Introduction
Type 2 diabetes (T2D) is a chronic disease characterized by excessive increases in blood glucose concentration, which causes hyperglycemia, especially in postprandial times (1,25 ). Postprandial hyperglycemia is a major prediction factor of microvascular and macrovascular chronic complications (6–8,25,40 ) and has been associated with endothelial dysfunction (7 ), arteriosclerosis (8 ), and cardiovascular diseases (CVDs), especially in women (3,6,20 ), who are affected mostly by hospitalizations and have a higher risk of mortality resulting from diabetes when compared with men (33 ). Furthermore, maintenance of chronic hyperglycemia can cause cellular apoptosis and lesions in organs and target tissues, such as kidneys, retinas, and the heart (13 ).
Attenuating postprandial hyperglycemia can be a good strategy to prevent CVDs, arteriosclerosis, and associated complications (8 ). Thus, it is important to highlight the importance of investigating the glycemic response of an individual with T2D, especially over a 24-hour period, which runs through the postprandial times. Such moments result in up to one-third of the day spent in a hyperglycemic state during control conditions without exercise performance for the individual with T2D. This exposure could decrease significantly up to 24 hours during the day with low-intensity aerobic exercise (AE) performance (25 ).
Physical exercise has been defined as an efficient strategy for blood glucose control in patients with T2D (10,23,37 ). This strategy reduces blood glucose concentration and decreases time spent in a hyperglycemic state (25,30,36,37 ). Although the scientific community has shown that AE is an important strategy in acute glycemic control (10,38 ), other authors such as Church et al. (9 ) investigated the effects of chronic AE and resistance exercise (RE) performed both alone and in combination, which resulted in better blood hemoglobin–glycated levels. Evidence regarding acute (14,16,28 ) and chronic (11,12,17 ) REs has been demonstrated in patients with T2D.
Little is known about the comparison among different domains of intensities (low vs. high) in different days with continuous blood glucose measurements over a period of 24 hours. An investigation of these characteristics was reported with AE intervention where the authors found that unlike a control session without exercise or with high-intensity AE performance, a low-intensity session resulted in significant glycemic control and also reduced the prevalence of hyperglycemia in a subsequent 24-hour period (25 ). However, evidence of the effects of different RE intensity performance could provide better support for exercise recommendations regarding the optimal prescription for patients with T2D. It is well known that low-intensity RE was effective in acute glycemic control (28 ). Analysis was performed over a short time period (2 hours) and within a laboratory environment without information of glycemic response during lunch and dinner postprandial moments and the sleeping period. Some studies have shown that high-intensity RE can improve insulin sensitivity (17,22 ) and increase muscle GLUT4 expression (17 ), which enhances the importance of investigating acute glycemic responses during a period of 24 hours after RE sessions at different intensities in patients with T2D.
Thus, the aim of this study was to compare blood glucose responses and prevalence of hyperglycemia within 24 hours after an RE session performed at low and high intensities in women with T2D. Based on these theoretical assumptions, low-intensity exercise results in better glycemic control (25,28 ), and considering the possible increases in sympathetic nervous activation and higher adrenergic release during high intensity (5 ), the hypothesis of this study was that daily glycemic control can be modulated in a late acute period after low RE performance in women with T2D.
Methods
Experimental Approach to the Problem
To test the main hypothesis, the design of this study included 4 experimental sessions completed during 2 weeks of intervention with 2 sessions each week. The intervention weeks were in a randomized order. On day 1 of each week, a control session (CONT40% one repetition maximum [1RM] or CONT80%1RM) was performed, and on day 2, an RE session (40%1RM or 80%1RM) was performed. In each session, the glycemic responses were analyzed during a 24-hour period with preintervention and postintervention measurements using a continuous glucose-monitoring system (CGMS).
