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Combined aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment. Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings.
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Aerobic and Resistance Training Effects Compared to Aerobic Training Alone in Obese Type 2 Diabetic Patients on Diet Treatment
Combined aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment. Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings.
Combined aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment. Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings.
Aerobic and resistance training effects compared to aerobic
training alone in obese type 2 diabetic patients on diet
treatment Pietro Lucotti a , Lucilla D. Monti b , Emanuela Setola a , Elena Galluccio b , Roberto Gatti c,d , Emanuele Bosi a,b,d , PierMarco Piatti a,b,d, * a San Raffaele Scientic Institute, Cardio-Metabolic and Clinical Trials Unit, Internal Medicine Department, and Metabolic and Cardiovascular Science Division, Milan 20132, Italy b San Raffaele Scientic Institute, Cardio-Diabetes and Core-Lab, Metabolic and Cardiovascular Science Division, Milan 20132, Italy c San Raffaele Scientic Institute, Laboratory of Movement Analysis, School of Physiotherapy, Milan 20132, Italy d San Raffaele Scientic Institute, Vita-Salute San Raffaele University, Milan 20132, Italy d i a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 a r t i c l e i n f o Article history: Received 9 June 2011 Received in revised form 20 July 2011 Accepted 1 August 2011 Published on line 3 September 2011 Keywords: Insulin resistance Endothelium Inammation Adipokine Glucose metabolism a b s t r a c t Aims: The study was designed to compare a combined aerobic and resistance training (ART) with an aerobic training (AT) over hemodynamic, glucose metabolism and endothelial factors, adipokines and pro-inammatory marker release in a population of obese type 2 diabetic patients. Methods: Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings, on the top of a diet regime. Anthropometric, metabolic, hormonal and inammatory variables were measured at hospitalization and discharge. Results: Both exercise programs equally improved body weight and fructosamine levels however ART only partially decreased HOMA index compared with AT (ART: 25% vs AT: 54%, p < 0.01). Mean blood pressure (AT: 3.6 mmHg vs ART: +0.6 mmHg, p < 0.05) and endothelin-1 (ET-1) incremental areas during walking test (AT: 11% vs ART: +30%, p < 0.001) decreased after AT while increased after ART. Adiponectin levels increased by 54%after AT while decreased by 13%after ART ( p < 0.0001) and matrix metalloproteinase-2 (MMP-2), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractan protein-1 (MCP-1) levels signicantly decreased in AT while increased in ART group. Conclusions: Compared with AT, ART similarly enhanced body weight loss but exerted less positive effects on insulin sensitivity and endothelial factors, adipokines and pro-inam- matory marker release. # 2011 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: Cardio-Diabetes and Clinical Trials Unit, Internal Medicine Department and Metabolic and Cardiovascular Science Division, Vita-Salute San Raffaele University, Scientic Institute San Raffaele, Via Olgettina 60, Milan 20132, Italy. Tel.: +39 02 2643 2819; fax: +39 02 2643 3839. E-mail address: piermarco.piatti@hsr.it (P. Piatti). Abbreviations: AT, aerobic training; ART, aerobic and resistance training; RT, resistance training; HOMA, homeostasis model assess- ment; MMP-2, matrix metalloproteinase-2; TNF-alpha, tumor necrosis factor-alpha; MCP-1, monocyte chemoattractan protein-1; FM, fat mass; FFM, fat free mass; NO, nitric oxide; FFA, free fatty acids; ET-1, endothelin-1. Cont ent s l i st s avai l abl e at Sci enceDi r ect Diabetes Research and Clinical Practice j ournal homepage: www. el sevi er. com/ l ocate/ di abres 0168-8227/$ see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.08.002 1. Introduction Aerobic exercise has shown many positive effects on insulin sensitivity and glucose homeostasis [1]. A chronic aerobic training (AT), even without changes in body composition, improves insulin sensitivity up to 30% both in impaired glucose tolerant (IGT) and type 2 diabetic patients [1]. Exercise intervention in adults with type 2 diabetes induces a mean fall in HbA1c percentage of 0.74 compared with control group, independently to body weight change [2]. In addition it promotes mobilization of visceral adipose tissue so reducing insulin resistance [3]. AT improves as well some cardiovascu- lar risk factors such as hypertension, dyslipidemia and brinolytic activity [4]. According to these benets daily AT was listed in guidelines for exercise in type 2 diabetes [5]. Resistance