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Original Article |
Departments of Medicine and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, and Nashville Veteran Affairs Medical Center, Nashville, Tennessee 37232-6303
Address all correspondence and requests for reprints to: Stephen N. Davis, M.D., 715 Preston Research Building, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303. E-mail: steve.davis{at}vanderbilt.edu.
Abstract
A marked sexual dimorphism in neuroendocrine and metabolic responses to moderate, prolonged exercise occurs in healthy humans. It is unknown whether similar differences occur in type 1 diabetes mellitus (T1DM). Fifteen patients with T1DM (7 women and 8 men) were studied during 90 min of euglycemic exercise at 50% of the maximum rate of O2 consumption. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness, and had no history or evidence of autonomic neuropathy. Hypoglycemia was scrupulously avoided during the week preceding tests. Exercise was performed under constant infusion of regular insulin (1 U/h) and a variable 20% dextrose infusion, as needed to maintain euglycemia. At 15-min intervals, neuroendocrine, metabolic (glucose kinetics, intermediate metabolism, lipolysis), and cardiovascular responses were assessed. Indirect calorimetry was performed during the last 10 min of exercise. Plasma glucose and insulin did not differ between genders at baseline or during exercise. Key neuroendocrine responses were significantly reduced in women, compared with men, during exercise (epinephrine, 360 ± 104 vs. 666 ± 126 pM; norepinephrine, 2.3 ± 0.8 vs. 4.1 ± 1.0 nM; GH, 10 ± 5 vs. 22 ± 8 µg/liter). Glucagon, cortisol, and pancreatic polypeptide responses were similar between genders. Despite reduced catecholamine responses in women, no gender differences were observed in endogenous glucose production (EGP) or exogenous glucose infusion rate during exercise. The lipolytic response to exercise (blood glycerol), on the other hand, was greater in women than in men.
In conclusion, a marked sexual dimorphism exists in counterregulatory responses to exercise in T1DM, including key neuroendocrine (catecholamine, GH) and metabolic (lipolysis) responses. Other responses, including glucagon and EGP, were similar between genders, suggesting that the glucagon to insulin ratio may be the primary determinant of EGP during moderate intensity exercise in T1DM.
WHEN CHALLENGED WITH various forms of stress, such as prolonged fasting or hyperinsulinemic hypoglycemia, healthy men and women react with a clear sexually dimorphic pattern of neuroendocrine and metabolic responses (1, 2, 3, 4). It is now generally accepted that in these conditions most counterregulatory responses are enhanced in men compared with women (1, 2, 3, 4).
A less clear consensus exists as to whether similar gender differences also extend to other forms of stress, such as physical exercise, that elicit counterregulatory response qualitatively comparable to hypoglycemia (5, 6, 7, 8, 9, 10, 11, 12). Available reports include, for instance, reduced or similar catecholamine responses during exercise in women (5, 6, 7, 8, 9, 10), relative to men, and increased or similar lipolytic responses (6, 8, 9, 10, 11, 12). This lack of homogeneity is probably due to the fact that previous studies exploring this issue have generally focused on one or just a few counterregulatory variables, used significantly different exercise protocols, and did not control for confounding parameters such as glucose or insulin levels during exercise. The only available report of a comprehensive, simultaneous evaluation of all key neuroendocrine and metabolic responses during strictly euglycemic exercise, however, supports the existence of significant gender differences in healthy humans (13). In the study of Davis et al. (13), epinephrine, norepinephrine, pancreatic polypeptide (PP), cardiovascular and carbohydrate oxidation responses were greater in men than in women, whereas lipolytic and ketogenic responses were greater in women.
Counterregulatory responses during stress are particularly relevant for patients with type 1diabetes mellitus (T1DM). A well known feature of this disease is the permanent loss of specific counterregulatory responses to stress, such as the glucagon response to hypoglycemia (14). Although patients with T1DM also often experience hypoglycemia in association with physical exercise, the mechanisms responsible for this phenomenon are still incompletely understood. In particular, it is unknown whether gender-related physiologic differences occur in counterregulatory responses to physical exercise in T1DM.
To test the hypothesis that a significant sexual dimorphism exists in neuroendocrine and metabolic responses to exercise in T1DM, eight male and seven female patients with T1DM underwent an integrated assessment of counterregulatory responses during 90 min of moderate [50% of the maximum rate of O2 consumption (VO2 max)] cycling exercise during euglycemic conditions.
