Clinical Care/Education/Nutrition

O R I G I N A L A R T I C L E

Effects of Exercise Training on Oxygen Uptake Kinetic Responses in Women With Type 2 Diabetes
SUZANNE L. BRANDENBURG, MD JANE E.B. REUSCH, MD TIMOTHY A. BAUER, MS BARRETT W. JEFFERS, MS WILLIAM R. HIATT, MD JUDITH G. REGENSTEINER, PHD

OBJECTIVE Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. RESEARCH DESIGN AND METHODS A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. RESULTS On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. CONCLUSIONS Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes beneted more from an exercise training program than did control subjects. These ndings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical signicance of exercise for people with type 2 diabetes is clear. Diabetes Care 22:16401646, 1999

ntrained people with type 2 diabetes have been shown to have a reduced VO2max compared with nondiabetic people, even in the absence of cardiovas-

cular disease (1). In addition, it has been reported that VO2 kinetics are impaired in women with type 2 diabetes (2). The causes of the exercise impairment are

From the Department of Medicine, Divisions of General Internal Medicine (S.L.B., T.A.B, J.G.R.), Endocrinology (J.E.B.R.), Renal Diseases and Hypertension (B.W.J.), Geriatrics (W.R.H), and Section of Vascular Medicine (W.R.H., J.G.R.), University of Colorado Health Sciences Center, Denver, Colorado. Address correspondence and reprint requests to Suzanne L. Brandenburg, MD, University of Colorado Health Sciences Center, Box B-212, 4200 E. Ninth Ave., Denver, CO 80262. E-mail: suzanne.brandenburg@ uchsc.edu. Received for publication 2 November 1998 and accepted in revised form 9 June 1999. Abbreviations: ANOVA, analysis of variance; ECG, electrocardiogram; FFM, fat-free mass; FSH, folliclestimulating hormone; LOPAR, Low Level Physical Activity Recall Questionnaire; LV, left ventricular; MET, metabolic equivalent; RER, respiratory exchange ratio. A table elsewhere in this issue shows conventional and Systme International (SI) units and conversion factors for many substances.

unknown, and thus the physiological and clinical signicance of these ndings warrants further study. VO2max is the classic measure of overall cardiorespiratory tness and describes the highest oxygen uptake obtainable by an individual for a given form of exercise despite increased effort and increased work rate. In contrast, VO2 kinetics measure the efficiency of the cardiorespiratory response to an imposed work demand. Specically, VO2 kinetics describe the rate at which the cardiorespiratory system is able to deliver oxygen to skeletal muscle and the rate at which oxygen is consumed by skeletal muscle at the beginning of exercise. VO2 kinetics are measured during repeated submaximal constant-load exercise bouts. The rise to steady state is described by a time constant, . is determined by tting an exponential curve to VO2 kinetics data (Fig. 1). A slowed is a marker of impaired oxygen delivery and/or extraction. It takes longer for an individual with a slowed to reach steady state. Although the exercise impairments in diabetes have been described, the effects of exercise training on VO2 kinetics in untrained women with diabetes and the baseline impairments discussed above are not well described. Although many studies have examined the metabolic effects of exercise training in subjects with diabetes (35), fewer investigators have studied the effects of exercise training on cardiovascular parameters such as VO2max in subjects with diabetes (3,4). In addition, the impact of exercise training on VO2 kinetics in subjects with type 2 diabetes has not been well characterized. It appears that the exercise effort expended by people with diabetes may be greater for a given workload (even at very low workloads) than for nondiabetic patients (2). Studying the cardiovascular response to exercise training in diabetes may provide insight into treatment recommendations, such as optimal exercise prescriptions, for this common disease with a signicantly increased risk of cardiovascular morbidity and mortality. We hypothesized that VO2max and VO2 kinetics would improve with exercise training in women with type 2 diabetes. To