training (RT) shows potential benets in rehabilitation, thanks to its ability in avoiding disease-related muscle wasting. Further, muscle contraction increases glu- cose uptake and improves insulin sensitivity in skeletal muscle thereby providing a rationale for its use in disease like type 2 diabetes [6,7]. RT enhances muscular strength and changes in body composition by increasing lean body mass and decreasing visceral and total body fat [8]. In particular, light to moderate loads (4060% of 1 RM) are recommended for local muscular endurance training performed at high repeti- tion using short resting period (<90 s) [9]. In addition, 3 days per week (3 d w 1 ) training frequency has been recently shown to be superior to 12 days per week for improving muscular endurance, coordination, balance and cardiorespiratory t- ness in older women [10], conrming meta-analytical data showing that strength gains in untrained individuals were highest with a frequency of 3 d w 1 [11]. In this light, recently published studies investigating the effect of aerobic and resistance training in patients with cardiovascular disease like chronic heart failure and stroke, adopted a 5 d w 1 training frequency in order to provide further evidence for the use of exercise as a clinical therapy in these patients [12,13]. Actually, few studies investigated the effect of a short program (about 3 weeks) of combined high frequency AT plus RT on glucose homeostasis and insulin sensitivity. In particular, there is small evidence of additional benet from combining RT and AT on some related risk factors for diabetes complications (endothelial function and sub-clinical inam- mation) in obese type 2 diabetic patients [14]. Therefore, the present study was designed to evaluate the effects of a short high frequency (5 d w 1 ) RT and AT added to a program of hypocaloric diet compared with a high frequency AT with a similar program of hypocaloric diet, on fat and lean body mass distribution, glucose levels, insulin levels and sensitivity, endothelial factors, adipokines and pro-inam- matory markers releases in obese type 2 diabetic patients. 2. Subjects 2.1. Informed consent Fifty middle-aged patients (30 males, 20 females) were included in the experimental protocol. All patients gave informed consent to participate into the study that was approved by the local Ethics Committee. 2.2. Study population Patients were severely obese (body mass index, 38.6 5.6; waist circumference, 113.1 12.7 cm), with type 2 diabetes mellitus and metabolic syndrome according to ATPIII [15]. Before hospitalization, all were treated by diet alone for type 2 diabetes and the 2 study groups had comparable treatments for hypertension and dyslipidemia and no changes were made during the study period. 3. Materials and methods 3.1. Diet program Patients were hospitalized for 21 days and submitted to a hypocaloric diet regime that consisted of 1000 kcal/day with 55% carbohydrate, 2530% fat (saturated fat 7%) and 1520% protein (animal protein 54 g) subdivided as follows: 15% for breakfast, 50% for lunch and 35% for dinner, administered under a daily supervision of a dietician. Diet was controlled not only for carbohydrate but also for cholesterol and natural ber content (176 mg and 25 mg, respectively). The diet provided about 50% of their estimated daily caloric needs, according with [16]. It was previously seen that obese patients who receive 3370% of their estimated caloric needs during critical illness have better clinical outcomes [17]. The nal goal was to induce a superimposable loss in FM and FFM and a minor decrease in insulin resistance as previously demonstrated by our group [18]. All in all, a moderate weight loss (5%) was achieved in our patients in the attempt not to overshadow the results obtained through different exercise programs on insulin resistance and inammation. In fact, recent data suggest that there may be a doseresponse effect between the degree of weight loss and its capacity to attenuate chronic inammation. In particular, it was found that at least 10% weight reduction is needed to achieve a signicant reduction in C-reactive protein levels [19]. 