Skeletal muscle tissue accounts for most of the insulin-stimulated glucose disposal in humans. The prolonged application of either endurance or the combination of resistance and endurance exercise training has been shown to improve whole-body glucose tolerance and/or insulin sensitivity in type 2 diabetes patients (7,8,18). However, even an acute bout of endurance (10) or resistance exercise (16) has been shown to improve insulin sensitivity and/or glucose tolerance. These effects have been reported to persist for periods of 2 h (24), 4-6 h (36), 12-16 h (10), 24 h (16), and up to 48 h after cessation of exercise (24).
So far, no studies have investigated the effects of an acute bout of exercise in long-standing, insulin-treated type 2 diabetes patients. The latter is likely secondary to the difficulties when trying to define an appropriate exercise program for these patients, who generally show exercise intolerance because of the presence of comorbidities. Because the population of type 2 diabetes patients on exogenous insulin therapy is growing progressively (9), it is of utmost importance to establish whether exercise can effectively modulate glycemic control and reduce episodes of glucotoxic hyperglycemia (defined as blood glucose concentrations greater than 10 mmol·L−1) in these patients.
A novel way to evaluate changes in blood glucose concentrations under free-living conditions is provided by the use of continuous subcutaneous glucose-monitoring systems (CGMS). CGMS can be used to obtain continuous information on ambulatory postprandial (13) and/or nocturnal glucose excursions (3) and have been shown to represent a sensitive tool to study the impact of dietary modulation on 24-h blood glucose profiles (4). Moreover, glucose-tolerance tests are generally not applicable in insulin-treated diabetes patients, which is likely one of the many reasons that intervention studies generally exclude insulin-treated type 2 diabetes patients with evident comorbidities. As such, CGMS represents a better alternative to the use of glucose-tolerance tests as a means to monitor short-term changes in glycemic control, without interfering with daily living activities.
In the present study, we applied CGMS to evaluate whether the implementation of a single bout of exercise would improve 24-h glycemic control in long-standing, insulin-treated, type 2 diabetes patients. Because both resistance (14,15) and endurance exercise (17) have been shown to improve peripheral insulin sensitivity and/or glucose disposal in type 2 diabetes patients, we hypothesized that a single session of a combination of these types of exercise would reduce the prevalence of hyperglycemic glucose excursions.
Eleven male type 2 diabetes patients were selected to participate in this study. Subjects had been diagnosed for more than 5 yr with type 2 diabetes and had been on exogenous insulin treatment for 7.0 ± 2.4 yr. They had no history of participating in any regular exercise program for more than 10 yr. All subjects had been on a stable regimen of diabetes medication for at least 3 months before being recruited. Seven subjects were using short-acting (Novorapid®, N = 6) or rapid-acting insulin (Humulin®, N = 1) before each meal (N = 7), either in combination with NPH insulin (Insulatard®, N = 5), premixed biphasic isophane insulin (Mixtard 30/70® in combination with metformin, N = 1), or a very long-acting insulin analogue (insulin glargine, N = 1), all administered before bedtime. Three subjects were using premixed biphasic isophane insulin twice a day (Mixtard 30/70®, N = 3) in combination with metformin. One subject used NPH insulin (Humulin NPH®) once a day before breakfast in combination with metformin and a sulphonylurea (glimepiride). Subjects continued the same oral medication and exogenous insulin schemes throughout the entire study period. Patients using thiazolidinediones and/or beta-blockers for less than 6 months, and subjects with impaired liver function, renal failure, severe retinopathy or a history of severe cardiovascular problems, were excluded from participation. Subjects' characteristics are shown in Table 1. The nature and the risks of the experimental procedures were explained to the subjects, and all gave their written informed consent to participate in the study, which was approved by the local Medical Ethical Committee of the Máxima Medical Center, Veldhoven, The Netherlands.
Body mass and waist circumference were measured using an analog weight scale and standard measuring tape. Segmental and whole-body bone mass and fat-free mass (FFM) were determined using whole-body DEXA (Hologic QDR-4500 Discovery A, software version 12.3:3, Hologic Inc. Bedford, MA, USA).
Peak Whole-Body Oxygen Uptake Capacity
Peak whole-body oxygen uptake capacity (V˙O2peak) and maximal workload capacity (Wmax) were measured during an incremental exhaustive exercise test until volitional exhaustion, performed on a cycle ergometer (Medifit Ergometer, Medifit systems, Maarn, The Netherlands) using a ramp protocol (37). Gas exchange measurements were performed continuously (Ergostar, PMS Professional Medical Systems, Basel, Switzerland). Cardiac function was monitored using a 12-lead electrocardiogram with heart rate recorded continuously (Polar Electro, Kempele, Finland) and sampled at 1 kHz through a data log device (Co2ntrol™, Tildesign, Zeewolde, The Netherlands).
