Secondary Logo

Sex Differences in the Effects of Type 2 Diabetes on Exercise Performance

REGENSTEINER, JUDITH G.1,2,3; BAUER, TIMOTHY A.1; HUEBSCHMANN, AMY G.1,3; HERLACHE, LEAH1; WEINBERGER, HOWARD D.2,5; WOLFEL, EUGENE E.2; REUSCH, JANE E. B.3,4,6

Medicine & Science in Sports & Exercise: January 2015 - Volume 47 - Issue 1 - p 58–65
doi: 10.1249/MSS.0000000000000371
BASIC SCIENCES
Free

Purpose People with uncomplicated type 2 diabetes (T2D) have impaired peak exercise performance compared with that of their nondiabetic counterparts. This impairment may represent the earliest indication of cardiovascular (CV) abnormalities in T2D. Women with T2D are known to have worse CV outcomes than those in men with T2D. We hypothesized that women with diabetes have a greater exercise impairment than that in men with diabetes compared with that in their nondiabetic counterparts.

Methods We studied 15 women (premenopausal) and 14 men with T2D as well as their nondiabetic counterparts (22 women and 13 men). Exercise testing was performed. Additional outcomes included measurements of insulin sensitivity, endothelial function, blood flow, and resting cardiac function.

Results Men and women with T2D but not controls had impaired insulin sensitivity. Women with T2D had a lower peak oxygen consumption (V˙O2peak) compared with that of nondiabetic women (24%, P < 0.05) than men with diabetes compared with that in nondiabetic men (16%, P < 0.05) (P value between groups < 0.05). The time constants (phase 2) of the V˙O2 kinetic response tended to be slower in men and women with T2D than those in nondiabetic controls (P = 0.08). There were no differences in resting ventricular function by Doppler echocardiography techniques between groups. Women with T2D had significantly lower flow-mediated dilation and blood flow responses to hyperemia than those in nondiabetic women (both P < 0.05), whereas men with T2D had lower flow-mediated dilation but not lower blood flow than those in nondiabetic men.

Conclusions Although both men and women with uncomplicated T2D had a lower V˙O2peak, the abnormality in women with T2D compared with that in nondiabetic women was greater than that seen in men. Because V˙O2peak has a strong inverse correlation with mortality, sex disparities observed in exercise capacity among people with T2D suggest a possible rationale for the increased CV morbidity and mortality observed in women compared with those observed in men with uncomplicated T2D.

1Department of Medicine, Division of Internal Medicine, University of Colorado School of Medicine, Aurora, CO; 2Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO; 3Department of Medicine, Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO; 4Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO; 5Department of Medicine, Division of Cardiology, National Jewish Health, Denver, CO; and 6Denver Veterans Affairs Medical Center, Denver, CO

Address for correspondence: Judith G. Regensteiner, Ph.D., Center for Women’s Health Research, University of Colorado School of Medicine, Mail Stop B180, Building AO1, 12631 East 17th Avenue, Room 8221, Aurora, CO; E-mail: judy.regensteiner@ucdenver.edu.

Submitted for publication December 2013.

Accepted for publication April 2014.

Almost 26 million people have diabetes in the United States (4), conferring an increased risk (two- to sixfold) of morbidity and mortality from cardiovascular (CV) causes compared with their nondiabetic counterparts (15,18). People with uncomplicated type 2 diabetes (T2D) consistently have an impaired CV exercise performance both in terms of peak and submaximal performance measures even in the absence of clinically apparent CV disease (1,13,17,32,33). Because low levels of physical activity and peak exercise capacity are associated with an increase in mortality, impaired exercise performance in people with T2D may be an early manifestation of CV problems, as peak exercise capacity is an indicator of CV reserve function (39). Impaired exercise capacity is also a potential harbinger of loss of functional ability, which can contribute to weight gain as well as limit mobility in these patients (2,35). Women with T2D seem to have a greater excess in CV morbidity and mortality than that in men with diabetes, and most but not all previous data suggest that women with T2D have a more pronounced exercise impairment than that of men with T2D (5,7,16,22,24,33). Despite these observations, relatively little research has focused on sex-based differences in CV function in T2D, and thus, the present study sought to compare differences in functional exercise capacity and measures of CV function in women and men with T2D because this may partly help explain the worse CV outcomes in women than those in men with diabetes. In addition, previous studies reporting on sex differences have not focused on younger participants (i.e., premenopausal women and men of similar age) with uncomplicated diabetes. We hypothesized that women with T2D have greater exercise impairment than that in men with T2D compared with that in their nondiabetic counterparts.