Subjects
Twelve postmenopausal women with T2D between 48 and 60 years old (55.2 ± 4.0; Table 1) took part in the study with a crossover randomized block design according to the CONSORT (Figure 1 ) (34 ). The inclusion criteria were (a) woman, (b) diagnosed with T2D, (c) clinically stable, and (d) aged between 40 and 60 years. Exclusion criteria considered were (a) use of exogenous insulin, (b) morbid obesity (BMI >40 kg·m−2 ), (c) decompensated blood glucose, (d) abnormalities on an electrocardiogram (ECG) at rest with acute cardiac ischemia, (e) heart disease, diabetic retinopathy, proliferative retinopathy, or severe autonomic neuropathy, (f) upper or lower limb amputation, (g) present uncontrolled hypertension (systolic >160 mm Hg or diastolic blood pressure >100 mm Hg), (h) presence of diabetic nephropathy (albuminuria ≥14 mg·L−1 or >30 mg·24 h−1 ), (i) chronic renal failure, (j) exercise performance limitation because of joint/bone/skeletal muscle injury, and (k) smokers.
Figure 1.: Consort flow diagram. RE = resistance exercise; 1RM = one repetition maximum.
All participants were informed of risks, benefits, and objectives of the study and gave written informed consent. This study was approved by the local Ethics Committee of Studies and Research from the Federal University of São Francisco Valley (No. 0005/180814). This study is also registered at www.clinicaltrials.gov (NCT02645448). The research was conducted according to the principles of the Declaration of Helsinki. The general characteristics of all participants are shown in Table 1 .
Table 1.: Mean ± SD of descriptive characteristics of the participants and habitual energy intake (24 hours).
Procedures
Initial Assessments and One Repetition Maximum Test
Initially, the participants were subjected to a resting ECG, and after a normal certificate of cardiac condition, women were subjected to experimental study procedures. On the first visit to the laboratory, all participants filled out an anamnesis regarding health history and anthropometric measurements such as waist circumference, height, and body mass for subsequent calculation of body mass index (24 ) and body fat percentage (31 ).
Two weeks before the study intervention, all participants underwent a familiarization with the exercise protocol during 3 alternate days. After 48 hours, 1RM test was performed (30 ) in the following exercises: bench press on the machine (pectoral, triceps, and anterior deltoid muscles), leg extension (quadriceps muscle), fly on the machine (pectoral muscle), leg curl (biceps femoris, semitendinosus, and semimembranosus muscles), lat pulldown (posterior muscles of the torso and biceps), leg press (quadriceps and gluteus muscles), and seated row (posterior muscles of the torso and biceps). All exercises were performed on Evidence (Cachoeirinha/RS—Brazil) and Physicus (Auriflama/SP—Brazil) equipment.
Standardization of Medication, Diet, and Physical Activity Before and After the Interventions
After the 1RM test, participants received instructions in relation to food intake and the practice of daily physical activities. It was recommended to avoid beverage consumption that contained caffeine and alcohol within 48 hours before the first day of the intervention, to fast during the days of the experimental sessions, and to receive a standardized breakfast containing 285 kcal: 45 g (180 kcal) of carbohydrates, 6 g (24 kcal) of proteins, and 9 g (81 kcal) of fat. Moreover, they were instructed to maintain the same diet during the 2-week period of the intervention and record their nutritional intake in a food diary over a 24-hour period, which was later analyzed and calculated by a trained nutritionist using Microsoft Excel software and the Brazilian Table of Food Composition (4 ). It was also recommended to take the main meals at the same time each day, with the breakfast controlled by the researcher (between 7:00 and 7:20 am ), lunch between 12:00 and 2:00 pm , and dinner between 6:00 and 8:00 pm . One-way ANOVA showed no significant differences in daily energy intake and consumption of macronutrients between the experimental sessions (Table 1 ). During the days of intervention, participants were instructed to refrain from any exercise and strenuous physical work, except for the scheduled experiment.
Continuous Glucose Monitoring System
After the manufacturer's instructions for the CGMS Guardian REAL-Time model (Minimed Medtronic, Inc., Northridge, CA, USA) before the first day of the trial session, (CONT40%1RM and CONT80%1RM) the glucose sensor (Sof-SensorTM) was inserted into the participant. The CGMS consisted of a sensor-transmitter inserted through a needle into the abdominal subcutaneous tissue using a Sen-Seter device and a display for reading by a wireless radio-frequency sensor (Guardian real-time). This system has been validated by studies regarding diabetes and its complications (26,35 ).
