Prior meal enhances the plasma glucose lowering effect of exercise in type 2 diabetes

PAUL POIRIER, SAMANTHA MAWHINNEY, LUC GRONDIN, ANGELO TREMBLAY, TOM BRODERICK, ROUX, CLAUDE CATELLIER, GILLES TANCRE ` DE, and ANDRE NADEAU JEAN CLE Quebec Heart Institute, Laval Hospital, the Diabetes Research Unit, the Hypertension Research Unit, Centre Hospitalier Universitaire de Que bec, and Physical Activity Sciences Laboratory, Laval University, Sainte-Foy, Quebec, CANADA; and the Preventive Medicine & Biometrics Department, Denver, CO

ABSTRACT ROUX, C. CATELLIER, G. TANCRE ` DE, POIRIER, P., S. MAWHINNEY, L. GRONDIN, A. TREMBLAY, T. BRODERICK, J. CLE and A. NADEAU. Prior meal enhances the plasma glucose lowering effect of exercise in type 2 diabetes. Med. Sci. Sports Exerc., Vol. 33, No. 8, 2001, pp. 1259 1264. Purpose: To compare the changes in plasma glucose and insulin levels in response to 1 h of exercise O2peak either in the fasted state or 2 h after a standardized breakfast in subjects with type 2 diabetes. Methods: performed at 60% of V Ten sedentary men with type 2 diabetes treated with oral agents and not under strict metabolic control were tested on two occasions (fasted and fed state) in a random order at a 1-wk interval. Results: Plasma glucose was slightly but not significantly higher at the beginning of exercise performed in the fed state versus the fasted state (12.4 1.3 vs 11.1 1.1 mmolL1 respectively; mean SE, P 0.06). However, after exercise, plasma glucose levels were much lower in the fed state (7.6 1.1 mmolL1) compared with the fasted state (10.0 1.0 mmolL1; P 0.009). Insulin levels were higher at the beginning of the exercise bout performed in the fed state (177 26 vs 108 19 pmolL1; P 0.05) and during exercise. Similar respiratory exchange ratio at identical workload indicated that the difference in glycemic response was not due to differences in whole body substrate utilization. Plasma concentrations of free fatty acids, glucagon, epinephrine, and norepinephrine were also similar during both experiments. Conclusions: One hour of aerobic exercise has a minimal impact on plasma glucose level when performed in fasted moderately hyperglycemic men with type 2 diabetes but induces an important decrease in plasma glucose level when performed 2 h after breakfast. Because glucose utilization increased similarly during exercise in both conditions, the higher insulin levels after the meal might have blunted glucose production, creating an imbalance between total glucose production and total peripheral utilization in the fed state in contrast to the fasted state. Key Words: DIABETES MELLITUS, EXERCISE, BLOOD GLUCOSE

xercise has long been known to play an important role in the management of diabetes mellitus (10). The concept that an exercise regimen should be part of the standard management in patients with type 2 diabetes together with diet and hypoglycemic agents has been reinforced recently (1). Nevertheless, knowledge about the impact of acute aerobic exercise on glucose homeostasis in subjects with type 2 diabetes is still incomplete (11,13,26,30). Many health care professionals generally assume that acute moderate exercise decreases blood glucose in subjects with type 2 diabetes (26). However, the current literature shows either a modest decrease (7,11,13,15,17,23) or no significant change (2,5,9,24) in blood glucose levels following aerobic exercise in the fasted state. Surprisingly, some individuals even show a sustained increase in plasma glucose levels after exercise in the fasted state (2,9). Although some investigators have documented a decrease in blood glucose levels after exercise in subjects with type 2 diabetes when performed in the fed state (8,12,16), the effect of

exercise on blood glucose levels in the fasted compared with the fed state has never been compared within the same research protocol in subjects with type 2 diabetes treated with oral agents. The objective of this study was to examine the effect of dietary status on changes in blood glucose concentrations in subjects with type 2 diabetes treated with oral hypoglycemic agents during an acute bout of exercise. A secondary objective was to investigate mechanisms by which either fasted or postprandial conditions could influence blood glucose change during exercise. Thus, glucoregulatory and metabolic responses to 1 h of exercise at 60% of peak O2peak) performed either in the fasted state oxygen uptake (V or 2 h after breakfast were investigated in men with type 2 diabetes treated with oral agents.