Back to Top | Article Outline

METHODS

Study Protocol

Subjects came for six visits. Evaluations included measurements of maximal and submaximal exercise capacity, endothelial function, blood flow, cardiac function, and markers of metabolic health and inflammation. The study was approved by the Colorado Multiple Institutional Review Board, and all subjects gave written informed consent to participate.

Back to Top | Article Outline

Specific Methods

Subjects

We enrolled and tested 29 moderately overweight (body mass index (BMI), ≤35 kg·m−2) persons (15 women and 14 men) with T2D and no clinically detectable complications or comorbid conditions and 35 healthy nondiabetic persons (22 women and 13 men) of similar ages, from a mix of sexes, and of similar weight (i.e., overweight). Participants were allowed to be on statins. Thirty-one other potential participants failed upon screening because of the study criteria. Of these, three were anemic or had other blood abnormalities, one had noncompressible vessels, 13 had elevated lipids, four had elevated glycosylated hemoglobin A1C (HbA1C), four had high FSH, one had type 1 diabetes, and five had a positive stress test result and abnormal resting ECG or echocardiogram.

All participants were sedentary. Physical activity level was assessed by the Low-Level Physical Activity Recall (LOPAR), as previously reported (30). The presence and diagnosed duration of T2D were documented by chart review.

Subjects with T2D were treated with diet or diet plus metformin and/or sulfonylureas and were taking no other medicines for their T2D because of the potential effects of other diabetes medicines on endothelial function, cardiac function, and exercise capacity. Persons with T2D were accepted for the study only if they had total HbA1C levels <9% on diet therapy. Smokers (current smoker or smoking within 1 yr) were not accepted for the study because of the potential effects on outcome measures.

Men and women between the ages of 30 and 55 yr only were chosen to limit the age range in the study because exercise performance is affected by age. All women were premenopausal on the basis of history of regular menstrual cycles and serum FSH levels. For purposes of consistency and to rule out the effects of widely differing levels of female hormones on exercise as well as to minimize the potential effects of progesterone on ventilation, women were tested beginning on days 5, 6, or 7 in the follicular phase of the menstrual cycle (34).

History and physical examination and laboratory testing confirmed the absence of comorbid conditions including clinically evident distal symmetrical neuropathy by evaluation of symptoms (numbness, paresthesia) and signs (elicited by vibration, pinprick, 10-g monofilament fiber, and ankle reflexes), abnormal lipid levels (including levels in people treated with statins or not treated with statins) (total cholesterol levels, >200; LDL-cholesterol level, >130; or triglyceride level, >250), abnormal cardiac function or evidence of ischemic heart disease by history, or abnormal resting or exercise ECG. A screening echocardiogram excluded abnormal global or regional systolic function, left ventricular (LV) hypertrophy, or more-than-mild valvular regurgitation. Doppler parameters of LV diastolic function were not used to exclude any subjects. Persons with angina or other cardiac or pulmonary symptoms limiting exercise performance were excluded. Abnormal blood pressure at rest (>140/90 mm Hg) or with exercise (>260/105 mm Hg) were also grounds for exclusion. Participants with autonomic insufficiency, assessed by RR interval variation during cycled breathing and by orthostatic testing detecting the presence of a >20-mm fall in upright systolic blood pressure without a change in HR, were excluded. In addition, the immediate HR response to a standing test was used to exclude presence of autonomic dysfunction. Subjects with proteinuria (urine protein, >200 mg·dL−1), creatinine ≥2 mg·dL−1, or microalbuminuria were excluded. Nondiabetic control subjects were screened identically as persons with T2D. These subjects were taking no medications and had a normal HbA1C and history. Controls were not accepted if they had an immediate family history of T2D, given the possibility of impaired peak oxygen consumption in this population (21).

Back to Top | Article Outline

Brachial artery diameter

Endothelial function as assessed by the brachial artery method was used, following the protocol described by Celermajer et al. (3) that measures dilation of the brachial artery by ultrasound after transient arterial occlusion (GE VingMed Vivid FiVe ultrasound system; GE, Milwaukee, WI) (using a 10.0-mHz linear array transducer), as described previously (30).

Back to Top | Article Outline

Forearm reactive hyperemia

Forearm blood flow was determined in seated participants by venous occlusion strain gauge plethysmography (DE Hokanson Inc., Issaquah, WA) using calibrated mercury-in-silastic strain gauges and was expressed in milliliters per 100 mL per minute, as previously reported (10).