At least 1 wk before the experimental exercise session, subjects participated in two exercise trials to become familiarized with the exercise protocol and the equipment. Proper technique was demonstrated and practiced for each of the three lower-limb exercises (leg press, leg extension, and lunges) and for the three upper-body exercises (vertical traction, vertical row, upright row). Maximum strength was estimated using the multiple-repetitions testing procedure, and at least 1 wk before the experimental trial, each subject's one-repetition maximum (1RM) was determined. After warming up, the load was set at 90-95% of the estimated 1RM and increased after each successful lift until failure. A 5-min resting period between subsequent attempts was allowed. A repetition was valid if the subject was able to complete the entire lift in a controlled manner without physical assistance.
Standardization of diet and activity before and after exercise.
After strength testing, subjects received instructions regarding the use of food intake and physical activity diaries. Subjects were asked to maintain a stable diet and constant medication schemes and to record their food intake for 3 d, starting 1 d before the CGMS device was attached. An overview of the study protocol is provided in Figure 1. Administration of oral blood glucose-lowering medication and daily exogenous insulin therapy, regarding dose and timing, was maintained throughout the entire study. Total daily exogenous insulin injection averaged 1.0 ± 0.1 IU·kg−1·d−1. Immediately after the 3-d monitoring period, a clinical dietician discussed the food intake records with each subject personally to ensure proper food intake assessment. Energy intake averaged 77.7 ± 5.7 kJ·kg−1·d−1 (with 75.1 ± 6.3, 77.9 ± 8.3, and 80.0 ± 6.0 kJ·kg−1·d−1 on days 0, 1, and 2, respectively. Macronutrient composition of the diet averaged 18.9 ± 1.1 energy percentage (En%) protein, 42.7 ± 1.4 En% fat, and 38.4 ± 1.4 En% carbohydrate on days 0, 1, and 2, respectively. Energy intake and meal composition did not differ between days, even though subjects were free to increase or decrease portion size of all meals, drinks, and snacks. All subjects were instructed to refrain from any sort of heavy physical labor or exercise during the entire period except for the exercise session.
Because of the intermittent nature of the exercise bout, energy expenditure during the exercise bout was not assessed in this study. Based on indirect calorimetry measurements performed during circuit resistance training both in older (29) and younger (2) adults, energy expenditure was estimated to range between 11 and 15 mL of oxygen per minute in the performed exercise regimen, which would be equivalent to 3.3-4.3 metabolic equivalents. As such, the implemented bout of exercise should be considered to be of moderate intensity (28).
On the first day, subjects reported to our laboratory at 9:30 a.m. and received a short training in the use of the capillary blood-sampling method (Glucocard Memory PC, A. Menarini Diagnostics, Firenze, Italy) used for the calibration of CGMS. All subjects were instructed to measure capillary blood glucose concentrations before every meal. After the subjects were fully instructed, a microdialysis fiber (Medica, Medolla, Italy) with an internal diameter of 0.17 mm and a cutoff weight of 18 kD was inserted into the periumbilical region, without anesthesia, using an 18-gauge Teflon catheter as a guide, as described previously (23). For the measurements, the microfiber was then connected to a portable CGMS (GlucoDay®S, A. Menarini Diagnostics, Firenze, Italy), which consists of a peristaltic pump that pumps Dulbecco's solution at 10 μL·min−1 through the microdialysis fiber. A detailed description of the device has been published previously (19). In brief, the subcutaneous interstitial fluid is taken up by the microdialysis fiber and is transported to the measuring cell. The glucose sensor, consisting of immobilized glucose oxidase, measures the glucose concentration every second and stores an average value every 3 min for a total measuring time of 48 h. After analysis, the dialysate is then pumped from the glucose sensor into a waste bag. The entire device, including the perfusion solution and the waste bag, weighs about 250 g and is worn in a pouch under the subjects' clothes. After the CGMS was checked for proper function, subjects were allowed to return home and resume their normal activities.