MATERIALS AND METHODS

Subjects. Ten sedentary men with type 2 diabetes gave written informed consent to participate in the study. The Ethics Committee of Laval University approved the protocol and the experimental procedures were in accordance with the policy statements of the American College of Sports Medicine. Characteristics of the subjects are shown in Table 1. None of the subjects used insulin but all were treated with oral hypoglycemic agents. Six subjects used 1259

0195-9131/01/3308-1259/$3.00/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE Copyright 2001 by the American College of Sports Medicine Submitted for publication June 2000. Accepted for publication November 2000.

TABLE 1. Characteristics of subjects with type 2 diabetes. O2peak V Total Daily Doseb Age (yr) HbA1(%)a (mL kg1 min1) (Oral Hypoglycemic Agents) 49 59 60 56 60 56 52 43 52 55 Mean SE 54 5
a

7.5 13.0 9.8 7.6 8.5 12.1 9.9 8.9 11.5 8.0 9.7 1.9

31.8 33.3 39.2 38.1 30.9 32.9 32.7 43.7 31.3 28.5 34.2 4.6

10 10 5 10 15 20 20 10 15 10

mg mg mg mg mg mg mg mg mg mg

G G G G G G G G G G

500 mg M 1gM 1gM 2gM

Normal range: 6.0 7.9%. b G, glyburide; M, metformin.

glyburide alone, whereas four were treated with a combination of glyburide and metformin (Table 1). Standard clinical and laboratory examinations showed no evidence of diabetic complications, cardiac, pulmonary, hepatic, or thyroid disease. Diabetes duration ranged from 2 to 19 yr. All subjects were previously accustomed to mild exercise but none engaged in a regular exercise program for 3 months before entering the study. They were instructed not to change their usual diet during the protocol. Measurement of maximal oxygen uptake. Peak O2peak) was determined on an ergocycle oxygen uptake (V beginning with a 5-min warm-up at 50 W, followed by progressive increases of 25 W every 3 min to the point of exhaustion, as described previously (20). Exercise protocol. All subjects were asked to abstain from exercise for 48 h and alcohol and caffeine for 24 h, respectively, before each exercise session, which consisted in exercising on a cycle ergometer (Monark 818, Stockholm, Sweden) for 60 min at a workload corresponding to O2peak. The prescribed workload was 60% of individual V O2peak test. established from the data obtained from the V Exercise was monitored using heart rate, power output, and oxygen consumption measured with an open circuit indirect calorimetry system (Energy Expenditure Unit, Model 2900, SensorMedics, Anaheim, CA). The brake force was period O2peak. Each subject ically altered to maintain target %V performed the exercise protocol in a randomized order at a 7-d interval, either in the fasted or in the fed state. An exercise physiologist directly supervised each exercise session. Preparation and sample collection. After an overnight fast, the subjects reported at the Diabetes Research Unit at Laval University Medical Center at 8:00 a.m. Subjects were then randomly assigned to exercise either in the fasted state or 2 h after a 395-kcal standardized breakfast (49% carbohydrate, 34% fat, 17% protein). The breakfast was solid and consumed within 20 min. No medication was taken the morning of the exercise sessions in both conditions. A 20-gauge polyethylene catheter was inserted into the left forearm vein for blood sampling. To ensure steady state, subjects remained supine for 20 min before baseline sampling. Between sampling, the left forearm vein was kept patent with a slow, continuous infusion of 0.9% saline. 1260
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Samples were kept on ice, centrifuged immediately after each experiment and stored at 20C for subsequent analysis. Plasma glucose (22), insulin (4), free fatty acids (FFA) (18), epinephrine and norepinephrine (3), glucagon, and C-peptide were assayed. Glucagon concentration was assessed using the 30K antibody of Unger (29) and precipitation with polyethylene glycol (4). C-peptide was measured with the M-1221 antiserum (Novo Industry, Bagsvaerd, Denmark) and polyethylene glycol precipitation (22). A blood sample was taken at the time of the first test for determination of glycated hemoglobin by using the method of Trivelli et al. (28). Blood samples were obtained at rest, at 15-min intervals during exercise, and at 15 and 30 min during the recovery period. Samples at time 15 min were drawn when the subjects were supine, whereas samples at time 0 min were drawn when subjects were sitting on bicycle before the exercise protocol per se. Indirect calorimetry. Throughout each exercise experiment, indirect calorimetric measurements were performed to determine whole body substrate oxidation. For each 5-min measurement, the first 2 min were used for adaptation to the nose clip and the mouth piece, and during the subsequent 3-min expiratory gas collection were used for the O2) and carbon determination of oxygen consumption (V CO2), which corresponded to the acdioxide production (V tual mean of nine 20-s collection measurements (Energy Expenditure Unit, Model 2900, SensorMedics). The respiratory exchange ratio (RER) was then calculated by dividing CO2 by V O2 and the oxidation rates of carbohydrates V (CHO) and lipids were estimated according to the table of Lusk (14). Statistical analysis. Results are expressed as mean SE unless otherwise designated. All statistical tests were two-sided with a significance level of 0.05. Time was considered to be a class variable for all analyses. For each outcome variable, mixed models were fit assuming a timeby-group interaction. Group comparisons were conducted by testing the contrast between groups for times 15 through 60 min. Adjustments for group differences at baseline were computed by subtracting the baseline value across time. For each outcome and group combination, a mixed model was fit with time as the predictor. The comparisons of interest were baseline (0 min) versus times 60, 75, and 90 min. Assuming time was a significant predictor, Dunnetts multiple comparisons procedure was used to adjust the corresponding P-values. All analyses were conducted using Version 8 of SASs mixed procedure (SAS Institute, Cary, NC).