Back to Top | Article Outline

Cardiac echocardiography

Standard two-dimensional and Doppler echocardiography were performed at rest using standard methods (9,29) to exclude the presence of LV systolic dysfunction, regional wall motion abnormalities (suggestive of CAD), pericardial disease, or significant valvular pathology. 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.

Back to Top | Article Outline

Diastolic function

Diastolic function was assessed under resting conditions using standard echocardiographic parameters (E and A wave velocities, E/A ratio, E wave deceleration time (mitral valve flow deceleration time [MVDT]) and tissue Doppler imaging of both the septal and lateral mitral annuli (E′ and A′ velocities, E′/A′ ratio). The E/E′ ratio was used to determine LV filling pressure (23). A single echo sonographer blinded to study group acquired all the echocardiographic data, and the images were read by a cardiologist blinded to diagnostic status. Echocardiograms were obtained by a commercially available ultrasound system (VingMed Vivid FiVe; GE, Milwaukee, WI) and were stored for offline measurement and interpretation (EchoPAC version 7.3.0; GE, Milwaukee, WI). Subjects were examined in the left lateral decubitus position using standard parasternal, apical, and subcostal views. All recordings and measurements were obtained according to the recommendations of the American Society of Echocardiography and were performed at the same time of the day to avoid the possible influence of circadian rhythm on LV diastolic function for each subject (38). Cardiac valves were examined to rule out significant valvular disease. LV mass (LVM) was calculated using the following formula: LVM (g) = 0.8 × 1.04 [(LVEDD + IVST + PWT)3 − (LVEDD)3] + 0.6, where LVEDD is LV end-diastolic internal diameter, IVST is interventricular septal thickness, and PWT is LV posterior wall thickness. Pulmonary capillary wedge pressure (PCWP) was calculated using the formula of Nagueh et al. (20), as follows:

Back to Top | Article Outline

Insulin sensitivity

The euglycemic–hyperinsulinemic clamp to measure insulin sensitivity was performed as previously reported (37), as was assessment for body composition and bone mineral density (11). Diet was controlled for 3 d before testing with regard to macronutrients, as previously reported (19).

Back to Top | Article Outline

Bicycle ergometer testing

Measurements made during bicycle ergometer testing. For all bicycle tests, peak oxygen consumption (V˙O2), carbon dioxide production (V˙CO2), and minute ventilation (V˙E) were measured breath by breath at rest and during exercise. Arm blood pressures (by auscultation) and HR (by 12-lead ECG) were obtained every minute during exercise. Cardiac status was continuously monitored throughout each test by 12-lead ECG. RER was calculated as V˙CO2/V˙O2.

Graded exercise test. To determine peak oxygen consumption (V˙O2peak) (primary outcome) and ventilatory threshold in all participants, a graded bicycle protocol to exhaustion was carried out as previously reported on a cycle ergometer (Medgraphics, Minneapolis, MN), breathing into the mouthpiece of the metabolic cart (Medgraphics CPX/D; Medical Graphics Corp., St. Paul, MN) (19,30) while workload was increased by 10–25 W·min−1 (according to patient ability) to bring the participant to maximal exercise capacity between 8 and 12 min. The ventilatory threshold was identified using the V-slope method. RER ≥1.1 was used to confirm a valid V˙O2peak result.

Constant-load tests. To obtain the oxygen uptake kinetic values, each test began with resting measurements, as described previously (10). After this period, a preselected workload (set at 85% of the ventilatory threshold for each participant) was imposed and the subject maintained pedaling at 65 rpm for 6 min per workload, which allowed all subjects to reach steady state. Each workload was performed three times on a given day (with 15-min rest periods between bouts), and responses were averaged to determine V˙O2 kinetics, as previously described (31).

Back to Top | Article Outline

Oxygen uptake kinetic measurements

Oxygen uptake kinetics were measured using a software program developed in our laboratory, as previously described (31). Pulmonary V˙O2 kinetic responses were evaluated using a two-component exponential model, allowing individual components of the V˙O2 kinetic response to be evaluated as previously reported (32). Model parameters including the phase 2 time constant of oxygen uptake (primary component), a coordinated marker of the ability to deliver and use oxygen at the level of the exercising skeletal muscle, were calculated.

Back to Top | Article Outline

Blood collection and preparation

Blood was drawn at baseline for the measurement of levels of glucose, insulin, estradiol, plasma FSH, HbA1C, adiponectin, C-reactive protein (CRP), and interleukin (IL) 6.