Subjects and Methods
Subjects
We studied 15 patients with T1DM (8 males and 7 females; aged 28 ± 2 yr) who had been diagnosed with T1DM 13 ± 2 yr before recruitment (for other patient characteristics, see Table 1
). Patients had no evidence of tissue complications of the disease (retinopathy, renal impairment, hypertension) or of diabetic autonomic neuropathy, as assessed by a standard bedside evaluation (including supine and standing blood pressure measurement and EKG changes during a Valsalva maneuver; Ref. 15). Women were studied during the follicular phase of their menstrual cycle.
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Preliminary exercise testing
At least 2 wk before the initial study, patients’ body composition was assessed by skinfold caliper technique (16) and whole-body plethysmography (Bod-Pod, Life Measurement Inc., Concord, CA). At this time, patients also performed an incremental work test on a stationary cycle ergometer to determine VO2 max and anaerobic threshold (AT). Airflow, O2, and CO2 concentrations in inspired and expired air were measured by a computerized open-circuit indirect calorimetry cart (Medical Graphics CardiO2 cycle, Medical Graphics Corp., St. Paul, MN) with a mouthpiece and nose clip system. The AT was determined by the V-slope method (17). The AT determined by gas exchange corresponds to the onset of an increased lactate to pyruvate ratio in blood and indicates the level of exercise above which anaerobic mechanisms supplement aerobic energy production (18). At workloads below the AT, exercise can be continued for a prolonged period, whereas above the AT, fatigue will occur considerably faster (19). The experimental work rate was established by calculating 80% AT. The AT was detected at 59 ± 3% of VO2 max, and 80% AT corresponded to 47 ± 2% of the subjects’ VO2 max. This workload was chosen because it is close enough to the AT to produce a physically challenging stress (i.e. large experimental signal) but is sustainable for a prolonged period of time. Subjects who were studied ranged from sedentary to regularly exercising, although not actively participating in competitive sports. Mean VO2 max for the group was 31 ± 2 ml/kg·min (range, 21–43 ml/kg·min).
Experimental design
Patients were asked to scrupulously avoid hypoglycemia during the 7 d preceding each visit; they checked their blood glucose four times per day and reported the recorded values to the investigators before admission. Detection of any value below 3.9 mM resulted in rescheduling of the study. Patients were also asked to avoid any exercise and consume their usual weight-maintaining diet for 3 d before each study. Each subject was admitted to the Vanderbilt General Clinical Research Center (GCRC) at 1600 h on the afternoon before an experiment. On admission, patients were asked to discontinue their usual insulin therapy, and two intravenous cannulae were inserted under 1% lidocaine local anesthesia. One cannula was placed in a retrograde fashion into a vein on the back of the left hand. This hand was placed in a heated box (55–60 C) so that arterialized blood could be obtained (20). The other cannula was placed in the contralateral arm so that insulin and 20% glucose (when needed) could be infused via a variable rate volumetric infusion pump (I Med, San Diego, CA). An insulin infusion was immediately started at a basal rate. Patients then consumed a standardized evening meal and a 1930 h snack, and they were requested not to ingest any food after 2200 h. The insulin infusion rate was increased during meal consumption. Through the night, blood glucose was measured every 30 min, and the insulin infusion rate was constantly adjusted to maintain glycemic levels of 4.4–6.9 mM.
During the whole day preceding the exercise test, patients were maintained at rest in the GCRC and underwent identical morning and afternoon 2-h hyperinsulinemic-euglycemic clamps so that insulin sensitivity could be assessed (21). On completion of the second glucose clamp, the insulin infusion was decreased to the morning basal rate, and patients consumed another standardized evening meal. Afternoon and night procedures were identical to those of admission night.
Exercise protocol
On the following morning, procedures started at 0800 h, after a 10-h overnight fast, and lasted 210 min (time, -120 min to 90 min), divided into an equilibration period (-120 to -30 min), a basal period (-30 to 0 min), and an exercise period (0 to 90 min). A primed (18 µCi) constant infusion (0.18 µCi/min) of [3-3H]glucose was started at t = -120 min and continued throughout the experiment.