RESULTS
Mean peak oxygen uptake was 34.2 4.6 mLkg1min1, and a similar percentage of peak oxygen uptake was attained during the two exercise sessions (55.5 3.6 vs 56.0 3.1%, fasted vs fed state, respectively). The 60-min exercise session was performed at an average power output of 96 13 W (range: 80 120 W). Plasma glucose concentrations during the preexercise (rest), exercise, and postexercise (recovery) periods are prehttp://www.acsm-msse.org

sented in Figure 1. There was a highly statistically significance difference between both conditions (fasted vs fed) in terms of glucose response to exercise (P 0.001) even when adjusted for baseline values (P 0.001). Plasma glucose levels were slightly but not significantly higher at the beginning of exercise performed in the fed state compared with the fasted state (12.4 1.3 vs 11.1 1.1 mmolL1; P 0.06). After 60 min of exercise carried out in the fasted state, there was a significant (P 0.003) fall in plasma glucose compared with baseline (0 min). However, during the recovery period (75 min), plasma glucose concentrations returned to levels, which were not different from preexercise (P 0.34). In contrast, in the fed state, plasma glucose concentrations decreased earlier during exercise and remained significantly lower for the rest of the exercise session and during the recovery period (P 0.001). In subjects in the fed state, the mean decrease in plasma glucose concentration was 4.8 1.9 mmolL1 (60 14% of baseline) after the 60-min exercise session. On the other hand, mean plasma glucose concentrations decreased considerably less (1.0 0.8 mmolL1) in subjects in the fasted state (91 6% of baseline). Hence, exercise carried out in the fed state improved much more and for a longer period of time the plasma glucose concentration than when performed in the fasted state. FFA concentrations are shown in Figure 2. There was different response between both conditions (fasted vs fed, P 0.0045). In the fasted state, FFA were significantly higher at rest and at the beginning of exercise compared to the fed state (P 0.05). In the fasted state, although not statistically significant, there was an increase in FFA levels during exercise (P 0.078). However, during recovery, FFA levels increased greatly compared with baseline (P 0.001). In the fed state, there was a significant increase in FFA levels after 60 min of exercise (P 0.002) and into the recovery period (75 and 90 min, both P 0.001). Plasma insulin and C-peptide concentrations are shown in Figure 3. There was a highly statistically significance dif-

FIGURE 2Plasma free fatty acids concentrations in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. * P < 0.05 fasted vs fed state; ** P < 0.01 baseline vs after 60 min of exercise; *** P < 0.001 baseline vs recovery period (75 and 90 min).

ference between both conditions (fasted vs fed) in terms of insulin response to exercise (P 0.001) even when adjusted for baseline values (P 0.001). Insulin levels were higher at the beginning of the exercise bout performed in the fed state (177 26 vs 108 19 pmolL1; P 0.05) and

FIGURE 1Plasma glucose concentrations in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. * P < 0.01 baseline vs after 60 min of exercise; ** P < 0.001 baseline vs after 60 min of exercise. EXERCISE IN SUBJECTS WITH TYPE 2 DIABETES

FIGURE 3Plasma insulin and C-peptide concentrations in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. * P < 0.05 fasted vs fed state; ** P < 0.01 baseline vs recovery period (75 and 90 min); *** P < 0.001 baseline vs after 60 min of exercise. Medicine & Science in Sports & Exercise