3.2. Exercise training program Patients were randomly assigned to AT or ART group with a 3:2 ratio in order to generate additional metabolic, inammatory and ET-1 data for AT group. This was done since we considered the possibility to have higher drop-out number in the group submitted to AT treatment during hospitalization, a program usually done in a home setting. The tests consisted in two different 3-weeks exercise program: AT alone (30 patients) and aerobic plus resistance exercise training (ART, 20 patients). AT program consisted of 30 min bid session of whole body exercise for 5 days a week. Each training session consisted in 30 min of aerobic exercise divided into row ergometer (15 min) and bicycle ergometer (15 min). The training program was performed at 70% of the individual age-predicted HR max according to Tanaka et al. [20]. Patients exercised under the supervision of a physician. ART program consisted in 45 min bid session composed by an aerobic session comparable to di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 396 that performed by aerobic training group followed by a resistance training session consisting in 9 resistance exercise for 15 min: 5 exercises for the upper part of the body (arm curls, military press, push-ups, upright rowing, back exten- sion) and 4 exercises for the lower part of the body (squats, knee extensions, heel raises and bent knee sit-ups). Resistance loads were 4050% of one repetition maximum testing (1RM) performed at baseline and at the end of the study. The subjects performed 10 repetitions per set for all upper body exercises and 20 repetitions per set for lower body exercises. One set for each exercise was performed, at a moderate contraction velocity (2 s concentric, 2 s eccentric). The resting interval between sets was <1 min. Weights were adjusted throughout the training program as strength level increased. Both exercise trainings were associated with a similar hypocaloric diet (1000 kcal/die) to achieve a greater improve- ment in physical function, as recently demonstrated [21]. 3.3. Experimental protocol According to protocol design, patients were evaluated at baseline and after 21 days of hypocaloric diet and exercise training program. After an overnight fast, blood pressure, heart rate and anthropometric measurements were evaluated after at least 30 min of rest in the supine position by the same examiner including waist circumference. Then, FM and FFM percentage, total body water content and basal metabolism were measured by bio-impedance using TANITA body fat analyzer (model SC3315, TANITA Corporation, Tokyo, Japan), which applies the principle of bioelectrical impedance measurements of voltage drop from foot-to-foot when a small alternative current is applied through contact with two metal foot pads. Previous studies showed a high correlation between bio-impedance analysis and DEXA results [22]. After this period, a 20 gauge plastic cannula was inserted in an antecubital vein of the arm for blood sampling and an exercise test was started which consisted in 6 min walking test (6MWT) at 85% of age-predicted HR max [23] conducted accordingly to American Thoracic Statement Guidelines [24]. The test was performed 24 h after the last bout of ART or AT exercises trying to avoid the effects on plasma volume changes and on metabolism of the previous single exercise bout which could have modied the measured parameters. Systolic and diastol- ic blood pressure and heart rate were assessed immediately at the end of the test and after 5 min of rest. Basal samples for glucose, insulin, lipids, adipokines and pro-inammatory factors were withdrawn immediately before the exercise test while endothelin-1, nitrate/nitrite (NOx), c-GMP, FFA and TNF-a were measured during the ergometric walking test at time 0, 6 min (end of the exercise) and 11 min (recovery). Since 6 min walking test is a functional manner to evaluate the benecial effects of exercise trainings, the choice to measure insulin sensitivity, endothelial function and inammation before and during the test was, in our opinion, a way to strengthen possible differences on the effects of ART compared to AT. HOMA model has been used to yield an estimate of insulin resistance from fasting plasma insulin(FPI) and glucose concentration (FPG) and calculated as follows: HOMA-IR = (FPI mU/l FPG mmol/l)/22.5 [25]. At baseline 4050% of 1RM was determined before exercise program start by means of dynamometry. Maximum strength was determined by one repetition maximum (1RM) in kp through a maximum of three attempts, the best score counts were recorded. The representative exercises for the determina- tion of 1RM included knee extension and military press, performed in a seated position. 3.4. Analytical measurements Blood glucose, HDL cholesterol, total cholesterol and trigly- cerides were measured with spectrophotometric methods adapted to Cobas MIRA using commercial kits (ABX, Mon- tpellier, France). FFA levels were measured using automated enzymatic spectrophotometric techniques adapted to Cobas MIRA using commercial kits (NEFA C, Wako Chemicals GmbH, Neuss). Serum insulin levels were assayed with a microparti- cle enzyme immunoassay (IMX, Abbott Laboratories). NOx levels were evaluated through the measurement of metabolic end products, i.e., nitrite and nitrate, using enzymatic catalysis coupled with Griess reaction. ET-1 samples were extracted on SepPack C18 minicolumn (Amprep, Amersham International, Buckinghamshire, UK) and assayed by a RIA kit (NEN Life Science Products, Boston, USA). Human leptin and adiponectin levels were assayed with an ELISA kit and a RIA kit (LINCO Research, St. Charles, Missouri, USA), respectively. Resistin levels were assayed with an ELISA kit (Chemicon International, Demecula, Canada). Human TNF- alpha and MCP-1 levels were assayed with ELISA kits (Bender Med Systems GmbH, Vienna, Austria). 