Postprandial hyperglycemia and glycemic variability have recently been identified as risk factors for the development of cardiovascular complications, independent from basal blood glucose concentrations (9,12,24). Therefore, blood glucose management should focus not only on basal blood glucose concentrations but also on postprandial blood glucose excursions (10). Despite the application of oral blood glucose-lowering medication and the adoption of a healthy diet, postprandial hyperglycemia and excessive glycemic fluctuations remain predominant features in patients with type 2 diabetes (28,33). Consequently, additional treatment strategies are warranted to improve postprandial blood glucose homeostasis in patients with type 2 diabetes.
Along with dietary modulation and proper medication, exercise is considered a cornerstone of type 2 diabetes treatment (15,30). The benefits of exercise on long-term glycemic control (i.e., HbA1c) can be largely ascribed to the cumulative glucoregulatory effects of each successive bout of exercise, rather than the structural adaptive response to prolonged exercise training (17,29). Indeed, with the application of continuous glucose monitoring, we (27,34) and others (16,23) have shown that a single bout of exercise substantially reduces the prevalence of hyperglycemia throughout the subsequent day. Such an effect can already be achieved by just 30 min of moderate-intensity exercise (35). The effect of a more prolonged exercise session has been shown to even last for up to 48 h (35). However, although exercise generally improves glycemic control, some patients seem to benefit more from the glucose-lowering properties of exercise than others (8).
Exercise has been shown to affect both insulin-independent and insulin-dependent glucose uptake (17). Therefore, the administration of exogenous insulin may interact with the glucose-lowering effects of exercise. Consequently, the response to exercise may differ between insulin-treated and non–insulin-treated type 2 diabetes patients. There are not much data available comparing the effect of exercise on glycemic control between insulin- and non–insulin-treated type 2 diabetes patients. On the basis of previous small-scale studies (27), we hypothesized that the effect of exercise on subsequent glycemic control does not differ in insulin-treated compared with non–insulin-treated type 2 diabetes patients. Another factor that may modulate the benefits of exercise is the baseline level of glycemic control. Recent studies suggest that the benefits of exercise training are mainly restricted to patients with suboptimal HbA1c levels (>7% [53 mmol·mol−1]) (3,14,19,32). Consequently, it is currently unclear whether well-controlled type 2 diabetes patients profit from additional exercise in their treatment regimen. This is of considerable interest, as even well-controlled patients show substantial hyperglycemia throughout the day (6,33). We hypothesized that exercise reduces the prevalence of hyperglycemia both in suboptimally and well-controlled type 2 diabetes patients.
In the present study, we determined the benefits of a single bout of moderate-intensity exercise on subsequent glycemic control in a large group patients with type 2 diabetes (n = 60). Furthermore, we assessed the potential effect of age, body mass index (BMI), exercise capacity, diabetes duration, type of glucose-lowering treatment, and baseline glycemic control as factors that may modulate the benefits of exercise on improving glucose homeostasis. For this purpose, we applied continuous glucose monitoring under strict dietary standardization, but otherwise free-living conditions, over a 24-h period after a single bout of moderate-intensity cycling exercise or no exercise at all (control).
A total of 60 men with type 2 diabetes were recruited to participate. Both insulin- (n = 23) and non–insulin-treated patients (n = 37) were selected. Patients were recruited as part of a greater project aiming to elucidate the effect of different exercise modalities on glycemic control. Data from all unique individuals participating in the different substudies (21,34,35) of this project were used in the current study. Exclusion criteria were renal failure, liver disease, morbid obesity (BMI > 40 kg·m−2), uncontrolled hypertension (>160 mm Hg systolic and/or >100 mm Hg diastolic), and a history of severe cardiovascular problems (myocardial infarction in the last year or stroke). All subjects were informed about the nature and the risks of the experimental procedures before their written informed consent was obtained. The Medical Ethical Committee of the Maastricht University Medical Centre+ had approved the study. The study is registered with ClinicalTrials.gov (NCT00945165).