Dialysate glucose concentrations were calibrated using one capillary and one venous blood sample obtained at least 12 h apart from each other (19,30,33). The venous blood samples were obtained immediately before the exercise bout. Glucose concentrations in the dialysate have been shown to correlate well with venous blood glucose concentrations (19) and generally show an accuracy of 98.1 and 93.4% in the normal and hyperglycemic range, respectively (35). However, the clinical accuracy in the hypoglycemic range (blood glucose < 3.9 mmol·L−1) tends to be lower, generally ranging between 57 and 60% (35). As such, individual sensor values in the lower range should be interpreted with some caution. Furthermore, there tends to be some lag time between subcutaneous interstitial glucose levels and venous plasma glucose concentrations, which has been estimated to vary from less than 3 to up to 7 min (19,35).
The day after the CGMS device was attached, subjects reported at the hospital after transport by car or public transportation at 11:00 a.m. Subjects performed a general warm-up procedure of 5-min cycling on a bicycle ergometer at 40% of their individual Wmax, followed by two sets of 10 repetitions on three resistance exercise machines targeting the upper body: vertical traction, vertical row, upright row, two sets of floor exercises (push-up and abdominal crunch), and two sets of 20 alternate left/right lunges without additional weight. The latter were included to provide a whole-body warm-up and to reduce the risk of injury. Thereafter, the resistance exercise session targeted the legs, with two sets of 10 repetitions on the horizontal leg-press machine (Life Fitness (Atlantic) BV, Barendrecht, The Netherlands) and two sets of 10 repetitions on the leg-extension machine (Life Fitness) with approximately 2 min of rest intervals between sets. All exercises were performed at 50% of the subjects' individual 1RM and averaged 148 ± 6 and 81 ± 3 kg for the leg press and leg extension, respectively.
Long-standing type 2 diabetes patients on exogenous insulin therapy generally suffer from reduced exercise tolerance, which complicates the design of an appropriate exercise program in these patients (32). In the present study, resistance exercise was followed by four bouts of 30-s high-intensity interval exercise on a bicycle ergometer, alternated with 60 s of 15-W recovery, which was applied to stress the working leg muscles without overloading the cardiovascular system (21). Work rate for the interval modes was set at 50% Wmax (30/60 s) during a steep ramp test (increments of 25 W·10 s−1, as described by Meyer et al. (21)), corresponding to 137 ± 9 W. The total training regimen required approximately 45 min to complete. The form and intensity of the exercise bout was chosen to recruit sufficient muscle mass without causing delayed onset muscle soreness or feelings of dyspnea in this deconditioned group of type 2 diabetes patients. All subjects were verbally encouraged during the test to complete the entire protocol.
Two weeks before the experiment, blood samples were collected the morning after a 10-h fast. A standardized meal was provided on the evening before the blood collection between 6:00 and 7:00 p.m. (35.2 ± 1.8 kJ·kg−1 BW, containing 53 En% fat, 10 En% protein, and 37 En% carbohydrate). Blood samples (4 mL) were collected in tubes containing a glycolytic inhibitor (sodium fluoride) and an anticoagulant (potassium oxalate), immediately centrifuged at 1000 × g and 4°C for 5 min, after which aliquots of plasma were frozen immediately in liquid nitrogen and stored at −80°C until analyses. Plasma glucose (Glucose 125 Hexokinase kit, ABX Diagnostic, Montpellier, France), serum cholesterol (CHOD-PAP, ABX Diagnostics), HDL cholesterol (543004, Roche Diagnostics, Basel, Switzerland), free fatty acids (Wako NEFA-C test kit, Wako Chemicals, Neuss, Germany), and triacylglycerol (GPO-Tinder 337B: Sigma Diagnostics, St Louis, MO) concentrations were analyzed with the COBAS FARA semiautomatic analyzer (Roche). To determine basal fasting blood HbA1c content, a 3-mL blood sample was collected in EDTA-containing tubes and analyzed by high-performance liquid chromatography (Bio-Rad Diamat, Munich, Germany). The serum concentration of adiponectin was quantified using a commercially available Human Adiponectin ELISA (#HADP-61K, Linco Research Inc. St. Charles, MO). C-peptide was analyzed through a electrochemiluminescent immunoassay (Nr 03184897, Elecsys Module, Roche GmbH, Mannheim).
To quantify and compare the CGMS glucose excursions 24 h before and after the exercise bout, mean dialysate glucose concentrations and the amount of time during which glucose concentrations reside at a level above 10.0 mmol·L−1 or below 3.9 mmol·L−1 were calculated. Except for the calibration values, all other capillary blood glucose measurements performed by our subjects were used to calculate the coefficient of variation (CV) of the CGMS data.
To assess intraday glycemic variability before and after exercise, continuous overall net glycemic action (CONGA), a novel method recently described by McDonnell et al. (20), was used. CONGAn has been defined as the standard deviation of the differences in glucose concentrations using varying time differences of n hours. We used CONGA1, CONGA2, and CONGA4, indicating intraday glycemic variability based on 1-, 2-, and 4-h time differences, respectively. In normal nondiabetic subjects, CONGA values vary between 0.4 and 1.2, and values above 1.5 indicate glycemic lability (20).