3.5. Statistical analysis All values are expressed as Mean SD at each time interval. Incremental areas of variables during ergometric walking test were calculated by the trapezoidal rule. All data were tested for normal distribution with the KolmogorovSmirnov test. Comparison between the two groups at baseline was performed by using the unpaired Students t-test. The treatment effects were determined by a repeated measured ANOVA. An adjusted p value of less than 0.05 was taken to indicate a signicant difference. Pearson correlations were conducted on change scores (differences between after minus basal levels). All analyses were performed using SPSS version 15.0 software (SPSS Inc., Chicago, IL). 4. Results Three patients of AT group withdrawn the study and all the results are related to 47 patients, i.e. 27 patients in AT group and 20 patients in ART group and in Table 1 are reported anthropometric parameters, systolic and diastolic blood pres- sure, lipids levels and glucose metabolism measurements for these patients. Before training period, no statistically signicant differences in anthropometric and metabolic variables were observed between the two groups as shown by Students t-test (Table 1). After 21 days of exercise training, a signicant decrement of body weight was achieved in both groups which consisted predominantly in FM loss since FFM was preserved in both groups, especially after ART training. Consistent with weight reduction, waist and hip circumferences comparably d i a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 397 decreased in both groups of treatment. Mean blood pressure showed a signicant reduction after AT training compared with ART ( p < 0.05). Although fructosamine, fasting blood glucose and insulin levels improved after both AT and ART, AT group showed a more signicant reduction in fasting blood glucose ( p < 0.03) and insulin levels ( p < 0.01, Fig. 1). Consequently, as compared with ART, AT induced a twofold decrement in HOMA-IR ( p < 0.01, Fig. 1). In addition, fasting FFA levels signicantly decreased in AT group while did not change after ART ( p < 0.05, Table 1). Finally, total cholesterol and triglycerides levels similarly decreased in both groups while HDL-choles- terol remained unchanged. In Table 1 and Fig. 2 are shown endothelial variables, adipokines and pro-inammatory markers before and after training programs. After 21 days of treatment, fasting ET-1 and NOx did not change signicantly in both groups. Interestingly, adiponectin levels signicantly increased by 54% after AT while decreased by 13% after ART; leptin levels signicantly decreased in AT group while remaining unchanged in ART. Consequently, leptin to adiponectin ratio, an index of atherosclerosis, signicantly decreased by 52% after AT but increased by 26% after ART ( p < 0.0003). Similarly, TNF-a, resistin, MMP-2 and MCP-1 levels showed a different behavior depending on type of training, being reduced after AT and increased after ART ( p < 0.009; p < 0.04; p < 0.0001; p < 0.003, respectively). After the period of diet and exercise training, the ergometric walking test demonstrated a signicant and similar increment in walked meters (AT: from 461.8 77.1 to 501.0 76.7 vs. ART: from 496.7 83.3 to 544.7 81.3, Table 1). Compared with baseline, mean blood pressure at the end of the 6 min walking test decreased in both groups, even if in AT there was a deeper decrement than in ART ( p < 0.01; Fig. 3) Interestingly, endothelin-1 incremental areas during ergo- metric walking test decreased by 11% after AT while increased by 30% after ART ( p < 0.01; Fig. 3). Conversely, NOx incremen- tal areas during ergometric test increased in AT while decreased in ART group ( p < 0.05, Fig. 3). 