Screening and pretesting
Non-insulin-treated type 2 diabetes patients underwent an oral glucose tolerance test (OGTT). Blood glucose-lowering medication was withheld 2 d before the OGTT. After an overnight fast, subjects arrived at the laboratory at 8:00 a.m. by car or public transportation. A fasting blood sample was obtained, after which an OGTT was performed to determine type 2 diabetes according to the American Diabetes Association (ADA) criteria (1). Insulin-treated type 2 diabetes patients were screened with a basal blood sample to determine their fasting plasma glucose concentration and HbA1c level. After blood sampling, all subjects performed an incremental exercise test on a cycle ergometer (Lode Excalibur, Groningen, the Netherlands) to determine their maximal workload capacity (Wmax). Cardiac function was monitored at rest and during exercise using a 12-lead ECG.
Subjects participated in a randomized crossover experiment, consisting of two intervention periods separated by at least 1 wk. Each intervention period consisted of 3 d during which blood glucose homeostasis was assessed under standardized dietary, but otherwise free-living conditions. During one intervention period, blood glucose homeostasis was assessed over the 24-h period after a single bout of exercise, whereas during the other intervention period, subjects performed no exercise at all (control).
On the first day of each intervention period, subjects started using a standardized diet. On the second day of each intervention period, subjects arrived at the laboratory in the morning after an overnight fast. A venous blood sample was drawn, and subjects received breakfast at 8:30 a.m. After a resting period, the exercise or control session was initiated in the midmorning between 10:00 and 11:00 a.m. After the exercise or control session, subjects went home to resume their normal daily activities. Glycemic control was assessed by continuous glucose monitoring over the subsequent 24 h after the exercise or control session.
Continuous glucose monitoring
The continuous glucose monitoring device (GlucoDay®S; A. Menarini Diagnostics, Firenze, Italy) was attached at least 2 h before the start of the exercise or control session, as described previously (28). Subjects received a short training in the use of the capillary blood sampling method (Glucocard X Meter; Arkray, Inc., Kyoto, Japan). Capillary glucose measurements were taken at least before each main meal and before the night. After the 24-h postexercise monitoring period, the continuous glucose monitoring device was removed. The data obtained by the continuous glucose monitor were downloaded to a personal computer with GlucoDay® software (V3.2.2), and glycemic profiles were calibrated using the capillary glucose values.
The exercise session consisted of 45–60 min of continuous cycling, performed on a cycle ergometer (Lode Excalibur, Groningen, the Netherlands). On the basis of earlier work (7,36), continuous cycling was performed at a moderate intensity targeting 35%–50% Wmax. During the control (no exercise) experiment, subjects were sitting upright in a chair next to the cycle ergometer for exactly the same duration as the exercise session.
Diet and physical activity
During each experimental period, subjects were provided with a healthy standardized diet, composed according to the ADA dietary recommendations for type 2 diabetes (4). The diet consisted of three meals and three snacks per day, distributed in preweighed packages and ingested at predetermined time points to ensure a fully standardized diet during the experimental periods. The diet provided 10.1 ± 0.9 MJ·d−1 consisting of 56 En% CHO, 14 En% protein, and 30 En% fat. The diet was designed to meet the energy requirements as calculated with the Harris and Benedict (18) equation multiplied with a physical activity level of 1.4.
All subjects were asked to maintain habitual physical activity patterns throughout the experimental period but to refrain from exhaustive physical labor and exercise training for 2 d before and during the experimental period. During the intervention periods, habitual physical activity was assessed using a validated triaxial accelerometer (Philips DirectLife, Eindhoven, the Netherlands) (5), worn in a belt around the waist. Habitual physical activity was determined by the sum of accelerometer counts obtained over the 24-h period after exercise (5). The resulting physical activity level did not differ between both intervention periods (1272 [1130–1414] and 1280 [1152–1408] kilocounts per day during the control and exercise intervention periods, respectively; P = 0.84).