Back to Top | Article Outline

Blood handling

Subjects’ blood was drawn in tubes free from any additives and was allowed to sit at room temperature for a minimum of 2 h. The retracted clot was removed, and the blood was then spun for 15 min at 2100 rpm in an International Equipment Company Centra MP4. The sera were removed, and the sample was frozen at −70°C.

Back to Top | Article Outline

Assay methods

Assays were done according to established methods, as previously reported. HbA1C was measured by glyc-affin GHB columns (Isolab). Serum insulin concentrations and estradiol level were measured by radioimmunoassay. Serum glucose concentration was measured by the glucose oxidase method. Plasma FSH was measured by a chemiluminescence assay. Adiponectin, CRP, and IL-6 were measured according to established methods (25,26,36).

Back to Top | Article Outline

LOPAR questionnaire

Physical activity was assessed using the LOPAR questionnaire, as previously described (30). Self-reported physical activity was calculated in metabolic equivalents (METs) and presented as MET-hours per week to quantify usual physical activity levels. One MET is equivalent to the energy expended at rest (30).

Back to Top | Article Outline

Statistical analysis

Primary end points were analyzed by ANOVA. Differences between groups assessed by ANOVA were identified using the Bonferroni post hoc test. Correlations between (primary outcome) and potential predictors were measured using the Pearson product-moment correlation coefficient. Significance was set at P < 0.05. All values are expressed as mean ± SD.

Back to Top | Article Outline

RESULTS

Demographic results

There were no significant differences in age, BMI, or habitual physical activity levels between groups (Table 1). HbA1C was higher in the subjects with diabetes than that in the nondiabetic subjects and not different between men and women with T2D. Six of 15 women and four of 14 men with T2D were taking metformin and/or sulfonylureas. One nondiabetic woman and two people in each of the other groups were taking statins. Insulin sensitivity (normalized by BMI) was greater in nondiabetic participants than that in persons with T2D. Adiponectin levels were higher in the nondiabetic women than those in women with T2D, whereas CRP levels were lower in nondiabetic participants than those in subjects with T2D. IL-6 levels were higher in subjects with T2D than those in nondiabetic participants. Estradiol levels did not differ significantly between women with and without diabetes.

TABLE 1

TABLE 1

Back to Top | Article Outline

Cardiac and vascular testing

Assessment of resting cardiac function (determined by echocardiography) revealed that there were no significant differences between any of the four groups with regard to any resting echocardiographic measurement (Table 2). Specifically, there were no significant differences in resting LV ejection fraction (LVEF), LV regional wall motion, mitral inflow Doppler measurements, and tissue Doppler imaging between men or women with T2D and their respective control groups or to each other. In addition, there were no abnormalities in resting LVEF (<50%) or Doppler measurements to indicate LV diastolic dysfunction of any severity at rest in either men or women with T2D using the criteria of the American Society of Echocardiography (20). However, endothelial function as measured by the vasodilatory response to hyperemia was decreased in men and women with diabetes compared with that in their nondiabetic counterparts (Table 2) (P < 0.05). In addition, hyperemic blood flow measured by strain gauge plethysmography was lower in women with T2D compared with that in nondiabetic women (P < 0.05) and tended to be lower in men with T2D compared with that in nondiabetic men (P = 0.08).

TABLE 2

TABLE 2

Back to Top | Article Outline

Exercise testing results

Both women and men with T2D had significantly lower V˙O2peak values compared with those of their nondiabetic counterparts. However, women with T2D had a lower V˙O2peak compared with that of nondiabetic women (24%) than men with T2D compared with nondiabetic men (16%) (P < 0.05) (Table 3). The RER showed comparable peak exercise effort in all groups. V˙O2peak in all persons with T2D was correlated with insulin sensitivity assessed by clamp (r = 0.43, P < 0.05) and negatively correlated with CRP (r = −0.45, P < 0.05). In addition, V˙O2peak in T2D was correlated with forearm blood flow by plethysmography (r = 0.48, P < 0.05) and flow-mediated dilation by ultrasound (r = 0.56, P < 0.05). No significant correlations were observed in nondiabetic controls of either sex. There were no significant correlations of V˙O2peak with resting LV systolic or diastolic function in men or women with T2D or in their respective control groups.

TABLE 3

TABLE 3

Compared with nondiabetic control subjects, the time constants (phase 2) of the V˙O2 kinetic response seemed slower in men and women with T2D as compared with those in nondiabetic controls, although this did not reach statistical significance (P = 0.08) (Fig. 1). A slower time delay before the phase 2 component was observed in women with T2D compared with that observed in nondiabetic control subjects.