All data are expressed as means ± SEM. Repeated-measures ANOVA was used to compare food intake on the three consecutive days. Student's t-test was applied to the CGMS parameters determined during the 24-h periods before and after the bout of exercise. Relationships between CGMS parameters and HbA1c were calculated using Pearson's correlation analyses. Statistical significance was set at P < 0.05.
Mean continuous glucose concentrations before and after exercise are illustrated in Figure 2. During exercise, glucose levels declined and remained lower for approximately 3 h after cessation of exercise (Fig. 2B). Average 24-h glucose concentrations before and after the exercise bout did not differ significantly (P = 0.26). The duration of hyperglycemic glucose excursions (>10.0 mmol·L−1) averaged 31.7 ± 6.0% of the day. The latter is equivalent to 7.6 ± 1.4 h·d−1. The duration of hyperglycemia (>10 mmol·L−1) was significantly lower on day 2 compared with day 1 (4.6 ± 1.1 vs 7.6 ± 1.4 h, respectively; P < 0.05; Fig. 3). Mild hypoglycemia occurred in 6 out 11 subjects throughout the 48-h period. The average amount of hypoglycemic episodes, defined here as blood glucose concentrations below 3.9 mmol·L−1, remained unchanged and averaged 51 ± 19 and 36 ± 16 min on days 1 and 2, respectively. Prevalence of hypoglycemia exceeded 100 min per 24 h in only two subjects. Total mean glucose concentrations in the dialysate did not reach values below 3.9 mmol·L−1 (Fig. 2). The CONGA n values, which can be regarded as a measure of the variability of the glucose concentrations during the day, were not different between days 1 and 2 (P = 0.34-0.61, Table 2).
CGMS measures versus bHbA1c concentration.
Mean glucose concentrations for 48 h as well as the prevalence of hyperglycemic periods for 48 h both correlated significantly with HbA1c concentration, measured 1 week before the CGMS measurements (Pearson's R = 0.69, P < 0.05). Mean CONGA1, 2, and 4 values for 48 h did not show a significant correlation with HbA1c (Pearson's R = 0.46-0.51, P > 0.05).
In the present study, we show that an acute bout of moderate-intensity exercise significantly modulates glucose concentrations during a 24-h period under free-living conditions in long-standing, insulin-treated, type 2 diabetes patients. An acute bout of exercise reduces the prevalence of hyperglycemia within a time frame of 24 h after cessation of exercise in these patients. The latter finding is of clinical relevance because it indicates that daily exercise represents an effective strategy to modulate 24-h blood glucose homeostasis in this subgroup of type 2 diabetes patients.
Both endurance and resistance exercise have been shown to improve blood glucose homeostasis in uncomplicated type 2 diabetes patients (7). The improvement in glucose disposal capacity after resistance and/or endurance exercise is attributed to improved insulin signaling downstream of the insulin receptor, resulting in increased GLUT4 translocation (14). In addition, more long-term resistance exercise training increases skeletal muscle mass (11). As skeletal muscle tissue accounts for more than 75% of the insulin-stimulated whole-body glucose disposal, a greater lean body mass will also augment total blood glucose disposal capacity. As such, both resistance and endurance exercise can substantially improve glucose tolerance and/or insulin sensitivity. In the present study, we implemented both types of exercise within a single exercise session. We investigated the beneficial effects of such an acute bout of exercise on 24-h blood glucose homeostasis in insulin-treated, long-term diagnosed type 2 diabetes patients.
Information about the benefits of exercise in insulin treated, long-term diagnosed type 2 diabetes patients is generally lacking in the literature. Because of the progressive nature of the disease, these patients often have a complex spectrum of cardiovascular, neuromuscular, and metabolic disorders. Their vulnerable health status, in combination with methodological difficulties, has withheld many scientists to investigate the therapeutic options of exercise in this subpopulation of type 2 diabetes patients. To obtain more insight into the responsiveness of this subpopulation of type 2 diabetes patients to exercise, we assessed the acute effects on 24-h glucose homeostasis under free-living conditions. The exercise bout reduced the duration of periods of hyperglycemia by almost 40% in the subsequent 24 h. As such, the subjects experienced hyperglycemia (>10 mmol·L−1) during 4.6 ± 1.1 h instead of 7.6 ± 1.4 h, as observed in the 24-h period before the exercise session. This modulating effect on postprandial hyperglycemia is of a similar magnitude as has been reported after energy intake restriction (6) or after the administration of an insulinotropic agent (1).