Subjects’ use of blood glucose-lowering medication is summarized in Table 1. Oral blood glucose-lowering medication and/or exogenous insulin treatment was continued as normal throughout the experimental period. Insulin-treated diabetic patients continued their habitual exogenous insulin treatment schemes when exercise was performed. Exercise was performed after breakfast, thereby reducing the risk of hypoglycemia after the onset of exercise.
Blood sample analysis
During the screening and test days, venous blood samples were collected in EDTA-containing tubes and centrifuged at 1000g and 4°C for 10 min. Aliquots of plasma were immediately frozen in liquid nitrogen and stored at −80°C until analyses. Glucose concentrations were determined enzymatically (Glucose HK CP; HORIBA ABX, Montpellier, France) with the COBAS FARA semiautomatic analyzer (Roche). Plasma insulin concentrations were determined by radioimmunoassay (HI-14K; Linco Research, Inc., St. Charles, MO). HbA1c content was determined in 3-mL venous blood samples by high-performance liquid chromatography (Bio-Rad Diamat, Munich, Germany).
Statistics and data analysis
The glycemic profiles obtained during the 24-h period after exercise were used to determine average daily blood glucose concentration, prevalence of hyperglycemia, prevalence of hypoglycemia, and the level of glycemic variability. On the basis of the ADA and European Association for the Study of Diabetes guidelines for glycemic control, the prevalence of hyperglycemia was defined as total time during which glucose concentrations exceeded 10 mmol·L−1 and the prevalence of hypoglycemia was defined as total time glucose concentrations were below 3.9 mmol·L−1 (2,26). Glycemic variability, which reflects acute glucose fluctuations, was assessed by the SD of the average 24-h glucose concentration and by continuous overlapping net glycemic action (CONGA) as described by McDonnell et al. (22). With this method, the difference between each glucose reading and the glucose reading n hours previously is calculated. The CONGAn is the SD of these differences (22). We used CONGA1, CONGA2, and CONGA4 based on 1-, 2-, and 4-h time differences, respectively.
Intervention effects were assessed by one-way repeated-measures ANOVA, with exercise treatment as within-subject factor, and incorporating both medication (insulin- vs non–insulin-treated) and HbA1c (HbA1c <7% vs HbA1c ≥7%) as between-subject factors. Correlations were calculated using the Pearson correlation coefficient. All statistical calculations were performed using the SPSS 22.214.171.124 software package. Statistical comparisons were considered significant when P values were <0.05. Unless otherwise specified, data shown represent means ± SD or means (95% confidence interval).
Subjects’ baseline characteristics
Subjects’ characteristics are presented in Table 1. Non–insulin-treated and insulin-treated patients did not differ with respect to age, BMI, fasting plasma glucose concentration, and maximum workload capacity. The insulin-treated patients had slightly higher HbA1c values (7.6 ± 1.0 vs 7.1 ± 0.9, P < 0.05) and had been diagnosed with type 2 diabetes for a longer period (12 ± 8 vs 7 ± 7 yr, P < 0.01) when compared with the non–insulin-treated patients. The average HbA1c level of the entire group (n = 60) was 7.3% ± 0.9%. Twenty-eight of these patients (47%) were well-controlled according to an HbA1c level <7.0% (53 mmol·mol−1).
During the control experiment, the daily prevalence of hyperglycemia (blood glucose >10 mmol·L−1) and average 24-h blood glucose concentrations assessed by continuous glucose monitoring were significantly correlated with HbA1c (r = 0.76 and r = 0.77, respectively; P < 0.001 for both variables), fasting plasma glucose (r = 0.65 and r = 0.64, respectively; P < 0.001 for both variables), and Wmax (r = −0.37 and r = −0.41, respectively; P < 0.01 for both variables).