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exercise performance (10). Distal symmetrical neuropathy was determined by evaluation of symptoms (numbness and/or paresthesia) and signs (elicited by vibration, pinprick, or ankle reexes). Subjects with proteinuria 200 mg/dl or a creatinine level 2 mg/dl, suggestive of renal disease, were excluded because renal disease may alter exercise performance (11). Echocardiograms were performed to rule out left ventricular (LV) dysfunction. Subjects with global or regional contractile abnormalities determined by resting echocardiogram were excluded (12). Subjects also were excluded if they had evidence of ischemic heart disease by history or by resting or exercise electrocardiogram (ECG) ( 1 mm at or downsloping ST segment depression). People with Figure 1Representative data showing the rate of rise of VO2 ( ) for a 30-W work rate transition from angina or any other cardiac or pulmonary rest to exercise. This gure contains time-aligned averaged data for a lean control subject (Normal) and symptoms potentially limiting exercise a subject with diabetes (DM). The subject with diabetes has a slower ; 72 vs. 40 s. TAU, the monoex - performance were excluded as well. Presponential time constant of VO2. ence of systolic blood pressure 130 mmHg at rest or 250 mmHg with exercise and presence of diastolic pressure evaluate the effects of exercise training, we type 2 diabetes were included in the study if 90 mmHg at rest or 105 mmHg with measured VO2max and VO2 kinetics before their diabetes was treated by diet or oral exercise were also grounds for exclusion. and after 3 months of supervised exercise agents but not insulin, because the latter Individuals with autonomic insufficiency training in women with type 2 diabetes. subjects tend to have more advanced dis- were excluded because of possible effects ease. Subjects with type 2 diabetes were tak- on exercise performance (13). RESEARCH DESIGN AND ing no other medicines. Duration of diabetes Control subjects were screened identiMETHODS (from diagnosis) was noted. Women with cally to subjects with type 2 diabetes. These type 2 diabetes were accepted for study only subjects were taking no medications, had a Subjects if they had total HbA1c levels 9% (moder- normal HbA1c, and had no active medical A total of 8 moderately overweight, seden- ately well controlled) on therapy. Current problems. Overweight control subjects and tary, premenopausal women with type 2 smokers were excluded. subjects with diabetes were at 110140% diabetes and no complications or comorbid Premenopausal women between the of ideal body weight. Informed consent conditions, 9 overweight but otherwise ages of 30 and 50 were chosen to limit the was obtained from all subjects before the healthy women of similar age and activity age range in the study, because exercise per- study. The study protocol was approved by levels, and 10 lean healthy women of simi- formance is affected by age. Premenopausal institutional review. lar age and activity levels were studied. The status was evaluated in all women by hislean group was included to control for the tory of regular menstrual cycles or by Study protocol potential effect of obesity (which is common measurement of serum follicle-stimulating Before the exercise training program, subin subjects with type 2 diabetes). Women hormone (FSH) levels. For the purpose of jects were evaluated over the course of six were enrolled because preliminary data sug- uniformity and to rule out effects of widely visits on separate days as described previgest that type 2 diabetes might negatively differing levels of female hormones on exer- ously (2). Patients made an initial visit to affect exercise performance to a greater cise, as well as to minimize potential effects the General Clinical Research Center for a extent in women than in men ( J.G.R., of progesterone on ventilation, subjects history and physical exam, blood work, unpublished observations). No subject with were tested in the midfollicular phase of the and administration of questionnaires. A type 2 diabetes or overweight control subject menstrual cycle, except for the two women resting ECG was obtained and a familiarwas 140% of ideal body weight. Sedentary (one woman with diabetes and one lean ization bicycle test performed. During the behavior was dened as not participating in control subject) who had undergone partial two subsequent visits, a diet interview was a regular exercise program ( 1 bout of exer- hysterectomy (8,9). conducted and underwater weighing and cise per week) and by the Low Level PhysiHistory, physical examination, and lab- echocardiogram were performed. From cal Activity Recall Questionnaire (LOPAR) to oratory testing conrmed the absence of 3 days before the fourth visit until the comensure that physical activity levels were sim- comorbid conditions and diabetic compli- pletion of the sixth visit (to control for the ilar between groups (6,7). Presence of type 2 cations. Individuals with type 2 diabetes effects of diet on exercise performance), diabetes was documented by chart review to who had clinically signicant distal sym- patients received all meals from the General conrm the diagnosis as well as the type of metrical neuropathy were excluded from Clinical Research Center. On visit four, subtreatment for diabetes. Individuals with further study because of possible effects on jects performed a graded bicycle exercise
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test to determine the lactate threshold and VO2max. On visits ve and six, patients performed constant-load exercise testing at three workloads to obtain steady-state VO2 kinetic measurements. Subjects performed three bouts of exercise at 20 W three bouts , at 30 W, and two bouts at 80 W over the 2-day period. Performance of multiple bouts enabled averaging of VO2 kinetic data within a workload to reduce variability of results. Subjects then participated in a supervised exercise training program three times per week for 3 months. At the end of the training program, underwater weighing and visits four through six were repeated to obtain postexercise training data. Graded maximal exercise test A graded bicycle protocol to exhaustion was used to determine VO2max and lactate threshold. Testing began with the subject seated on the cycle ergometer (Cardio-2, Medical Graphics, Minneapolis, MN) breathing into the mouthpiece of the metabolic cart (CPX-D, Medical Graphics). To eliminate the need to overcome inertia of the ergometer ywheel at the start of exercise, the ywheel was driven at 60 rpm by an electric motor during rest and deactivated at the start of exercise. During exercise, the work rate was increased in 10 W/min increments, and the incremental portion of the test lasted 1215 min. Maximal VO2 was dened as a VO2 that increased 1 ml kg 1 min 1 for 30 s despite an increment in workload (14). Oxygen consumption and carbon dioxide production (VCO2) were measured breath-by-breath, at rest, and during exercise. Peak VO2 data were averaged over 30-s intervals. Arm blood pressure (by auscultation) and heart rate (by 12-lead ECG) were recorded every minute during exercise. Cardiac status was monitored by a continuous 12-lead ECG. The respiratory exchange ratio (RER) was calculated as VCO2/VO2. Venous blood was drawn every minute during the rst VO2max test to enable determination of the lactate threshold. The lactate threshold was dened as the point during exercise at which blood lactate concentration began to rise progressively. Constant-load exercise tests Each test began with 3 min of resting baseline measurements. After this period, the preselected workload (20, 30, or 80 W) was imposed with the motor-driven ywheel as described above, and the subject maintained pedaling at 60 rpm for 7 min.
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This protocol allowed all subjects to reach steady-state VO2 at 20 and 30 W. The 80-W workload was above the lactate threshold by design to allow evaluation of a nonsteady-state workload. Kinetics measurements during exercise Using breath-by-breath techniques, we measured the kinetics of VO2 below and above the lactate threshold. The data were transferred to an ASCII le, ltered, and timealigned by seconds. The tests were averaged using a program developed and validated at our laboratory. To dampen noise and enhance resolution of the data, the data from repetitions within a workload were temporally aligned to a time at the start of exercise and superimposed to yield a single secondby-second averaged record of the tests for each subject at a given workload. The time constant and the actual change in VO2 from rest to steady-state VO2 were calculated using a statistical program, as previously described (15). This program was used to t a single exponential data curve from the onset of exercise to the end of the 6th min of steady-state exercise in 20 and 30 W transitions. Eighty-watt transitions were analyzed using a single exponential curve t from the onset of exercise to the end of the 3rd min of exercise in order to minimize the impact of a phase 3 drift in VO2. Exercise training program Each subject participated in a 3-month program of supervised exercise, three times per week, in the cardiovascular rehabilitation facility at the University of Colorado Health Sciences Center. Each session included a 5-min warm-up period, 50 min of moderate intensity exercise, and a 5-min cooldown period. The individually determined exercise prescriptions were based on the graded test at study entry. Each subject exercised on treadmills, rowing machines, and bicycle ergometers at a work intensity to keep heart rate at 7085% of maximum. Telemetry monitoring was performed weekly to ensure that subjects achieved target heart rates. Blood pressure was monitored before and after exercise. Specic methods Echocardiographic measurements. Twodimensional and Doppler echocardiography were performed (12) to exclude the presence of signicant valvular pathology, LV global dysfunction, and segmental wall motion abnormalities. Chamber sizes, LV