FIGURE 1

FIGURE 1

Back to Top | Article Outline

DISCUSSION

We found that peak exercise capacity is impaired in both premenopausal women and men of similar age with uncomplicated and relatively recently diagnosed T2D compared with that in their nondiabetic counterparts of similar age and habitual physical activity level. However, the peak exercise impairment was more pronounced in women than in men with T2D. Peak oxygen consumption was lowest in women with T2D compared with that in the other three groups. V˙O2 kinetics, an assessment of submaximal fitness level, tended to be slowed in both men and women with T2D. All subjects with T2D exhibited impaired flow-mediated vasodilatation, whereas only women with T2D had a significant decrement in forearm blood flow by plethysmography. Taken together, measures of exercise capacity and vascular function were more consistently impaired in women with T2D compared with those in nondiabetic women and in men with diabetes compared with those in their nondiabetic counterparts. These findings occurred in the absence of resting cardiac function (systolic and diastolic) abnormalities in patients with uncomplicated T2D.

In spite of the numerous previous studies assessing exercise performance in T2D, few studies have examined differences in exercise performance between men and women with diabetes compared with their nondiabetic counterparts. In addition, previous studies have not evaluated differences in exercise performance between relatively young (premenopausal) women and men of similar age with T2D.

Previous research by our group and others on adults and adolescents has shown that individuals with T2D have impairments in peak exercise capacity and some measures of submaximal exercise (19,31,33) compared with those in nondiabetics of similar age and activity. V˙O2peak has typically been shown to be lower by between 10% and 30% in adults and adolescents with T2D (19,33). In a study on adolescent girls comparing subjects with T2D with lean and overweight controls, those with T2D had the lowest peak exercise capacity among the groups and achieved a mean of only 7.1 METs, significantly less than that achieved by lean and overweight controls (19). In some but not all studies, V˙O2 kinetics have also been shown to be slower in people with T2D compared with those in nondiabetic controls (1,30,31,41). However, in the present study, they only tended to be slower in participants with T2D.

In the present study, the lower V˙O2peak correlated with impaired endothelial function, blood flow, and insulin resistance in men and women with T2D. Although this study was not designed to show cause and effect, future studies should explore whether impaired endothelial function might be a cause of impaired exercise capacity.

Previous reports are mixed in terms of findings about sex differences in T2D in exercise capacity (5,8,22,33). Regensteiner et al. (33) previously reported that the difference in V˙O2peak levels between subjects with and without diabetes was greater in women (31%) than that in men (20%) in a small sample. Fang et al. (5) also found that being a female was an independent predictor of lower peak exercise capacity in participants with T2D. This report highlighted that factors associated with lower exercise capacity may differ between women and men (e.g., HR recovery and duration of diabetes). In contrast to these previous studies and our current findings, O’Connor et al (22) found no sex differences in peak exercise capacity between older men and women with T2D, although both groups had reduced maximal and submaximal exercise capacity compared with those in nondiabetic controls. The reasons for the difference between our findings and those of O’Connor et al. (22) are not clear, but they may be partly related to differences in the study subjects. One difference in design between our study and that of O’Connor et al. (22) (and also a point of novelty) was our examination of younger premenopausal women with relatively uncomplicated and recently diagnosed T2D who were studied in the midfollicular phase of the menstrual cycle. In older participants, elimination of the sex disparities we observed could be related to the development of additional CV abnormalities in both sexes due to the presence of both T2D and aging, such as the development of resting LV diastolic function. An alternative explanation for the difference in findings could be related to decreased insulin sensitivity among nondiabetic females after menopause because insulin sensitivity is typically better in premenopausal women than that in postmenopausal women (28). Because insulin sensitivity is correlated to V˙O2peak, this relationship is of importance and may help explain exercise abnormalities.

We included premenopausal women in the present study because one of the predetermined goals of our study was to examine the effect of diabetes on exercise function in this younger group. Estrogen is known to regulate nitric oxide synthase, which contributes to both endothelial function and tissue perfusion measured by plethysmography (40). We did not find a significant difference between estradiol levels in women with T2D and nondiabetic women. However, we did observe differences in both vasomotion (flow-mediated vasodilatation), blood flow (plethysmography) as well as peak exercise capacity between women with and without diabetes. Although estradiol levels were not different between people with diabetes and nondiabetic people in our study, the impairments in endothelial function and plethysmography may still partially be explained by differences in the vascular effects of estradiol in women with and without T2D because these effects can be disrupted in diabetes.