Average 24-h glucose concentrations
Overall, average 24-h blood glucose concentrations were 0.9 mmol·L−1 (0.7–1.2 mmol·L−1) lower over the 24-h period after a single bout of moderate-intensity exercise when compared with the control condition (P < 0.001; Fig. 1A). The glucose-lowering properties of exercise were comparable between the non–insulin-treated and insulin-treated type 2 diabetes patients (0.9 [0.6–1.3] and 0.9 [0.4–1.4] mmol·L−1 reduction, respectively; group–treatment interaction, P = 0.57). Nevertheless, we observed large interindividual differences in response to exercise (Fig. 2), with exercise being effective in lowering average 24-h glucose concentrations in most of the patients. The change in average 24-h glucose concentrations after exercise correlated significantly with subjects’ HbA1c level (r = 0.38, P < 0.01) but not with any of the other baseline characteristics (i.e., age, BMI, Wmax, diabetes duration). In accordance, the reduction in average 24-h glucose concentration after exercise was significantly greater in the suboptimally controlled patients compared to the well-controlled patients (1.2 [0.9–1.6] and 0.6 [0.2–0.9] mmol·L−1, respectively; treatment–group interaction, P < 0.05; Fig. 3A).
Prevalence of hyperglycemia
Despite the provision of a healthy diet and the use of glucose-lowering medication, hyperglycemia (blood glucose >10 mmol·L−1) was prevalent for as much as 8:16 h:min (6:44 to 9:48 h:min) of the day (7:35 h:min [5:49 to 9:41 h:min] and 9:05 h:min [6:25 to 11:46 h:min] in the non–insulin-treated and insulin-treated patients, respectively). A single bout of exercise reduced the prevalence of hyperglycemia to 5:38 h:min (3:17 to 7:00 h:min) over the subsequent 24-h period (P < 0.001; Fig. 1B). With hyperglycemia being reduced with 2:27 h:min (1:22 to 3:32 h:min) and 2:54 h:min (1:35 to 4:13 h:min) in the non–insulin- and insulin-treated patients, respectively, exercise was equally effective within both subpopulations (treatment–group interaction, P = 0.86). The change in the prevalence of hyperglycemia over the 24-h period after exercise correlated significantly with HbA1c content (r = 0.33, P < 0.05) but not with any of the other baseline characteristics (i.e., age, BMI, Wmax, and diabetes duration. In agreement, the absolute reduction in the prevalence of hyperglycemia over the 24-h period after exercise tended to be greater in the suboptimally controlled patients (3:25 h:min [2:14 to 4:35 h:min]), when compared with the well-controlled patients (1:43 h:min [0:38 to 2:49 h:min], group–treatment interaction P = 0.06; Fig. 3B). However, when expressing the reduction in hyperglycemia as a relative rather than an absolute decrease, no differences were observed between the effect of exercise in suboptimally as opposed to well-controlled patients with type 2 diabetes (33% [22%–44%] vs 28% [7%–48%], respectively).
Prevalence of hypoglycemia
During the control experiment, hypoglycemia (blood glucose <3.9 mmol·L−1) was prevalent for a duration of 0:23 h:min (0:08 to 0:38 h:min). The prevalence of hyperglycemia did not significantly change over the 24-h period after exercise (0:05 h:min [0:22 to −0:10 h:min]). The change in hypoglycemia after exercise did not differ between the suboptimally and well-controlled patients (0:10 h:min [−0:03 to 0:24 h:min] vs 0:01 h:min [−0:27 to 0:30 h:min]; treatment–group interaction, P = 0.75). In addition, the effect of exercise on hypoglycemia did not differ between the non–insulin- and insulin-treated subpopulations (0:15 h:min [0:02 to 0:28 h:min] vs −0:10 h:min [−0:47 to 0:28 h:min]; treatment–group interaction, P = 0.16). Independent of the exercise treatment, the prevalence of hypoglycemia was approximately threefold higher in the insulin-treated patients compared with the non–insulin-treated patients (estimated marginal means: 0:42 h:min [0:26 to 0:58 h:min] vs 0:14 h:min [0:02 to 0:26 h:min], respectively; between-group effect, P < 0.01). The prevalence of hypoglycemia assessed during the control experiment correlated significantly with the level glycemic variability (r = 0.40 and r = 0.28 for SD and CONGA4, respectively; P < 0.05 for both variables).