end-systolic and diastolic chamber dimensions and wall thickness, fractional shortening, and the area-length method for measurement of cardiac volume (to measure ejection fraction) were quantitated by standard techniques for all individuals. All echocardiograms were analyzed by a cardiologist skilled in these readings and blinded to the diagnostic status of the patients. Measurements of diastolic lling were obtained by Doppler assessment of mitral valve and pulmonary venous ow patterns. Body composition and hydrodensitometry. Hydrodensitometry measures were used to determine body composition and then to derive fat-free mass (FFM). Percent body fat was estimated from body density using the revised equation of Brozek et al. (16). Body fat distribution was determined using waistto-hip ratio, where the waist circumference was measured at one-half the distance from the xiphoid process to the navel and the hip circumference was measured at the level of the greater trochanter. Tests of autonomic insufficiency. We measured variation in R-R intervals with cycled breathing to screen for autonomic insufficiency (13,17). The measurements were obtained as the patient, while resting supine, breathed ve times per minute, coordinating breaths with a visual electronic signal. The duration of testing was 5 min. To obtain data, maximum inspiratory heart rate was subtracted from the minimum expiratory heart rate. Variations of 30 bpm were considered normal, and values 20 bpm were considered abnormal (13,17). In addition, testing for autonomic insufficiency included measuring lying and standing heart rates and blood pressures (the test was positive if there was a 20-mm fall in upright systolic blood pressure without a change in heart rate). Three subjects were excluded from study because of autonomic insufficiency during baseline testing. Blood collection and preparation. Blood was drawn at baseline for measurements of glucose, insulin, plasma FSH levels, and HbA1c. Blood lactate concentrations were measured every minute during the graded exercise test to determine the lactate threshold in all subjects. In addition, lactate was measured at rest and at peak exercise during the constant-load tests. For the measurement of blood lactate concentration, a 20gauge intravenous catheter was placed in a forearm vein, with a three-way stopcock to facilitate blood drawing, and patency was maintained with heparinized saline. For