5. Discussion The present study investigates the effects of high frequency resistance exercise added to an aerobic exercise intervention carried on in controlled conditions as add-on to a strict diet regime administered under a daily supervision of a dietician in a population of obese type 2 diabetic patients; results observed after 3 weeks of therapy show at least three major aspects that need to be discussed: (1) a combination of aerobic and resistance high frequency exercise training improves overall glucose metabolism but partially blunt the benecial effects over glucose metabolism which is achieved by an aerobic high frequency exercise training; (2) the addition of resistance to aerobic high frequency exercise may have a deleterious effect over endothelial function and hemodynamic balance through a stimulation of endothelin-1 release and a concomitant increase in mean blood pressure levels; nally (3) aerobic and Table 1 Changes in anthropometric, metabolic, and hormonal variables before and after aerobic alone (AT) training or aerobic plus resistance (ART) training (Mean W SD). AT ART Students t-test Treatment effect Before After Before After Anthropometric and clinical variables Patients (F/M) 27 (17/10) 20 (13/7) Age (year) 58.1 9.9 61.5 11.5 p < 0.33 Body weight (kg) 103.9 17.7 100.5 16.4 b 106.6 20.8 103.2 20.3 b p < 0.34 p < 0.29 BMI (kg/m 2 ) 38.8 4.5 37.5 4.2 b 39.9 7.3 38.6 7.2 b p < 0.51 p < 0.58 Free fat mass (kg) 57.6 11.1 55.7 12.6 57.9 10.5 57.6 10.7 p < 0.92 p < 0.29 Fat mass (kg) 45.5 12.4 43.6 10.7 a 49.3 16.2 46.5 15.0 a p < 0.34 p < 0.29 Waist (cm) 114.3 10.4 106.3 14.9 b 118.6 11.6 112.6 11.9 b p < 0.30 p < 0.59 Hip (cm) 121.2 7.5 119.1 7.4 b 125.0 15.5 121.5 14.9 b p < 0.35 p < 0.09 Syst. BP (mmHg) 124.4 11.6 118.6 12.3 b 127.0 15.0 126.7 14.0 p < 0.51 p < 0.17 Diast. BP (mmHg) 78.0 6.4 75.2 6.5 78.5 8.7 79.5 8.8 p < 0.82 p < 0.17 Mean BP (mmHg) 93.5 7.0 89.7 7.7 b 94.7 9.1 95.3 9.2 p < 0.62 p < 0.05 Walk test distaice (m) 461.8 77.1 501.0 76.7 b 496.7 83.3 544.7 81.3 b p < 0.14 p < 0.56 Metabolic and hormonal variables Fructos. (mmol/1) 272.0 57.0 219.1 44.6 b 294.8 61.6 244.8 36.1 b p < 0.20 p < 0.46 HbAlc (%) 7.3 1.8 6.9 1.3 7.9 1.9 7.3 1.9 p < 0.28 p < 0.85 F. FFA (mmol/1) 0.81 0.20 0.65 0.20 a 0.80 0.19 0.79 0.24 p < 0.89 p < 0.05 AUC FFA (mmol/l*6 min) 8.53 1.9 7.16 1.9 a 7.77 1.7 7.98 1.9] p < 0.17 p < 0.03 F. Total chol. (mg/dl) 200.6 37.2 174.4 33.4 194.9 44.8 171.9 39.2 a p < 0.62 p < 0.99 F. HDL chol. (mg/dl) 38.5 8.5 39.5 10.2 41.3 15.8 40.1 8.4 p < 0.61 p < 0.61 F. Triglyc. (mg/dl) 187.1 63.2 126.4 44.5 172.8 62.0 125.4 32.1 b p < 0.36 p < 0.70 F. NOx (mmol/1) 15.3 5.9 13.4 4.8 16.3 7.0 17.7 8.4 p < 0.60 p < 0.13 F. ET-l (pg/ml) 10.0 2.8 10.2 5.3 9.85 5.6 11.7 5.1 p < 0.88 p < 0.42 BP, blood pressure; Fructos, fructosamine; F., fasting; FFA, free fatty acids; Chol, cholesterol; Triglyc., triglyceride; NOx, nitrite and nitrate; ET-1, endothelin-1. a p < 0.05 after vs before. b p < 0.01 after vs before. di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 398 resistance high frequency exercise training seems to have a pro-inammatory effect as suggested by an increment of their circulating markers. Interestingly all these results become evident even after a short, although intensive, training period in controlled conditions. The different impact observed over glucose metabolism and other metabolic parameters could not be ascribed entirely to weight loss as both AT and ART groups have the same weight loss (3 kg). The relative short duration of the study period could explain the blunted ART effect on fat free mass as compared with AT, as expected. A possible alternative explanation may come from the prevalence of contraction type, concentric vs. eccentric, followed in the resistance exercise protocol. It is known that an eccentric contraction compared with a concentric one induces a disproportionate increase in protein synthesis resulting in largest improvement in muscle size [26]. Resistance exercises were performed in order to equally distribute the concentric and eccentric exercise component, suggesting a rationale to explain the weak impact of combined exercise on free fat mass amount. Both training regimens showed similar improvement in overall glucose metabolism consisting in 20% reduction of fructosamine levels, on the contrary the two type of trainings showed a different impact over insulin resistance. In fact, fasting glucose and insulin levels reduction observed after AT was partially blunted after ART resulting in only a modest reduction in HOMA index as compared with AT group. In this light recent evidence support a role of resistance exercise in modulating muscle signaling pathways in fasting conditions through an inhibition of Akt/PKB pathway [27]. Akt/PKB signaling represents a primary molecular mechanism by which insulin regulates glucose transport in skeletal muscle. Therefore, it is possible that a reduction in Akt/PKB signaling in human skeletal muscle by resistance exercise may explain the only slight improvement in insulin sensitivity observed in ART group while with AT insulin sensitivity was greatly increased. In addition, acute resistance training has been shown to induce a rapid increase in FFA secondary to enhanced lipolysis [28], a well known cause of insulin resistance. Although improvement in cardio-respiratory t- ness appears to be linked with improvement in HbA1c in type 2 diabetes mellitus [29], recent data