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FIGURE 4 Plasma glucagon concentrations in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. * P < 0.05 baseline vs after 60 min of exercise.

during exercise. There was no significant decrease in plasma insulin levels during exercise in the fasted state (P 0.139) and insulin levels were comparable to baseline after 30 min into the recovery period (P 0.139). In the fed state, plasma insulin concentrations declined earlier, i.e., at 30 min of exercise, and continued to decrease at 45 min and at 60 min (P 0.001) compared to baseline. Plasma insulin levels increased during the recovery compared to the end of exercise but still remained lower than the baseline values (P 0.005 at 90 min). As expected, C-peptide curves somewhat reflected the insulin curves. In the fasted state, there was no significant change in C-peptide levels during exercise and recovery period compared to baseline. An increase in C-peptide was observed during the recovery period compared to the end of exercise but this was not statistically different from baseline (P 0.978). In the fed state, C-peptide decreased during exercise compared with baseline (P 0.001) and increased significantly 30 min after the end of exercise compared to end of exercise (P 0.015). Plasma glucagon levels are depicted in Figure 4. There was no difference in response between both conditions (fasted vs fed, P 0.68); thus, a similar increase from baseline into exercise (P 0.03) was observed in both experiments. During the recovery period, glucagon concentrations continued to increase in the fasted state compared with baseline. Glucagon levels were higher during recovery compared with baseline both in the fed state (90 min; P 0.007) and in the fasted state (90 min; P 0.032). Epinephrine and norepinephrine are shown in Figure 5. There was no difference in response between both conditions (fasted vs fed) for epinephrine (P 0.63) and norepinephrine (P 0.19). Therefore, epinephrine and the norepinephrine curves changed similarly in both conditions. Thus, in the fasted and the fed state, epinephrine increased from baseline to 60 min (P 0.001). In the recovery period, epinephrine levels returned to baseline in both conditions. Norepinephrine levels increased significantly in the fasted 1262
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FIGURE 5Plasma epinephrine and norepinephrine concentrations in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. ** P < 0.01 baseline vs after 60 min of exercise.

state (P 0.001) and in the fed state (P 0.001). However, norepinephrine levels returned to baseline 30 min into recovery in both conditions. Of note, the slight increments in epinephrine and norepinephrine levels between time 15 min and time 0 min were probably induced by the change from the supine position while in bed to the upright position on the ergocycle. Respiratory exchange ratio data are shown in Figure 6. There was no difference in response between both conditions (fasted vs fed, P 0.72). Oxygen consumption and carbon dioxide production varied similarly in both experiments. Consequently, there was no statistical difference in the respiratory exchange ratio in both situations. As expected during exercise, total body substrate oxidation shifted, as illustrated by the decrease in the respiratory exchange ratio, from primarily glucose to more fat utilization in both conditions.

DISCUSSION
The objective of this study was to investigate the impact of the dietary status on the lowering effect of one bout of acute exercise on plasma glucose levels and elucidate possible regulatory mechanisms involved in sedentary men with type 2 diabetes treated with oral agents. The present
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FIGURE 6 Respiratory exchange ratio in 10 subjects with type 2 diabetes in the fasted state (open symbols) and in the fed state (closed symbols) measured at 15-min intervals starting 15 min before exercise and up to 30 min after a 60-min exercise period. *** P < 0.001 baseline vs after 60 min of exercise.

study compared, in random order, the same subjects on two occasions: 1) in the postprandial state and 2) in the fasted state. The results demonstrated that although exercise began with moderately elevated plasma glucose levels in both situations, the plasma glucose decline was rather small (~9%) when subjects exercised while fasted, whereas an important decrease (~40%) occurred when exercise was performed 2 h after breakfast. Of importance, blood glucose levels after exercise remained lower in the fed state compare to the fasting state. In nondiabetic subjects, a decrease in plasma insulin concentrations is usually observed during exercise of mild to moderate intensity, permitting the liver to increase its glucose production to maintain plasma glucose concentration within normal limits. The decrease in insulin level is explained, at least in part, by an alpha-adrenergic nervous inhibition of the pancreatic beta cells (6). The physiological insulin response to exercise, namely a fall in the insulin levels, has also been observed in subjects with type 2 diabetes (5,12,13), but this decrease in the insulin levels has been inconsistent (2,79,17,19,23). Absence of a decrease in insulin levels might explain that during mild to moderate exercise, glucose production may have been partially inhibited and peripheral glucose uptake enhanced compared with what is generally observed in nondiabetic subjects. The imbalance results in a decrease in plasma glucose concentration (7,17,25). As shown in previous studies, the increased peripheral glucose utilization during exercise support the concept that contraction-mediated glucose transport and oxidation is probably not severely impaired in exercising subjects with type 2 diabetes despite insulin resistance that characterizes glucose homeostasis during resting conditions (2,12,15). This condition coupled with a diminished increase in glucose production secondary to higher circulating insulin levels increases the imbalance between glucose production and utilization (13,17). Despite the fact that hepatic glucose production was not assessed in the present study, the higher plasma insulin levels during exercise in the
EXERCISE IN SUBJECTS WITH TYPE 2 DIABETES