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Table 1Subject characteristics Lean control subjects n Age (years) Fasting insulin (mU/ml) Fasting glucose (mmol/l) HbA1c (%) Disease duration (years) Weight (kg) Before After BMI (kg/m2) Before After FFM (kg) Before After LOPAR (MET h/week) Before After 10 37 6 9.5 3.9 4.89 0.43 6.3 2.8 63 11 64 11 23.5 2.3 23.6 2.7 41 7 41 6 223 64 190 46 Overweight control subjects 9 37 6 12.4 7.9 5.12 0.67 5.4 0.5 80 10 81 10 30.3 3.5 30.9 3.9 48 5 49 5 218 67 238 53 Type 2 diabetic subjects 8 43 7 28.5 18.5* 11.90 3.80* 9.5 1.9* 32 80 18 78 15 31.8 6.5 30.5 4.9 47 5 47 6 172 46 223 65

increase their LOPAR values, although there was a trend in this direction (P = 0.06). The lack of signicance may be due in part to the fact that exit LOPAR data were obtained in only 4 of the 8 subjects with diabetes, 7 of 9 overweight subjects, and 9 of 10 lean control subjects. Exercise training data There was no signicant difference in number of sessions or duration of training between groups. Exercise training data were incomplete for two subjects with diabetes, one lean control subject, and two overweight control subjects. Based on actual start and nish dates, the subjects for whom data were incomplete participated in at least 36 exercise sessions. Specically, the mean number of sessions was determined to be 35.5, 35.2, and 35.3 (NS) for the diabetic, lean, and overweight groups, respectively. The mean durations of the training period were 101.5, 114.1, and 104.1 days (NS), respectively. Pre- and postexercise VO2max data On entry, women with type 2 diabetes had the lowest VO2max of the three groups (Table 2). The RER and maximum heart rate did not differ between groups. The RER values were 1.10, suggesting a maximal effort during VO2max testing. After 3 months of exercise training, the group with type 2 diabetes and the overweight control group demonstrated a signicant improvement in VO2max. Of note, the subjects with diabetes showed the greatest absolute and percent increase in VO2max. They improved their VO 2max by 28%, compared with 5 and 8% for the lean (not signicant) and overweight (signicant) control subjects, respectively (P 0.05). The maximum heart rate values did not change after exercise training. There were no signicant differences between RER (Table 2), lactate concentration, and steady-state VO2 (data not shown) before or after training at any workload. There was a not statistically signicant trend toward decreased RER at low workloads (20 and 30 W) in the subjects with diabetes after exercise training. Pre- and postexercise kinetics data At entry, VO2 kinetics were slowest in subjects with type 2 diabetes (Table 3). After training, the VO2 kinetics improved in subjects with type 2 diabetes by 39 and 22% at 20 and 30 W, respectively (both P 0.05). At 80 W, there was a tendency toward faster
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Data are means SD. *P 0.05 for difference between the group with diabetes and the other two groups; P 0.05 for difference between the lean control group and the other two groups.