Immediately after CGMS installation (laboratory environment), the equipment calibrations were performed according to factory instructions (Minimed Medtronic, Inc., Northridge, CA, USA). Moreover, CGMS calibrations were also done during experimental session moments (daily life of the participant). Such calibrations were performed every 6 hours for 24 hours after the experimental sessions (CONT40%1RM, 40%1RM, CONT80%1RM, and 80%1RM). The researcher went to the participant's location (home or workplace) to obtain blood glucose samples using a glucose monitor (Accu-Check Performa; Roche Diagnostics, Mannheim, Germany) and for immediate calibration of the CGMS. The participants were blinded regarding CGMS measurements, which occurred every 5 minutes during the 24-hour period of each experimental session, as well as blood glucose during the equipment calibration times.
Participants with T2D were instructed to keep their regular routines of daily life while using the CGMS, which has a capacity of glucose measurement for a period of up to 72 hours after installation. Thus, each equipment insertion allowed the realization from 2 to 4 experimental sessions proposed in this study. At the end of the 48 hours of glucose measurements corresponding to 2 experimental sessions, the CGMS was removed, and data were exported from the portable monitor (Guardian REAL-Time) to an online program (CareLink; MedTronic Inc., Northridge, CA, USA), where it converted the signals measured in glucose values according to the manufacturer's instructions (35 ). The glucose concentrations were analyzed on day 1 (2 weeks) over 24 hours to observe the effect of the control sessions (CONT40%1RM and CONT80%1RM) and on day 2 (2 weeks) for the next 24 hours to observe the effect of sessions with RE (40%1RM and 80%1RM).
Study Design
Figure 2 presents the schematic overview of the study design. The control sessions of the RE at 40%1RM and 80%1RM (CONT40% and CONT80%, respectively) were performed 24 hours before the respective RE sessions. The glucose concentrations were analyzed for 4 experimental sessions, in which the same were divided into 2 blocks, separated into 7 days, and in a randomized order: block-A (day 1: CONT40% and day 2: RE at 40%1RM) and block-B (day 3: CONT80% and day 4: RE at 80%1RM).
Figure 2.: Schematic overview of the study design. CGMS = continuous glucose monitoring system; RE = resistance exercise; 1RM = one repetition maximum.
Preintervention (Rest)
Before any intervention, the participants remained seated in the laboratory for a period of 20 minutes (between 8:00 and 8:20 am ) in a quiet room with no noise interference.
Intervention (Control and Resistance Exercise)
The RE intensities were established based on the American College of Sports Medicine (ACSM) and American Diabetes Association (ADA) for individuals with T2D recommendations (10 ) and classified as 40%1RM as low exercise intensity and 80%1RM as high exercise intensity. All interventions (RE or control) lasted 40 minutes (between 8:20 and 9:00 am ) each (Figure 2 ). The RE sessions were conducted with 3 circuits of 7 exercises each in the same sequence as the 1RM test. During the RE session at 40%1RM, 16 repetitions of each exercise were performed with 60-second recovery intervals and 120 seconds between circuits. During the RE session at 80%1RM, 8 repetitions of each exercise were performed with a 90-second interval and 120 seconds between circuits. The length of the repetition in each series of RE was 3 seconds, with 1 second in the concentric phase and 2 seconds in the eccentric phase. In control sessions, participants remained seated in a comfortable chair and in the same environment of the RE sessions.
Postintervention
At the end of each intervention (between 9:00 and 8:00 am ), participants were released to their routines of everyday life and oriented to record the daily nutritional intake (day 1) and repeat the same consumption in the next day (day 2) in each of the 2 weeks of experiment. Moreover, the researcher told the participants to avoid doing exercises of any kind and to maintain the use of recommended doses of medication throughout the experiment.