Over the 24 h after exercise, a significant reduction was observed for CONGA1, CONGA2, and CONGA4 (P < 0.05 for all variables), whereas a tendency was observed for SD (P = 0.06; Fig. 4). Despite a higher level of glycemic variability in the insulin-treated as opposed to non–insulin-treated patients (between-group effect, P < 0.05 for CONGA4 and SD), exercise induced a comparable reduction in glycemic variability in both groups (group–treatment interaction, P > 0.05 for all indices of glycemic variability). The level of glycemic variability was also higher in the suboptimally controlled patients when compared with the well-controlled type 2 diabetes patients (between-group effect, P < 0.05 for CONGA2, CONGA4, and SD). However, the reduction in glycemic variability after exercise did not differ between the suboptimally and well-controlled patients (group–treatment interaction, P > 0.05 for all indices of glycemic variability).
The present study showed that hyperglycemia is highly prevalent throughout the day in type 2 diabetes patients. Hyperglycemia and glycemic variability were substantially reduced over the 24-h period after a single bout of moderate-intensity exercise in both insulin- and non–insulin-treated type 2 diabetes patients. The magnitude of the response, however, showed considerable variation between patients. Patients with higher HbA1c levels (≥7% [53 mmol·mol−1]) experienced greater absolute reductions in blood glucose concentrations after exercise when compared with well-controlled patients. Nonetheless, even well-controlled patients with an HbA1c level below 7% (53 mmol·mol−1) showed considerable improvements in daily glycemic control after a single bout of exercise.
In the present study, we examined the glycemic profiles of 60 patients with type 2 diabetes treated with or without exogenous insulin. In agreement with our previous work (33), hyperglycemic blood glucose concentrations (>10 mmol·L−1) were experienced for as much as 8:16 h:min (6:44 to 9:48 h:min) of the day, representing 34% of the time. As such, the maximal postprandial blood glucose concentrations of 10 mmol·L−1, as advised by the ADA and European Association for the Study of Diabetes (2,26), were exceeded throughout a considerable part of the day. The daily prevalence of hyperglycemia did not differ between the insulin-treated and non–insulin-treated patients (7:35 h:min [5:49 to 9:41 h:min] and 9:05 h:min [6:25 to 11:46 h:min], respectively; between-group effect, P = 0.94). Regardless of the prevalence of hyperglycemia, the glycemic profiles of insulin- and non–insulin-treated patients differed with respect to glycemic variability and the prevalence of hypoglycemia. In agreement with Monnier et al. (25), both glycemic variability and the prevalence of (asymptomatic) hypoglycemia were higher in the insulin-treated as opposed to the non–insulin-treated patients. These data suggest that simply intensifying type 2 diabetes treatment with exogenous insulin is not a prerequisite for improved glycemic control. In general, both insulin- and non–insulin-treated patients with type 2 diabetes would greatly benefit from treatment strategies that effectively lower the prevalence of hyperglycemia in parallel with reduced glycemic variability.
In the present study, we showed that a single bout of moderate-intensity endurance-type exercise substantially reduced the prevalence of hyperglycemia over the subsequent 24 h by as much as 31% (Fig. 1B; P < 0.001). Moreover, with the prevalence of hyperglycemia being reduced by 33% and 29% in, respectively, insulin and non–insulin-treated type 2 diabetes patients, exercise was equally effective for both subpopulations (treatment–group effect, P = 0.86). These results clearly indicate that the benefits of exercise on glycemic control can be achieved on top of regular pharmacological treatment with either exogenous insulin or oral glucose-lowering medication. As such, the present study firmly establishes previous observations in smaller studies (27,34,35) by showing the glucoregulatory benefits of a single bout of exercise per se on subsequent daily glycemic control in a cohort of 60 patients with type 2 diabetes patients.