each sample, 50 l of blood was withdrawn, immediately deproteinized in 3% perchloric acid, and stored at room temperature. Assay methods. Lactate concentration was assayed by a lactate dehydrogenase method (18). HbA1c was measured by glyc-affin GHb columns (Isolab, Akron, OH). Serum insulin concentrations were measured by radioimmunoassay (19,20). Serum glucose concentrations were measured by the glucose oxidase method (21). Plasma FSH level was measured by a chemiluminescence assay (22). LOPAR. LOPAR, a validated questionnaire, estimates habitual physical activity (6,7). The subjects were asked in a series of questions to categorize their time (reporting specic activities) into work, leisure, and housework categories for the previous week. Questionnaire results were expressed in metabolic equivalents (METs) where one MET equals resting VO2 (3.5 ml kg 1 min 1). Scores are given in MET hours per week. This questionnaire quantied the activity level of all participants before the exercise training program and ensured that all subjects were sedentary. Statistical analysis. A between-subjects analysis of variance (ANOVA) was used to compare the three groups at baseline. When differences were found in these analyses, post hoc analyses were performed. Repeated-measures ANOVA test-

ing was used to measure changes over time (before and after exercise training) between and within groups. Where data were nonparametric, the Kruskal-Wallis one-way ANOVA test was used to make betweengroup comparisons. RESULTS Demographic data At entry, the subjects in the three groups were of similar age and physical activity level as measured by the LOPAR (Table 1). LOPAR values in this range, 170240 MET hours per week, indicate very sedentary lifestyles. The lean control subjects had signicantly lower body weight, BMI, and FFM than the other two groups. The two control groups had similar fasting insulin, fasting glucose, and HbA1c. The subjects with diabetes had higher values than did the control subjects for these three tests, which is consistent with the diagnosis of diabetes. Among the subjects with diabetes, six were treated with glyburide, two were treated with glipizide, and two were controlling their diabetes by diet alone. There were no medication changes during the study. The overweight control subjects and those with diabetes maintained similar weights, BMIs, and FFMs. Despite participating in a 3-month exercise program of moderate intensity, subjects did not signicantly

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Table 2Graded exercise testing results before and after exercise training Lean control subjects VO2max (ml kg1 min1) Before After RER Before After Heart rate (bpm) Before After 25.1 4.7 26.0 6.0 1.13 0.08 1.12 0.13 174 15 167 12 Overweight control subjects 21.8 2.9 23.0 1.8 1.12 0.06 1.15 0.05 167 12 164 10 Type 2 diabetic subjects 17.7 4.0* 22.4 5.5* 1.16 0.13 1.12 0.03 166 11 164 18

Data are means SD. *P 0.05 for difference between the group with diabetes and the other two groups; P 0.05 for difference between before and after exercise training.

VO2 kinetics in subjects with diabetes. After training, VO2 kinetics also improved by 30% in lean control subjects at the 30 W workload only (P 0.05). CONCLUSIONS In this study, women with type 2 diabetes beneted from an exercise training program of moderate intensity, as reected by improved VO2max and faster VO2 kinetics. This response occurred despite the nding that these women with mild diabetes had impaired maximal and submaximal cardiovascular responses to exercise at baseline. In addition, the group with diabetes, which began with the lowest VO2max and slowest kinetics, demonstrated a greater improvement after exercise training than did the lean or overweight control groups. The improved VO2max and VO2 kinetics in subjects with uncomplicated diabetes may reect improvements in both conditioning and other undetermined diseasespecic defects in oxygen delivery and/or utilization. The response to exercise training and the relationship between improvements in VO2max and VO2 kinetics has not been well characterized previously in premenopausal women. Although VO2max improved signicantly in two of the three groups after exercise training, there was an absolute as well as a proportionally greater improvement in the group with diabetes. In addition, VO2 kinetics improved only in the group with diabetes. The ndings are unlikely to be attributable to differences in baseline conditioning or age, because subjects in all groups were similar in terms of age and physical activity level. Controlling for weight by the inclusion of an overweight control group improved the likelihood that
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obesity alone could not affect the results. The exercise training differences between the overweight and lean control groups were smaller than the differences between the overweight control and diabetes groups. Thus diabetes, and not obesity, appears to be the determinant of the signicant ndings. Oxygen uptake kinetics are inuenced by a combination of cardiovascular and peripheral factors. Studies are currently underway to determine whether cardiac output, arteriovenous oxygen difference, aspects of skeletal muscle metabolism, or a