suggest that combined aerobic and resistance training do not provide additional benet compared with resistance training alone in physical tness evaluated by means of maximal treadmill exercise test. In addition results from the DARE trial show that the association between changes in strength (muscle cross- sectional area) and HbA1c was signicant only after resistance training, falling just near to statistical signicance with combined exercise suggesting that greater work volumes (i.e. up to three sessions per week of resistance exercise training) may be necessary for people with type 2 diabetes to achieve signicant improvements in HbA1c [30]. Accordingly, results from our study show no further gains in glucose metabolism indices (HbA1c and fructosamine) following combined exercise compared with aerobic exercise alone probably due to the lack in free fat mass gain. Further, recently it was demonstrated an improvement of HbA1c in type 2 diabetic patients when a combination of aerobic and resis- tance training was performed compared with the non- exercise control group in a study lasting 9 months [31,32]. Thus, it is possible that a longer period of study is needed to achieve favorable results after resistance training in our study groups but this was not possible in our study design since patients were hospitalized. Although resistance training alone is known to potentially increase arterial stiffness with a raise in blood pressure [33], few data are available concerning vascular function following a combination of resistance and aerobic exercise. In the present study a direct measurement of vascular function was not performed but samples for endothelial vasopeptides like ET-1 and end product of nitric oxide metabolism, i.e. nitrite and nitrate (NOx) were obtained both in resting condition and during ergometric walking test. ET-1 incremental areas increased while NOx incremental areas decreased during walking test in ART group. This nding is in agreement with recent studies investigating the relationship between plasma ET-1 concentrations and cardiovascular response during resistance exercise. In particular, it was demonstrated that resistance exercise, especially when consisting in concentric contractions, is associated with ET-1 production and with a greater increase in blood pressure levels [34]. Although patients of both groups signicantly improved their individual Fig. 1 Glucose (A), insulin (B) and HOMA-IR (C) before and after 21 days of AT (left) or ART (right) in obese type 2 diabetic patients. Data are presented as Mean W SD. *p < 0.03 for treatment effect; **p < 0.01 for treatment effect; (a) p < 0.05 after vs before. d i a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 399 performance in terms of meters walked at nal walking test, compared with AT, ART group showed a concomitant increase in mean basal blood pressure, known as the result of heart rate and peripheral resistance interaction. This nding is of particular interest in order to better investigate the hemody- namic effects that follow the association of resistance to aerobic exercise. In the present study leptin to adiponectin ratio, a novel pro- atherosclerotic index, was halved after 21 days of AT as a consequence of the marked increase in adiponectin levels while in ART group L/A ratio signicantly increased mainly since, in this group, adiponectin levels did not change. Accordingly, in a recent study, Fernandez-Real et al. did not found signicant changes in adiponectin levels in obese women after diet plus resistance training [35]. A possible explanation of the differences between AT and ART trainings on adiponectin levels could be related to the fact that TNF-a were higher in ART than in AT and it was demonstrated that TNF-a down-regulates adiponectin levels in vivo [36]. AT determined also a signicant improvement in pro- inammatory markers consisting in about 20% reduction in TNF-a, and MMP-2 and 10% reduction in MCP-1 levels in agreement with previous studies. In particular, recently Balducci et al. showed that an intensive physical intervention comprehensive of aerobic and resistance training was able to improve inammatory markers irrespective of weight loss in a population of type 2 diabetic patients with metabolic syndrome [37]. In line with our data, Reed et al. demonstrated Fig. 2 Leptin (A), adiponectin (B), resistin (C), TNF-a (D), MCP-1 (E) and MMP-2 (F) before and after 21 days of AT (left) or ART (right) in obese type 2 diabetic patients. Data are presented as Mean W SD. *p < 0.01 for treatment effect; **p < 0.0001 for treatment effect; (a) p < 0.05 after vs before; (b) p < 0.01 after vs before. di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 400 that weight loss after 4-month moderate to vigorous aerobic exercise training (4 times per