Previous studies have demonstrated abnormal LV diastolic function in patients with T2D, and these abnormalities could explain a reduction in exercise capacity (27). We did not find any abnormalities in resting ventricular diastolic function using tissue Doppler imaging, the most sensitive noninvasive method to evaluate LV diastolic function, in either men or women with T2D. The lack of findings of resting cardiac abnormalities could be related to the relatively short duration of T2D, inclusion of participants with uncomplicated T2D, and younger age of our subjects, compared with those included in the previous studies where LV diastolic dysfunction has been reported even in the absence of coronary disease. Our data do not exclude a possible cardiac role for the reduction in exercise capacity in both men and women with T2D in our study because we did not evaluate cardiac function during exercise. In a previous study involving the invasive measurement of pulmonary capillary wedge pressure (PCWP), the findings were normal at rest but the PCWP increase with exercise was exaggerated during exercise (32). There was also a trend for a correlation between the peak exercise PCWP and V˙O2peak in that study, which included a small number of subjects. In that study, there were no abnormalities in resting Doppler indicators of LV diastolic dysfunction and V˙O2peak, similar to our current study. It is interesting to speculate that a subclinical cardiac functional impairment with exercise, similar to what we previously reported, could underlie the sex differences in maximal exercise that we observed (32). The use of a stress test with tissue Doppler imaging immediately after exercise may help elucidate this hypothesis. This evaluation was not performed in the current study.

There were correlations between forearm blood flow by plethysmography and endothelial function by brachial artery vasoreactivity with V˙O2peak in both men and women with T2D in our study. Women seemed to have a greater reduction in forearm blood flow compared with that of their nondiabetic counterparts than did the men with T2D compared with that of nondiabetic men, suggesting that differences in vascular function may explain partly the more reduced exercise capacity in women with T2D when compared with that in men. Endothelial dysfunction has been reported in most (although not all) studies of even uncomplicated T2D (12,42). The abnormalities in forearm blood flow such as those we observed are less established and require further study because our finding of impaired blood flow has not been universally reported in T2D (42). Further studies are also needed to more rigorously characterize endothelial function and blood flow abnormalities as contributors to the sex differences in T2D. Differences in study findings may be related to patient age (because endothelial function and forearm blood flow may be affected by age), to differences in medications that people with diabetes take, and to methodological differences between studies.

Differences in V˙O2 kinetics between participants with diabetes versus nondiabetic participants have been reported in some, but not all, previous studies (22,41). V˙O2 kinetics are a measure of the rate of adaptive V˙O2 after the onset of exercise at constant work rate. Faster V˙O2 kinetic responses are related to better fitness and integrative physiological control, with slowed responses indicative of impairments in muscle oxidative metabolism, oxygen delivery, or both. In the present study, we observed a prolonged time delay before the primary component of V˙O2 increase (phase 2) in women with T2D compared with that in nondiabetic women. However, the time constant of the primary component did not statistically differ between either women or men with T2D and their nondiabetic counterparts, although the data support a trend for slowed responses in T2D in both sexes (Fig. 1). O’Connor et al (22) found that V˙O2 kinetics were slower in both men and women with T2D compared with those in nondiabetic controls but did not observe a sex difference, and a previous study by Wilkerson et al. (41) failed to demonstrate any differences in V˙O2 kinetics in older men with T2D compared with those in their nondiabetic counterparts. The reason for inconsistencies in the V˙O2 kinetic findings in T2D between studies is unclear. However, the differing age of study participants, duration of diabetes, or other factors among the studies performed to date may explain some of the variability of the observations. In addition, there remains the possibility that submaximal exercise responses may not elicit the degree of impairment observed with peak exercise in these studied populations.

The data from the present study have important clinical implications. Diabetes seems to eliminate the relative survival advantage experienced by premenopausal nondiabetic women compared with that experienced by men with regard to CHD. Whereas men with T2D have a twofold increased risk of CHD, women with T2D have a fourfold increased risk (7,14). In addition, Framingham data reveal that the risk of developing congestive heart failure is 5.1-fold in women with T2D compared with 2.4-fold in men with T2D (6). Evaluation of endothelial function, fibrinolysis, and other risk factors for CV disease shows that these markers of CV health also may become more abnormal in women than those in men in the prediabetic and diabetic state (2,35). The causes of these sex differences are not understood. CV fitness (measured by V˙O2peak) is a robust predictor of CV status in people with and without diabetes (39). As such, it is possible that the observed greater impairment in functional exercise capacity contributes to the increased mortality in women with T2D compared with that in men with T2D.