combination of factors plays a role in the exercise abnormalities of women with otherwise uncomplicated diabetes. In contrast to its physiological signicance, the clinical signicance of VO2 kinetics has not been well evaluated. If even the ability to begin exercise and to exercise at low workloads is impaired, the performance of exercise may be perceived as more difficult. Therefore, improving the initial responses to exercise may help overcome a disincentive to participate in exercise. Most individuals do not exercise at maximal levels, and people with type 2 diabetes are reported to be more sedentary then the general population (6). In this sedentary population, a moderate-intensity exercise program may improve the ability to begin exercising at lower as well as higher levels of exercise intensity. In support of this concept, there was a trend toward decreased RER at 20- and 30-W workloads. This nding suggests that the effort required to exercise at low levels was decreased. In a training study, it is important to determine whether or not the differences between groups could be due to differences in intensity of training. The exercise program was well supervised, and each subject completed 35 sessions, so it is unlikely that one group received more or less training or that signicant variability of

Table 3Oxygen uptake and heart rate kinetics during constant-load submaximal exercise before and after exercise training Lean control subjects 21.4 8.9 18.2 9.5 0.80 0.04 0.83 0.08 28.8 5.3 24.3 6.8 0.85 0.05 0.86 0.09 42.8 7.5 39.5 6.6 1.03 0.08 1.01 0.10 Overweight control subjects 17.3 10.4 17.3 13.3 0.81 0.03 0.88 0.93 27.7 9.9 18.9 21.1 0.85 0.04 0.92 0.11 41.3 9.2 47.9 30.5 0.99 0.06 1.01 0.08 Type 2 diabetic subjects 45.9 25.8* 28.6 8.9 0.88 0.12 0.83 0.08 47.7 4.7* 37.4 15.0 0.91 0.12 0.84 0.05 58.8 22.1* 57.1 21.0 1.05 0.12 1.00 0.07

VO2 kinetics 20-W (s) Before After 20-W RER Before After 30-W (s) Before After 30-W RER Before After 80-W (s) Before After 80-W RER Before After

Data are means SD. *P 0.05 for difference between the group with type 2 diabetes and the other two groups; P 0.05 for difference between before and after exercise training.

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exercise intensity occurred. In theory, the subjects with diabetes may have been more motivated to benet from exercise training than the control groups because of their interest in minimizing the long-term effects of this chronic disease. However, objective measures of the intensity and duration of the exercise training program and observations during exercise sessions do not support this explanation. All subjects exercised at 7085% of their maximum heart rate. In the current study, the improvement in the group with diabetes may be the most dramatic, in part because these subjects began with the lowest VO2max. However, the dramatic improvement in VO2max and the consistent improvement in VO2 kinetics may also indicate that women with mild diabetes and a baseline defect in exercise performance respond sooner and/or better to a moderate-intensity exercise program than do women without diabetes. After training, subjects did not signicantly increase their activity levels as measured by the LOPAR, although there was a trend in this direction. Perhaps this trend would become signicant with a longer duration of exercise training or by studying more subjects. Other investigators also have reported improved VO2max in subjects with diabetes after exercise training (3,5). However, few studies have specifically examined the effects of exercise training in women. Verity and Ismail (5) studied the effects of a 4-month training program on postmenopausal women with relatively mild type 2 diabetes. After training, the women had improved VO2max and decreased total cholesterol concentrations. Other studies have included some women but have not separately analyzed data based on sex. We chose to study women because preliminary data (J.G.R., unpublished observations) suggested that women with diabetes had greater exercise impairments than men with diabetes. One unexpected observation was the lack of consistent improvement in VO2 kinetics in our control groups. The results of previous studies are variable. It has been documented that exercise training improves VO2 kinetics in healthy young men (2326). Previous studies have also shown improvement in VO2 kinetics after an exercise training program in people with other types of chronic disease (27,28). As suggested earlier, women with diabetes may respond better than women without diabetes to shorter and/or lower-intensity training programs.