It has been reported that throughout the day, hyperglycemia is generally most pronounced 1.5-2 h after breakfast in non-insulin-dependent type 2 diabetes (26). In accordance, in the present study, similar 24-h dialysate glucose patterns were observed. As a consequence, the exercise trial coincided with the downward slope of the glucose curves. Linear trend line analysis, based on a least square fit procedure, revealed that the average slope of the glucose curve from 10:00 to 12:00 was significantly steeper on day 1 than on day 2 (−1.9 ± 0.3 vs −1.1 ± 0.3 mmol·L−1·h−1, respectively, t-test, P < 0.05). The latter implies that an acute exercise bout contributes to a faster reduction of postprandial hyperglycemia. Because hyperglycemia is directly related to the formation of advanced glycation end-products and the genesis of microvascular disease (34), our data show that even in this high-risk, insulin-treated, type 2 diabetes population, exercise represents an effective means to improve blood glucose homeostasis. Therefore, daily moderate-intensity exercise can be applied to reduce glucotoxicity and might subsequently prevent or delay the development of complications in this group of type 2 diabetes patients.
The use of CGMS provides a safe and effective means to assess the modulating effects of acute exercise on blood glucose excursions under normal dietary conditions. Although the deconditioned status of these patients forced us to apply a bout of moderate-intensity exercise, our data show that even such relatively low-impact exercise represents a sufficient stimulus to improve blood glucose homeostasis. The latter is of important clinical relevance to the design of exercise intervention programs for this category of type 2 diabetes patients, who often suffer from complications and who generally experience some degree of exercise intolerance. In this population, intermittent types of exercise seem to be preferred, because repeated high-intensity interval exercise of short duration still increases peripheral glucose uptake (31) without overloading the cardiorespiratory system or causing excessive delayed onset muscle soreness (22). However, it should be noted that even though acute exercise clearly improved glucose homeostasis by reducing the prevalence of hyperglycemia, it was evident that there was a large intersubject variability in the magnitude of this response (Fig. 2). This variability in response to an acute bout of resistance exercise has already been described in both healthy and insulin-resistant subjects (5,12).
As described before (19), CGMS measurements have been reported to show a bias between −2.0 and 11.2% when compared with venous blood glucose measurements. In this study, the mean CV between CGMS and 94 randomly taken capillary blood glucose measurements was 6.0%. Accordingly, Bland-Altman plots and Clark's grid-error analyses of CGMS using a microdialysis biosensor technique have shown that CGMS measurements provide reliable information on glucose excursions in insulin-resistant populations (19,35). Clinical accuracy of the microdialysis sensor readings have been shown to range between 93 and 98% in the normal and hyperglycemic range, whereas in the hypoglycemic range, the accuracy is still a matter of some concern (35). The latter does not affect the data presented in this study, because the prevalence of hypoglycemia was very limited (3.0 ± 1.2%) and did not differ between days 1 and 2.
In the present study, we observed a strong and positive correlation (R = 0.69) between the duration of hyperglycemia during the 48-h period and blood HbA1c concentration. Although HbA1c corresponds to a weighted 1- to 3-month average (27), the latter suggests that approximately 50% of the variation in blood HbA1c content in this population of type 2 diabetes patients could be attributed to the prevalence of hyperglycemic periods as assessed by CGMS. However, the measurement of prospective changes in blood HbA1c content only has sufficient sensitivity to detect changes in glucose homeostasis or insulin sensitivity during middle- to long-term interventions (25). Therefore, the present study underscores the notion that CGMS is a promising tool when evaluating short-term (< 3 months) changes in glucose homeostasis after pharmacological, dietary, and/or exercise interventions (19).
In conclusion, an acute bout of exercise substantially reduces the prevalence of hyperglycemia in long-standing, insulin-treated, type 2 diabetes patients. Therefore, daily, moderate-intensity exercise represents a valuable adjunct to the therapeutic arsenal to improve glycemic control in a subpopulation of type 2 diabetes patients, which have proven difficult to manage.
Stephan Praet is supported by a research grant from the Dutch Ministry of Health, Welfare and Sport. The authors would like to thank Hanneke van Milligen, Bjørn Beerten, and Gerry Hovens for their technical support and assistance with the GlucoDay® system and Carla van Mensvoort for the detailed analysis of the food intake records. We are also grateful to Jaap Swolfs, Paul Rietjens, and Paul Chatrou for supervising the exercise program.
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