recovery in strength-trained healthy volunteers following three strength exercise sessions. Based on our main findings, we accept the hypothesis that gliclazide MR 90 mg enhances strength performance (assessed by VL) and muscle recovery (assessed by CK-MM, LDH, TNF-α and IL-6 levels and 1-RM and ROM recovery) and improves perceived pain and recovery. However, the use of gliclazide MR at a dose of 90 mg can cause adverse effects, especially associated with reduced blood glucose levels leading to hypoglycemic events.\u003c/p\u003e \u003cp\u003eThe rationale for the use of gliclazide in amateur and professional athletes is that it stimulates endogenous insulin secretion [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and optimizes nutrient uptake (mostly glucose and amino acids) in skeletal muscle [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] during and after exercise, thus possibly enhancing performance and muscle recovery. In fact, oral administration of gliclazide MR 90 mg in a single daily dose increased insulin levels across all exercise sessions and during recovery (24 hours and 48 hours post-exercise) compared to placebo in our study, which demonstrates that our intervention protocol was effective.\u003c/p\u003e \u003cp\u003eChange in exercise capacity has been used as a parameter of strength performance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. We tested a high-intensity exercise protocol (80% of 1-RM), which is characterized by predominantly lactic anaerobic activity [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. There is a consensus in the literature that moderate-high intensity exercise performance is dependent on greater availability of nutrients especially carbohydrate in the form of glucose/glycogen stores [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. During exercise, the secretion of endogenous insulin is reduced. Insulin-independent mechanisms promote glucose uptake by muscle cells in response to muscle contraction which is possibly a compensatory effect to reduced insulin levels during exercise [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The insulinotropic action of gliclazide is not a response to exercise. So, there is \u0026ldquo;twice the effect\u0026rdquo; on glucose uptake in muscle cells during exercise: through insulin-independent mechanisms triggered by muscle contraction and increased circulating levels of insulin due to pharmacological stimulation. This could explain enhanced performance seen as early as the first exercise session of our study. In contrast, we reported previously that a single-dose administration of gliclazide MR 60 mg did not improve performance in a single session of strength exercise at 65% of 1-RM (unpublished data). The ergogenic effect of this drug may be dose-dependent, requiring a higher dose and may involve exercise at greater intensity to elicit a metabolic response.\u003c/p\u003e \u003cp\u003eThe assumption of increased glucose uptake during strength exercise is further supported by the fact that three participants in the gliclazide group experienced hypoglycemic events during exercise. In addition, the participants in the placebo group probably experienced residual fatigue as a result of consecutive exercise sessions as their performance dropped by 8% from session 1 to session 2 and by 11.5% from session 2 to session 3. This decline in performance was not seen in the gliclazide group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). It could be that more rapid muscle glycogen restoration occurred between sessions in the gliclazide group, though we did not measure glycogen in the present study.\u003c/p\u003e \u003cp\u003eWe evaluated 1-RM and ROM as functional parameters of muscle recovery. Exercise-induced muscle damage has been associated with the ability to generate maximum dynamic strength following an exercise session [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In our study, maximum [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]assessed by 1-RM decreased by 9.8% (bench press) and 13.3% (squats) in the gliclazide group and by 16.6% (bench press) and 18.6% (squats) in the placebo group 24 hours post-exercise. Then the participants recovered 96.1% (bench press) and 95.6% (squats) of their strength in the gliclazide group and 92.1% (bench press) and 90.3% (squats) in the placebo group 48 hours post-exercise. Though these values are small, they may indicate potential ergogenic effects of gliclazide on recovery of muscle strength. Similar effects have been shown for other interventions, such as nutritional supplements ingestion such as creatine, carbohydrates and proteins [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. We did not find in the literature data of these effects with the use of gliclazide.