Statistical Analyses
Data were presented as mean and SD . The data normality was confirmed by the Shapiro-Wilk test. The glucose values were used to determine the response throughout the postexperimental session period and area under the curve (AUC) of glucose concentration. The prevalence of hyperglycemia, which corresponded to blood glucose concentrations above 160 mg·dl−1 (18 ), was calculated during the postmeal periods of each experimental session: breakfast (9:00– 12:00 pm ), lunch (1:00–7:00 pm ), dinner (7:00–11:00 pm ), and during sleep time (11:00 pm –6:00 am ). One-way ANOVA for repeated measures was performed to test the possible differences between the experimental conditions (CONT40%1RM vs. 40%1RM vs. CONT80%1RM vs. 80%1RM). The Tukey post hoc test was used when the value of “F ” was considered significant for the identification of pairs of differences. A p value ≤ 0.05 was considered statistically significant. All analyses were performed using the STATISTICA software for Windows v. 6.0 (StatSoft, Inc.).
Results
Participants were diagnosed with T2D around 5.7 ± 3.7 years and all were classified with irregular physically active levels (Table 1 ). The use of medication was maintained according to the routine of each volunteer during the experiment. Analysis of food records showed that the total daily caloric intake was not statistically different (F [3,33] = 0.389, p = 0.765) between the experimental sessions. Moreover, when analyzing daily carbohydrate (F [3,33] = 0.868; p = 0.533), protein (F [3,33] = 0.320; p = 0.813), and lipid (F [3,33] = 0.150; p = 0.929) ingestion, similar values were observed between the experimental sessions (Table 1 ). Finally, it is important to note in Table 1 that the mean glucose concentrations in the preintervention of experimental sessions showed no difference in fasting glucose (F [3,33] = 0.117; p = 0.949) and resting glucose (F [3,33] = 1.869; p = 0.148).
Glucose Concentration During Total Period
Figure 3 shows the kinetics of the blood glucose concentration during all periods of the experimental sessions.
Figure 3.: Mean glucose concentrations throughout the postintervention period. Vertical gray bar indicates rest (8:00– 8:20 am ) and intervention with control or RE (8:20– 9:00 am ). Vertical dashed lines indicate time of lunch (12:00 am ), dinner (7:00 pm ), and breakfast (7:00 am ). Horizontal dashed lines indicate hyperglycemic cutoff (160 mg·dl−1 ). 1RM = one repetition maximum.
Figure 4A shows the AUC glucose concentration in the total period of different experimental sessions. It was possible to observe an interaction between sessions (F [3,33] = 12.413; p < 0.001) with a significant reduction in the 40%1RM session compared with other sessions (p ≤ 0.05).
Figure 4.: Area under the curve (AUC) of glucose concentrations (A). Prevalence of hyperglycemia (expressed as percentage of the total time during which glucose concentrations exceeded 160 mg·dl−1 ) within the 24-hour assessment period after performing sessions (B). *Significant difference 40%1RM vs. CONT40%1RM (p < 0.01); †significant difference 40%1RM vs. CONT80%1RM and 80%1RM (p < 0.01). 1RM = one repetition maximum.
Hyperglycemia Prevalence
Interaction between the experimental sessions was found in hyperglycemia (F [3,33] = 12.362; p < 0.001), which was prevalent in 77.4 ± 18.3%, 20.8 ± 21.2%, 69.4 ± 24.6%, and 66.0 ± 33.7% for the 24-hour periods of CONT40%1RM, 40%1RM, CONT80%1RM, and 80%1RM sessions, respectively (Figure 4B ). The 40%1RM session was found to be statistically different when compared with the other sessions (p ≤ 0.05). The 80%1RM session showed no significant difference when compared with the CONT80%1RM (p = 0.986) and CONT40%1RM (p = 0.681) sessions for the prevalence of hyperglycemia in the postintervention period (Figure 4B ).
Regarding the hyperglycemia prevalence conditions after meals and during the sleeping times, there were significant interactions between the sessions in the 4 hours after breakfast (F [3,33] = 22.000; p < 0.001), the 5 hours after lunch (F [3,33] = 10.570; p < 0.001), and within 4 hours after dinner (F [3,33] = 28.105; p < 0.001). Although there was significant interaction between sessions (F [3,33] = 4.540; p < 0.01), a significant difference (p < 0.01) was found only between the 40%1RM and 80%1RM sessions (Table 2 ) in the sleeping period (11:00 pm –6:00 am ).