Overall, people with diabetes have a two- to fivefold increase in CV mortality despite aggressive CV risk factor intervention. It is therefore important to understand additional components related to diabetes that incur this excess risk. Decreased physical fitness observed in people with diabetes is a plausible mediator of excess CV and all-cause mortality in T2D. The data in this article add to current findings related to decreased exercise function in people with diabetes by demonstrating sex-based differences.

The limitations of this study include the inclusion of only relatively young participants and the small sample size. Therefore, the results are not applicable to all people with T2D, and studies on older people with T2D would be of value. In addition, this study did not clarify mechanisms that could cause the sex differences observed. Future studies should evaluate this important question. In addition, future studies should attempt to further clarify the causes of the exercise impairment, which is associated with even mild diabetes of more recent onset and with no complications in both men and women. These patients provide an opportunity to determine the mechanisms of exercise intolerance with no confounding effects of the various end-organ complications that would definitely cause a reduction in exercise capacity.

Traditional CV risk factors fail to account for the increase in heart disease among women with T2D compared with that among their nondiabetic female counterparts (especially evident in the premenopausal age group). We observed impairments in V˙O2peak, endothelial function, and tissue blood flow, which were more pronounced in women than in men with T2D. Impairments in CV exercise performance in women with T2D may be a biomarker of a “pre–heart disease” state. Future research should focus on the causes of this important problem in women’s health and look for ways to address it.

We sincerely thank the participants in this study who made this research possible. We also thank Shawna McMillin, M.S., and Dylan Mogk, B.S., for their assistance with data analysis.

This research was funded by a clinical research grant from the American Diabetes Association. The research was also supported by the National Institutes of Health/National Center for Research Resources Colorado CTSI grant number UL1 RR025780. The electrodes for the study were provided by Vermed.

J. G. R. designed the study, analyzed the data, and wrote the manuscript. T. A. B. designed the study, helped with data analysis, and edited the manuscript. A. G. H. helped with data analysis and edited the manuscript. L. H. performed study visits, helped with data analysis, and edited the manuscript. H. D. W. helped design the study, performed study visits, and edited the manuscript. G. E. W. helped design the study, analyzed the data, and edited the manuscript. J. E. B. R. designed the study, helped with data analysis, and edited the manuscript.

Dr. Eugene E. Wolfel and Dr. Jane E. B. Reusch are considered joint senior authors of this article.

The clinicalTrials.gov identifier for this article is NCT01993121.

There are no relevant conflicts of interest to report. The results of the present study do not constitute endorsement by the American College of Sports Medicine.