fed state have probably partially blunted hepatic glucose production, resulting in a glucose production/utilization imbalance and in a greater decrease in plasma glucose levels in subjects in the fed state when compared with the fasted state (27). The same phenomenon has been recently demonstrated in fasted subjects with type 2 diabetes where hepatic glucose production was partially inhibited during exercise by glibenclamide-induced increment in insulin levels (13). Of interest, Hu binger et al. (7) showed a comparable decrease in blood glucose levels (1.2 vs 1.5 mmolL1, respectively) in subjects with type 2 diabetes with and without basal hyperinsulinemia values when subjects exercised in the fasted state. Insulin levels did not decrease during exercise and blood glucose decline was comparable between the two groups, i.e., with and without basal hyperinsulinemia (7). Although the baseline insulin levels characterize different insulin resistant states, this suggests that glucose production is not tightly regulated by the absolute concentrations of insulin but rather by the changes in insulin concentrations during exercise as in the present study. Accordingly, it has been shown that hepatic glucose production did not decrease in the fasted state when insulin levels remain stable during exercise (11,15). In the present study, the greater plasma glucose decrease during exercise carried out in the fed state cannot be ascribed to higher baseline glucose levels and different exercise inten O2peak, power output, epinephrine, sity because percentage V and norepinephrine levels were similar between the two experimental conditions. There was no difference in respiratory exchange ratio in both experiments, suggesting that the same percentages of CHO and lipid were utilized during the two exercise sessions. Thus, the starting differences in blood glucose levels between the two experiments had no significant impact on the percentage of substrate utilization. This is in agreement with results reported by Kang et al. (11), who showed that CHO and fat oxidation were comparable between subjects with type 2 diabetes and nondiabetic subjects despite higher blood glucose levels in the former. Subjects included in this study were treated with different drug regimens. The patients physician used these regimens in order to enhance metabolic control. Of importance, no subjects used exogenous insulin while participating in the study. Different drug regimens between subjects may be a limitation to our study but each individual consists of his own control since all subjects performed exercise, in a random order, in the two nutritional state (fed and fasted). Therefore, this represents a strength of our study and is somewhat representative of a real life situation in which health care professionals are confronted everyday. It is important to remember that there is little published data regarding this important clinical issue in subjects with type 2 diabetes treated with oral hypoglycemic agents. Moreover, in order to motivate subjects with type 2 diabetes to be physically active, a 40% decrease in blood glucose levels after 1 h of aerobic exercise is certainly important. Although these results need to be confirmed by other study, this study provides information about the safety of aerobic exercise in the fasted state in subjects with type 2 diabetes. Moreover,
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this is accordance with a recent publication that has reported, compiling over 1000 aerobic exercise sessions, similar glycemic response in subjects with type 2 diabetes (21). In conclusion, results of the present study suggest that breakfast-induced relative hyperinsulinemia potentiates the blood glucose lowering effect of a 60-min aerobic exercise session. Furthermore, these data show that exercise performed in the fasted state has little impact on blood glucose in subjects with type 2 diabetes treated with oral hypoglycemic agents. REFERENCES
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This work was supported in part by a grant from Health and Welfare Canada. Paul Poirier and Luc Grondin were the recipients from the Fonds de la Recherche en Sante du Que bec (FRSQ). The authors thank S. Desjardins, R. Duchesne, M. Fillion, M. Martin, Y. Montreuil, and J. Renaud for their support and excellent technical assistance. We also express our gratitude to Tere Marcell and Dr. Troy Donahoo in the preparation of the manuscript. Address for correspondence: Paul Poirier, M.D., Associate Professor of Pharmacy, Quebec Heart Institute/Laval Hospital, 2725 Chemin Sainte-Foy, Sainte-Foy, Que bec, Canada, G1V 4G5; E-mail: Paul.Poirier@crhl.ulaval.ca.

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