\u003c/p\u003e \u003cp\u003eROM for shoulder horizontal abduction and knee extension is another parameter of muscle recovery [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] assessed in this study. Our findings were similar to those for 1-RM. Reduced ROM seen in the placebo group during recovery (24 and 48 hours post-exercise) is consistent with that reported for control groups in other studies testing nutritional interventions [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Mean ROM reduction was 9% with nearly 95% recovery 48 hours after exercise. It suggests that our sample was comparable to those used in other studies, which further supports our findings of the effects of gliclazide MR on muscle recovery.\u003c/p\u003e \u003cp\u003eIndirect markers of exercise-induced muscle damage, mainly CK-MM and LDH, are widely used to quantitatively assess the effects of exercise on muscle recovery [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The activities of CK-MM and LDH showed the same pattern in our study, which is consistent with that reported by Bernat-Adell et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In this study, the exercise protocol produced an acute increase in the levels of both markers\u0026mdash;CK-MM and LDH\u0026mdash;across all sessions. From session 2, CK-MM and LDH levels pre-exercise were lower in the gliclazide group compared to placebo, which suggests improved muscle damage recovery from previous sessions. Peak levels of CK-MM and LDH occurred 24 hours after the last exercise session. This finding corroborates that reported in other studies [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] although they occurred at later times after exercise session [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Our research group, while examining the effect of gliclazide 60 mg in a single dose on the levels of CK-MM and LDH in response to a strength exercise session, reported similar changes, but they were lower in the gliclazide group compared to placebo.\u003c/p\u003e \u003cp\u003eSome studies [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] have shown a moderate positive correlation (r\u0026thinsp;=\u0026thinsp;0.44) between CK-MM levels and VL. Nosaka and Clarkson [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] measured muscle volume involved in (unilateral or bilateral) strength exercise with the same VL and found similar increase in CK levels. We would expect that exercise requiring larger muscle groups would also result in greater muscle damage and thus higher CK levels, but this was not seen. Probably, several factors may be involved and will determine the extent of muscle damage. Indirect blood markers of damage should be evaluated together with other measures.\u003c/p\u003e \u003cp\u003eChanges in IL-6 and TNF-α concentration levels are often used as markers of the inflammatory response [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The mechanical overload of concentric and eccentric contractions during strength exercises primarily induces functional adaptations in skeletal muscles due to transient desired structural changes in sarcomeres. During recovery, exercise-induced damage results in muscle inflammation and, consequently, sarcomere repair [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Here, the protocol of strength exercises caused a continuous increase in IL-6 levels across all sessions, as well as during recovery 24 hours after exercise. These findings corroborate that reported in other studies [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] suggesting that IL-6 levels increase in response to metabolic and mechanical stress that occur with exercise. Bartolomei study [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] showed that, after a single session of strength exercise at high intensity or with high VL, IL-6 concentration returned to pre-exercise levels 24 hours and 48 hours of recovery. Interestingly, muscle damage markers (CK-MM and LDH) showed similar response in our study. IL-6 levels were increased in the placebo group and reduced in the gliclazide group 48 hours of recovery. This finding suggests that gliclazide has an ergogenic effect, accelerating muscle recovery and reducing inflammation. We also evaluated plasma TNF-α concentration, which clearly increased across the three exercise sessions of the study and then it remained high over a 24-hour period. Concentration levels were then reduced twice 48 hours of recovery in both the gliclazide and placebo groups. Yet, this increase was of small magnitude in the gliclazide group at all times. Considering that TNF-α is essentially a pro-inflammatory cytokine, this finding reinforces its action to reduce exercise-induced inflammation.\u003c/p\u003e \u003cp\u003eCollectively, markers of muscle damage and post-exercise recovery\u0026mdash;CK-MM, LDH, IL-6 and TNF-α\u0026mdash;were lower in the gliclazide group than placebo. Perceived pain and recovery scores were also lower in the gliclazide group, which further supports that gliclazide enhances recovery after strength exercise.