Table 2.: Mean ± SD of glucose concentrations throughout postintervention period and prevalence of hyperglycemia expressed as the total amount of time after meals and during sleep.*
Table 2 also shows the absolute concentrations of postmeal glucose from primary meals (after breakfast, lunch, dinner, and sleeping) in different experimental sessions. There was a significant reduction in glucose concentration in the 40%1RM session compared with other sessions (p < 0.01) in the period of 4 hours after breakfast (F [3,33] = 14.068; p < 0.0001), 5 hours after lunch (F [3,33] = 5.758, p < 0.01), and 4 hours after dinner (F [3,33] = 11.280; p < 0.0001). In sleeping time, there was a significant difference only between sessions 40%1RM and 80%1RM (F [3,33] = 6.190; p < 0.01).
Discussion
The main findings showed that RE performed with low intensity (40%1RM) reduced the AUC glucose concentration (Figure 3 ) and the prevalence of hyperglycemia in the 24-hour period (Figure 4A, B ), with 73.1 ± 37.7% and 68.4 ± 51.1% when compared with CONT40%1RM and 80%1RM (high intensity) sessions, respectively, during total time postinterventions. Moreover, these results have an important clinical application for patients with T2D based on postmeal moments during the low-intensity RE session that had significant decreases in glucose concentration and in hyperglycemic prevalence in the 24-hour period when compared with other experimental sessions (Table 2 ).
Other studies find similar results in relation to 24-hour blood glucose concentration and hyperglycemia prevalence (25,36,39 ). However, the intervention used in these previous studies was performed with AE in men, which the literature has already documented as a method which provides good glycemic control (19 ). However, this study focuses on the investigation of RE performed with different intensities in women with T2D. This population has a higher risk of mortality resulting from diabetes when compared with the male population (33 ) because of psychosocial and biological factors, such as higher androgen hormone concentration that leads to insulin release and hepatic glucose production (20 ).
Resistance exercise has been investigated because it reduced HbA1c levels (11 ), enhanced GLUT4 expression (17 ), and improved insulin sensitivity (11,22 ). The investigations found in the literature only compared the effect of AE with RE (2 ), AE with the combined exercise (15 ), only the combined exercise (30 ), and the order of combined exercise execution (41 ). In our laboratory, it was possible to analyze the acute effect of different intensities of RE (28 ) comparing a super low (23%1RM) and low (43%1RM) exercise intensities. There was good glycemic control in both RE sessions, possibly because they are in the same physiological domain of intensity (low to moderate) as shown by Moreira et al. (28 ). In addition, blood glucose was monitored only 2 hours after the proposed interventions under controlled laboratory conditions, leaving a lack of information in extended acute effects, especially with higher intensities of RE and under real conditions of daily living patients with T2D. This study investigated different exercise domains of intensity (low vs. high intensity) and used the CGMS during a long day period after the intervention. It was shown that on the days that the RE was not performed, there was a prevalence of hyperglycemic state (24 hours) in the CONT40%1RM and CONT80%1RM sessions, with mean values in 77.4 ± 18.3% (18:35 ± 4:23 hours) and 69.4 ± 24.6% (16:40 ± 5:54 hours) for each period, respectively (Figure 4B and Table 2 ).
The results of this study corroborate previous research (25,36,40 ), where the standard oral-drug treatment does not seem to promote sufficient protection against the hyperglycemic state. Thus, van Dijk et al. (40 ) reported that to improve glycemic control in patients with T2D, the use of pharmacological strategies must be associated with changes in lifestyle, such as nutritional interventions and exercise. As shown in the RE sessions, the low RE intensity session significantly reduced the prevalence of hyperglycemia in the total period (20.8 ± 21.2%; 5:00 ± 5:05 hours) in relation to other sessions (Figure 4B and Table 2 ). Although it was not the aim of this study, it is speculated that the possible mechanism of this benefit found with the low intensity of RE is associated with muscle contraction through the AMPK pathway and subsequent translocation of GLUT4, where the glucose uptake because of the cascade of intracellular events occurs regardless of the insulin action (29,32 ). However, RE performed with high intensity showed no reduction in the hyperglycemic state in the same 24-hour period (66.0 ± 33.7%; 15:50 ± 8:04 hours) when compared with the lower intensity session (Figure 4B and Table 2 ). This result can be explained by an exaggerated increase in the counter-regulatory hormonal response (21 ) driven by a speed increase of anaerobic glycolysis (27 ), which leads to higher hepatic and muscle glycogenolysis, and higher gluconeogenesis because of higher sympathetic nervous activity after high-intensity exercise (5 ).