Perhaps the exercise training program in the present study was not of adequate intensity or duration to impact VO2 kinetics in the subjects without diabetes. In healthy subjects, most investigators have used highintensity exercise programs to demonstrate improved VO2 kinetics (2325). Berry and Moritani (26) found that higher-intensity exercise training increased VO2 kinetics more than moderate-intensity exercise training in healthy young men. The idea that a greater intensity of training may have been required to improve the oxygen uptake kinetics is especially likely because, although the control women were sedentary, their oxygen uptake kinetics were fairly normal at baseline. Regular exercise has long been a cornerstone of treatment for diabetes, and the present study suggests an additional benet from this intervention. Previous studies have shown that exercise training improves exercise capacity (3) and glycemic control (35). In the present study, we found that exercise training improves exercise capacity and exercise performance. In addition, the ability to exercise at low workloads may be improved by an exercise training program, as suggested by the VO2 kinetics data. Despite an impaired ability to perform exercise, women with diabetes responded better than control subjects to exercise training. Although the mechanism for the defect(s) in VO2max and VO2 kinetics among women with type 2 diabetes is still under investigation, it is clear that this population benets from exercise training.
Acknowledgments This study was funded by a clinical research award from the American Diabetes Association to J.G.R. and by the General Clinical Research Center RR501RR00051. The authors thank Susan Smith, Andria Vogelsong, Linda Cranford, Michelle Lemenager, and the participants, who gave generously of their time and effort. This study was submitted in abstract form to the American Federation for Clinical Research. References 1. Allenberg K, Johansen K, Saltin B: Skeletal muscle adaptations to physical training in type II (non-insulin-dependent) diabetes mellitus. Acta Med Scand 223:365373, 1988 2. Regensteiner JG, Bauer TA, Reusch JEB, Brandenburg SL, Sippel JT, Vogelsong AM, Smith S, Wolfel EE, Eckel RH, Hiatt WR: Abnormal oxygen uptake kinetic responses in type 2 diabetes mellitus: evidence for an early defect. J Appl Physiol 85:310317, 1998

3. Saltin B, Lindgarde F Houston M, Horlin R, , Nygaard E, Gad P: Physical training and glucose tolerance in middle-aged men with chemical diabetes. Diabetes 28 (Suppl. 1):3032, 1979 4. Trovati M, Carta Q, Franco Cavalot SV, Banaudi C, Lucchina PG, Fiocchi F, Emanuelli G, Lenti G: Inuence of physical training on blood glucose control, glucose tolerance, insulin secretion, and insulin action in non-insulin-dependent diabetic patients. Diabetes Care 7:416420, 1984 5. Verity LS, Ismail AH: Effects of exercise on cardiovascular disease risk in women with NIDDM. Diabetes Res Clin Pract 6:2735, 1989 6. Regensteiner JG, Sippel J, McFarling ET, Wolfel EE, Hiatt WR: Effects of non-insulin dependent diabetes on maximal exercise performance. Med Sci Sports Exerc 27: 875 881, 1995 7. Regeinsteiner JG, Steiner JF, Hiatt WR: Exercise training improves functional status in patients with peripheral arterial disease. J Vasc Surg 23:104115, 1996 8. LaVoie J-M, Dionne N, Helie R, Brisson GR: Menstrual cycle phase dissociation of blood glucose homeostasis during exercise. J Appl Physiol 62:10841089, 1987 9. Regensteiner JG, Woodard WD, Hagerman DD, Weil JV, Pickett CK, Bender PR, Moore LG: Effects of estrogen, progestin and mild exercise on ventilatory drives in women. J Appl Physiol 66:808813, 1989 10. Graham C, Lasko-McCarthey P: Exercise options for persons with diabetic complications. Diabetes Educ 16:212220, 1992 11. Barnea N, Drory Y, Iaina A, Lapidot C, Reisin E, Eliahou H, Kellermann JJ: Exercise tolerance in patients on chronic hemodialysis. Isr J Med Sci 16:1721, 1980 12. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, Sahn DJ, Schiller NB, Tajik A, Teichholz LE, Weyman AE: Report of the American Society of Echocardiography Committee on Nomenclature and Standards in two-dimensional echocardiography. Circulation 62:212217, 1980 13. Genovely H, Pfeifer MA: The autonomic test of choice in diabetes. Diabete Metab Rev 4:255271, 1988 14. Weber CT, Janicki JS, McElroy PA: Cardiopulmonary exercise (CPX) testing. In Cardiopulmonary Exercise Testing. Weber CT, Janicki JS, Eds. Philadelphia, WB Saunders, 1986, p. 151167 15. Dixon WJ: BMDP Statistical Software. Berkeley, CA, Univ. of California Press, 1983 16. Brozek J, Grande G, Anderson J, Keys A: Densitometric analysis of body composition: revision of some quantitative assumptions. Ann N Y Acad Sci 110:113140, 1963 17. Fagraeus L, Linnarson D: Autonomic origin of heart rate uctuations at the onset of muscular exercise. J Appl Physiol 40:679682, 1976
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