Back to Top | Article Outline

REFERENCES

1. Bauer TA, Reusch JE, Levi M, Regensteiner JG. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes. Diabetes Care. 2007; 30 (11): 2880–5.
2. Bean JF, Olveczky DD, Kiely DK, LaRose SI, Jette AM. Performance-based versus patient-reported physical function: what are the underlying predictors? Phys Ther. 2011; 91 (12): 1804–11.
3. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol. 1994; 24 (6): 1468–74.
4. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States. Atlanta (GA): US Department of Health and Human Services; 2011.
5. Fang ZY, Sharman J, Prins JB, Marwick TH. Determinants of exercise capacity in patients with type 2 diabetes. Diabetes Care. 2005; 28 (7): 1643–8.
6. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther. 1994; 8 (1): 65–73.
7. Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med. 2007; 147 (3): 149–55.
8. Gusso S, Hofman P, Lalande S, Cutfield W, Robinson E, Baldi JC. Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus. Diabetologia. 2008; 51 (7): 1317–20.
9. Henry WL, DeMaria A, Gramiak R, et al. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in two-dimensional echocardiography. Circulation. 1980; 62 (2): 212–7.
10. Hiatt WR, Huang SY, Regensteiner JG, et al. Venous occlusion plethysmography reduces arterial diameter and flow velocity. J Appl Physiol (1985). 1989; 66 (5): 2239–44.
11. Hill JO, Peters JC, Reed GW, Schlundt DG, Sharp T, Greene HL. Nutrient balance in humans: effects of diet composition. Am J Clin Nutr. 1991; 54 (1): 10–7.
12. Huebschmann AG, Kohrt WM, Regensteiner JG. Exercise attenuates the premature cardiovascular aging effects of type 2 diabetes mellitus. Vasc Med. 2011; 16 (5): 378–90.
13. Joshi D, Shiwalkar A, Cross MR, Sharma SK, Vachhani A, Dutt C. Continuous, non-invasive measurement of the haemodynamic response to submaximal exercise in patients with diabetes mellitus: evidence of impaired cardiac reserve and peripheral vascular response. Heart. 2010; 96 (1): 36–41.
14. Kanaya AM, Grady D, Barrett-Connor E. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med. 2002; 162 (15): 1737–45.
15. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979; 241 (19): 2035–8.
16. Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care. 2000; 23 (7): 962–8.
17. Mac Ananey O, Malone J, Warmington S, O’Shea D, Green S, Egaña M. Cardiac output is not related to the slowed O2 uptake kinetics in type 2 diabetes. Med Sci Sports Exerc. 2011; 43 (6): 935–42.
18. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001; 44 (2 Suppl): S14–21.
19. Nadeau KJ, Zeitler PS, Bauer TA, et al. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab. 2009; 94 (10): 3687–95.
20. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quiñones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol. 1997; 30 (6): 1527–33.
21. Nyholm B, Mengel A, Nielsen S, et al. Insulin resistance in relatives of NIDDM patients: the role of physical fitness and muscle metabolism. Diabetologia. 1996; 39 (7): 813–22.
22. O’Connor E, Kiely C, O’Shea D, Green S, Egaña M. Similar level of impairment in exercise performance and oxygen uptake kinetics in middle-aged men and women with type 2 diabetes. Am J Physiol Regul Integr Comp Physiol. 2012; 303 (1): R70–6.
23. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation. 2000; 102 (15): 1788–94.
24. Orchard TJ. The impact of gender and general risk factors on the occurrence of atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Ann Med. 1996; 28 (4): 323–33.
25. Paz-Pacheco E, Lim-Abrahan MA, Sy RA, Jasul GV, Sison CM, Laurel AF. Adiponectin levels and its association with hyperglycaemia in adult Filipino participants in the 2003–04 National Nutrition and Health Survey. Diabetes Vasc Dis Res. 2009; 6 (4): 231–7.
26. Pledge D, Grosset JF, Onambélé-Pearson GL. Is there a morning-to-evening difference in the acute IL-6 and cortisol responses to resistance exercise? Cytokine. 2011; 55 (2): 318–23.
27. Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care. 2001; 24 (1): 5–10.
28. Polotsky HN, Polotsky AJ. Metabolic implications of menopause. Semin Reprod Med. 2010; 28 (5): 426–34.
29. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr. 2002; 15 (2): 167–84.
30. Regensteiner JG, Bauer TA, Reusch JE. Rosiglitazone improves exercise capacity in individuals with type 2 diabetes. Diabetes Care. 2005; 28 (12): 2877–83.
31. Regensteiner JG, Bauer TA, Reusch JE, et al. Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus. J Appl Physiol (1985). 1998; 85 (1): 310–7.
32. Regensteiner JG, Bauer TA, Reusch JE, et al. Cardiac dysfunction during exercise in uncomplicated type 2 diabetes. Med Sci Sports Exerc. 2009; 41 (5): 977–84.
33. Regensteiner JG, Sippel J, McFarling ET, Wolfel EE, Hiatt WR. Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise. Med Sci Sports Exerc. 1995; 27 (5): 661–7.
34. Regensteiner JG, Woodard WD, Hagerman DD, et al. Combined effects of female hormones and metabolic rate on ventilatory drives in women. J Appl Physiol (1985). 1989; 66 (2): 808–13.
35. Rejeski WJ, Ip EH, Bertoni AG, et al. Lifestyle change and mobility in obese adults with type 2 diabetes. N Engl J Med. 2012; 366 (13): 1209–17.
36. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003; 107 (3): 363–9.
37. Sadur CN, Eckel RH. Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique. J Clin Invest. 1982; 69 (5): 1119–25.
38. Voutilainen S, Kupari M, Hippelainen M, Karppinen K, Ventila M. Circadian variation of left ventricular diastolic function in healthy people. Heart. 1996; 75 (1): 35–9.
39. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med. 2000; 132 (8): 605–11.
40. White RE, Gerrity R, Barman SA, Han G. Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women. Steroids. 2010; 75 (11): 788–93.
41. Wilkerson DP, Poole DC, Jones AM, et al. Older type 2 diabetic males do not exhibit abnormal pulmonary oxygen uptake and muscle oxygen utilization dynamics during submaximal cycling exercise. Am J Physiol Regul Integr Comp Physiol. 2011; 300( 3): R685–92.
42. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996; 27 (3): 567–74.
Keywords:

OXYGEN CONSUMPTION; OXYGEN UPTAKE KINETICS; FUNCTIONAL IMPAIRMENT; CARDIOVASCULAR

© 2015 American College of Sports Medicine