The current study demonstrated that patients with type 2 diabetes can substantially reduce average 24 h blood glucose concentrations simply by implementing a daily exercise session. When looking at the individual level (Fig. 2), the exercise-induced changes in 24-h glycemic control displayed considerable variation among the various patients. The individual change in average blood glucose concentrations over the 24-h period after exercise ranged from −4.3 to +1.7 mmol·L−1 (Fig. 2). Of all measured baseline factors, the blood glucose-lowering effect of exercise correlated with subjects’ HbA1c level only (r = 0.38, P < 0.01). In accordance, the absolute decline in average 24-h glucose concentrations was greater in the suboptimally controlled patients with an HbA1c level ≥7% compared with the well-controlled patients (1.2 mmol·L−1 [0.9 to 1.6 mmol·L−1]) and 0.6 mmol·L−1 [0.2 to 0.9 mmol·L−1], respectively; treatment–group interaction, P < 0.01). This finding agrees with previous observations in long-term exercise intervention studies (3,14,32), which have indicated that exercise training has a greater effect on reducing HbA1c levels in the patients with suboptimal glycemic control at baseline. Thus, from an absolute point of view, patients with higher blood glucose levels can achieve greater improvements in glycemic control after exercise. The results obtained in the previous exercise intervention studies also suggested that well-controlled patients gain little or no benefit from exercise training (3,14,32). However, the present data refute this view and show that even well-controlled patients can successfully improve daily glycemic control by implementing exercise in their daily routine (Fig. 3). In fact, the relative reduction in the prevalence of hyperglycemia was comparable between the suboptimally and well-controlled patients (28% and 33% reduction, respectively; Fig. 3B).
Some (13,24), but not all (20,31), research groups recognize glycemic variability as an important component of glycemic control. Glycemic variability reflects the frequency and amplitude of both upward and downward glucose excursions throughout the day. These acute glucose excursions have been implicated in the activation of oxidative stress and subsequent risk for the development of diabetes complications (11). A recent study by Mikus et al. (23) has shown that short-term endurance-type exercise narrows the range of blood glucose concentrations observed throughout the day. This finding suggested that exercise reduces the magnitude of glycemic variability. In the present study, we further extended on this finding. By using well-established markers of glycemic variability, we observed a reduction in glycemic variability over the 24-h period after a single bout of exercise (Fig. 4). Although glycemic variability was higher in the insulin-treated as opposed to the non–insulin-treated patients, both groups experienced equal benefits with respect glycemic variability (treatment–group effect, P > 0.05 for all indices of glycemic variability). Equal effects of exercise were also observed in the suboptimally as opposed to the well-controlled patients (treatment–group effect, P > 0.05 for all indices of glycemic variability). Altogether, these data indicate that the level of glycemic variability, as a risk factor for the development of type 2 diabetes complications, can be improved by simply implementing a session of moderate-intensity exercise in the patients’ daily regimen.
The present study was performed under strict dietary standardization with identical diets provided under both experimental conditions. The strength of this approach is that the improvements in glycemic control as observed in the present study cannot be attributed to differences in food choice, appetite and energy intake, macronutrient composition, and/or glycemic index of the food consumed. On the other hand, the similar energy intake during the exercise and control condition led to a difference in net energy balance between both conditions (approximately 300–400 kcal). This difference might have contributed to the glucose-lowering effects of exercise as observed in the present study.
Taken together, the present study highlights the importance of exercise as a treatment strategy in type 2 diabetes. We conclude that a single bout of moderate-intensity exercise substantially reduces hyperglycemia and glycemic variability throughout the subsequent day in insulin- and non–insulin-treated type 2 diabetes patients. The glucoregulatory properties of exercise are not restricted to patients with suboptimal HbA1c levels, as even well-controlled patients (HbA1c <7% [53 mmol·mol−1]) can substantially reduce the prevalence of hyperglycemia by performing moderate-intensity exercise. Therefore, regular exercise should be an integral part of treatment for all patients with type 2 diabetes.
J.W.v.D. designed the study, collected the data, researched the data, and wrote the article. E.E.C. and R.J.F.M. collected the data, contributed to the discussion, and reviewed and revised the manuscript. W.v.M., F.H., and C.D.A.S. contributed to the discussion and reviewed and revised the manuscript. L.J.C.v.L. designed the study, researched the data, and wrote the article.
The described work was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw, The Netherlands). None of the authors had any personal and/or financial conflict of interest about this study. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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