\u003c/p\u003e \u003cp\u003eOur study has some limitations. The main limitation lies in the unfeasibility to evaluate the effects of gliclazide for longer periods of time, which is related to ethical aspects. A second limitation is that only plasma glucose levels, but not insulin, were measured at different times. Concurrent plasma glucose and insulin measurements would have allowed a more in-depth discussion of their association with exercise. Another important point is that we did not examine counter-regulatory effects of anti-inflammatory cytokines on IL-6 and TNF-α. Still, we believe that these limitations do not weaken our results.\u003c/p\u003e \u003cp\u003eIn conclusion, this randomized, placebo-controlled, double-blind crossover randomized clinical trial showed that gliclazide MR 90 mg at single daily dose taken 8 hours before strength exercise sessions had an ergogenic effect, enhancing strength performance and accelerating muscle recovery. However, these beneficial effects were counterbalanced by blood glucose reductions during and/or immediately after exercise, including three episodes of symptomatic hypoglycemia, which is a cause for concern.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe also thank Mara Lane Zardin at the biochemistry laboratory of Grupo Hospitalar Concei\u0026ccedil;\u0026atilde;o (GHC) and Ricardo Benitez at the laboratory of clinical analysis for their assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.B.M. and A.M.L. designed the study. J.B.M. collected and analyzed the data. J.B.M., T.D., B.D.S. and A.M.L. carried out the interpretation of data. J.B.M. drafted the manuscript. T.D., B.D.S and A.M.L. helped prepare the manuscript and revised it critically. All authors contributed to manuscript preparation, reviewed and approved its final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailability of data and material: The dataset supporting the conclusions of this article is included within the article and its additional file.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interests.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eManu, P., Rogozea, L.M. \u0026amp; Cernea, S. Pharmacological Management of Diabetes Mellitus: A Century of Expert Opinions in Cecil Textbook of Medicine. \u003cem\u003eAm J Ther\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, e397-e410 (2021).\u003c/li\u003e\n\u003cli\u003eKeitel, S. 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Use and abuse of HOMA modeling. \u003cem\u003eDiabetes Care\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 1487-1495 (2004).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"muscle strength, doping in sports, muscle recovery, insulin, glucose","lastPublishedDoi":"10.21203/rs.3.rs-4450743/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4450743/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo examine the acute effect of gliclazide on exercise performance and recovery of muscle strength in healthy participants. We conducted a randomized, double-blind, placebo-controlled crossover clinical trial in 44 strength-trained men. They were allocated to gliclazide modified release (MR) (90mg, 8h before exercise sessions) or placebo, undergo three consecutive sessions of strength exercise (four sets, 80% of one-repetition maximum [1-RM] of bench press and free squat exercise). We evaluated total volume-load (VL) (#repetitions x 80%1-RM), range of motion (ROM), insulin and glucose levels, creatine kinase MM (CK-MM), lactate dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), hemodynamic parameters, perceived pain and recovery scores. Gliclazide enhanced strength exercise performance with improvements in total VL (bench press 23.3%, p \u0026lt; 0.001; squats 23.2%, p \u0026lt; 0.001), and improved muscle recovery 24-48h post-exercise: ROM (shoulder 1.1%, p \u0026lt; 0.001; knee 1.6%, p = 0.004), CK-MM (–13.2%, p \u0026lt; 0.001), LDH (–12.8%, p \u0026lt; 0.001), TNF-α (–17.4%, p \u0026lt; 0.001), IL-6 (–5.3%, p \u0026lt; 0.001), pain (–17.7%, p \u0026lt; 0.001) and recovery scores (32.5%, p = 0.001). However, hypoglycemia events were observed in 3 participants in the gliclazide group. In conclusion, Gliclazide MR 90mg, 8h before strength exercise, produced ergogenic effects (exercise performance and muscle recovery), although hypoglycemia was observed in 7% of subjects. Registration: “www.clinicaltrials.gov”, “NCT04443777” (Primary Completion: 01/08/2020; Study Completion: 31/10/2023).\u003c/p\u003e","manuscriptTitle":"Gliclazide enhances exercise performance and recovery of muscle strength in healthy trained individuals: a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 18:47:03","doi":"10.21203/rs.3.rs-4450743/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1eaf7540-1bda-4583-a777-180e16bb0960","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-08T06:48:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-13 18:47:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4450743","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4450743","identity":"rs-4450743","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}