week) and caloric restriction (20 35% of the estimated baseline energy needs) was effective in reducing inammatory markers [38]. Surprisingly, the addi- tion of resistance to aerobic exercise did not further improve inammation and on the contrary, induced a signicant increment in inammation. Contradictory results were found comparing resistance exercise and inammatory mediators. In fact, although previous studies, investigating of inamma- tory mediators changes after resistance exercise, found a slight increase in these indices [39], Kohut et al. showed that only cardiovascular but not exibility/strength exercise showed positive effects over serum IL-6, IL-18 and CRP levels [40]. In our study, several factors like exercise intensity, different duration of ART than AT time of exercise and frequency or adaptation to exercise may have inuenced the extent to which serum inammatory markers was altered in the two groups. In particular, short recovery periods between resistance exercises may impair specic anabolic processes for up to 48 h after exercise and generate an acute inamma- tory response [41]. A possible limitation of the present study is the short duration of treatment (3 weeks) since previous studies evaluating the effect of resistance training alone over metabolic parameters for longer period showed a positive effect in terms of glucose, insulin sensitivity, blood pressure control and free fat mass preservation in type 2 diabetic patients [42,43]. This might have inuenced the lack of additional benecial effects of ART than AT alone in our group of obese, type 2 diabetic patients. Further, training modality may have inuenced our results and more studies with longer follow-up are needed to better investigate clinical benets of training modalities (inclusive of frequency, dura- tion and volume) in the same class of patients [44]. Due to our short (3 weeks) study design in hospitalized patients, we are not able to rule out the specic contribution of diet alone on amelioration of insulin sensitivity and inammatory markers and the lack of a personalized dietary restriction might have inuenced the nal results, as negative energy balance could have been higher for certain patients with high BMI compared to others with lower BMI. However, it is known that hypocaloric diet alone resulted in specic reduction of inammatory markers and improvement in metabolic measurements [45]. In addition, recently it has been published data suggesting that caloric restriction can inuence protein metabolism and FFM maintenance irre- spective of obesity level [46]. Conversely, in our opinion, the strength of the present study was that all patients were hospitalized and study was conducted in highly controlled condition both for the diet treatment and for exercise training. In conclusion, 3 weeks of high frequency AT alone have benecial effects on insulin sensitivity, endothelial function, and adipokine release while 3 weeks of high frequency ART on Fig. 3 Mean blood pressure at the end of the walking test (A), ET-1 incremental area (B), TNF-alpha incremental area (C), NOx incremetal area (D), during walking test before and after 21 days of AT (left) or ART (right) in obese type 2 diabetic patients. Data are presented as Mean W SD. *p < 0.05 for treatment effect; **p < 0.01 for treatment effect; (a) p < 0.05 after vs before; (b) p < 0.01 after vs before. d i a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 9 4 ( 2 0 1 1 ) 3 9 5 4 0 3 401 sequential day, even if similarly improved body weight loss as high frequency AT alone, exerted less positive effects on insulin sensitivity, additionally having an adverse effect on endothelial function, hemodynamic balance with a greater pro-inammatory response in obese type 2 diabetic patients. In clinical perspective, even if ART remains an important tool in the therapy of obese type 2 diabetic patients, duration and mostly frequency of ART may adversely impact its benecial effects inducing a more pro-inammatory pathway, especially in a population of sedentary, severely obese, diabetic patient at the beginning of a physical activity program. The negative results of combined ART exercise on sequential days achieved in the present study strongly support ACSM/ADA Guidelines suggesting that such patients should exercise on alternate days. Acknowledgment The excellent technical support of Ms. Sabrina Costa and Barbara Fontana is gratefully acknowledged. Conict of interest There are no conicts of interest. r e f e r e n c e s [1] Trovati M, Carta Q, Cavalot F, Vitali S, Banaudi C, Lucchina PG, et al. Inuence of physical training on blood glucose control, glucose tolerance, insulin secretion, and insulin action in non-insulin-dependent diabetic patients. Diab Care 1984;7:41620. 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