One limitation of this study was not knowing the origin of the measured glucose. Although we showed blood glucose reduction in the 40%1RM session, these results should be interpreted with caution because moderate to high-intensity resistance exercise may also contribute to improvements in insulin sensitivity within 24 hours after exercise (22 ). Further studies with techniques for measuring glucose uptake and its endogenous production alone are welcome to elucidate future conclusions on this subject.
In addition, when using CGMS, it was possible to analyze glucose concentration responses during sleeping and postmeal times (breakfast, lunch, and dinner), which had similar habitual energy intake during the 24 hours of experimental sessions (Table 1 ). With the exception of the low-intensity RE session, there was hyperglycemia in other sessions during all postmeal times. The 40%1RM session showed less prevalence of hyperglycemia at breakfast (−64.6 ± 22.5% and −58.5 ± 37.4%), lunch (−71.2 ± 41.1% and −61.4 ± 58.3%), and dinner (−92.3 ± 32.1% and −91.2 ± 61.1%) when compared with CONT40%1RM and 80%1RM sessions, respectively. These results show high clinical relevance because postmeal hyperglycemia can be related more to atherosclerosis development and progression and CVDs (7,8 ) than the fasting glucose, which means a greater risk for cardiovascular events, especially in women with T2D (6 ). After postmeal times, the 40%1RM session also resulted in a decrease in the prevalence of hyperglycemia during the hours of sleeping compared with the 80%1RM session (Table 2 ). Previous studies (25 ) observed lower hyperglycemia during sleep times both after exercise sessions and control sessions without exercise. It is speculated that there was an increased sympathetic activation during the 24 hours after the 80%1RM session (5 ), which may have provided a higher production of glucose than glucose uptake in women in this study (Table 2 ). Further studies are needed to investigate the relationship of hyperglycemia after meals and the sleep period with the autonomic nervous system indicators in individuals with T2D.
This study only standardized the breakfast for the participant with T2D during the experimental sessions, suggesting another limitation and a lack of standardization in food intake for the remainder of the day. However, there is the external validity of our results because the participants with T2D maintained their daily feeding routines, as shown in statistical analysis of the participants' food records among the 4 experimental sessions (Table 1 ). Another limitation of this study is that the results can only be extrapolated for women with T2D. It was therefore concluded that a single RE performed at low-intensity (40%1RM) improved glucose concentration control and reduced the prevalence of hyperglycemia during 24 hours especially after meals and sleep periods in women with T2D.
Practical Applications
The practical application of these results may be useful in exercise sessions designed for people with T2D. Therefore, for individuals with a hyperglycemic state (24 hours), a single RE session over 40 minutes with 3 circuits (16 repetitions in 7 exercises in each circuit) at 40% of 1RM intensity is recommended. The recovery period between exercises should be 60 seconds in which the participant should change the exercise, and the targeted muscle groups should be the larger ones, and the exercise should be performed in an alternating fashion (preferably). As shown in this study, this intervention may be effective in lowering blood glucose and prevalence of hyperglycemia during a 24-hour period (after meals and sleeping times) in women with T2D. Despite those exercise intensities being considered low and thus secure in terms of cardiovascular and endocrine stress, a previous medical screening, including an orthopedic, cardiovascular, and metabolic evaluation, is strongly recommended, especially to RE sessions at higher intensity.
Acknowledgments
The authors thank CAPES to fund scholarships and CNPq proc. 470593/2013-0 (Research support foundation of the Brazil). The authors state that the results of this study do not constitute endorsement of the product by the authors or the NSCA. The authors declare no conflict of interest. Trial registration: This study is registered at www.clinicaltrials.gov (No. NCT02645448).
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