Exercise consisted of 90 min of continuous pedaling (at 60–70 rpm) on an upright cycle ergometer (Medical Graphics, Yorba Linda, CA) at 80% of the individual’s AT (
50% VO2 max). Plasma glucose was measured every 5 min and maintained equivalent to baseline levels throughout the study via variable rate infusion of 20% dextrose. In an attempt to reproduce the drop in insulin levels that physiologically occurs with exercise of this intensity, the basal insulin infusion rate was decreased by 40% after the first 30 min of exercise, provided that the resulting reduced rate was at least 1 U/h. In cases in which a 40% reduction of the basal rate would have resulted in an insulin infusion rate of less than 1 U/h, a minimum rate of 1 U/h was maintained. The choice of this minimum rate of insulin infusion was meant to reproduce the basal insulin levels of T1DM patients maintained on a basal/bolus regimen of multiple daily insulin injections, rendering our findings more clinically applicable to everyday diabetes life. Potassium chloride was also infused (5 mmol/h) during exercise. After completion of the exercise protocol, patients consumed a meal and were discharged.
Tracer methodology
Rates of glucose appearance (Ra), endogenous glucose production (EGP), and glucose use were calculated according to the methods of Wall et al. (22). EGP was calculated by determining the total Ra (this comprises both EGP and any exogenous glucose infused to maintain euglycemia) and subtracting from it the amount of exogenous glucose infused. It is now recognized that this approach is not fully quantitative, because underestimates of total Ra and rate of glucose disappearance (Rd) can be obtained. This underestimate can be largely overcome by use of HPLC-purified tracer and taking measurements under steady state conditions (i.e. constant specific activity). To minimize the exercise-induced change in glucose specific activity, a 2- to 3-fold increase in tracer infusion rate (based on preliminary data for this group of patients at this work intensity) was implemented during the first 30 min of exercise. Thus, a new steady state was achieved during the last 30 min of exercise, and only data recorded at baseline and during the last 30 min of exercise were used in calculating glucose turnover.
Analytical methods
The collection and processing of blood samples have been described elsewhere (23). Plasma glucose concentrations were measured in triplicate using the glucose oxidase method with a glucose analyzer (Beckman, Fullerton, CA). Glucagon was measured according to a modification of the method of Aguilar-Parada et al. (24) with an interassay coefficient of variation (CV) of 12%. Insulin was measured as previously described (25) with an interassay CV of 9%. Catecholamines were determined by HPLC (26) with an interassay CV of 12% for epinephrine and 8% for norepinephrine. We made two modifications to the procedure for catecholamine determination: 1) we used a five-point rather than a one-point standard calibration curve; and 2) we spiked the initial and final samples of plasma with known amounts of epinephrine and norepinephrine so that accurate identification of the relevant respective catecholamine peaks could be made. Cortisol was assayed using the Clinical Assays Gamma Coat RIA kit with an interassay CV of 6%. GH was determined by RIA (27) with a CV of 8.6%. PP was measured by RIA using the method of Hagopian et al. (28) with an interassay CV of 8%. Lactate, glycerol, alanine, and ß-hydroxybutyrate were measured in deproteinized whole blood using the method of Lloyd et al. (29). Nonesterified fatty acids were measured using the WAKO kit adopted for use on a centrifugal analyzer (30).
On d 2, blood samples for glucose flux were taken every 10 min throughout the basal period and every 15 min during exercise. Blood for hormones and intermediary metabolites was drawn twice during the basal period and every 15 min during the exercise period. Cardiovascular parameters (pulse, systolic and diastolic arterial pressure) were measured every 10 min from t = -30 min to t = 90 min. Gas exchange measurements were performed during the basal period and during the final 10 min of exercise.
Materials
HPLC-purified [3-3H]glucose (NEN Life Science Products, Boston, MA) was used as the glucose tracer (11.5 mCi/mM). Human regular insulin was purchased from Eli Lilly \|[amp ]\| Co. (Indianapolis, IN). The insulin infusion solution was prepared with normal saline and contained 3% (vol/vol) of the subjects’ own plasma.
Statistical analysis
Data are expressed as mean ± SE, unless otherwise stated, and analyzed using standard, parametric, two-way ANOVA with repeated measures design. This was coupled with Duncan post hoc test to delineate at which time points statistical significance was reached. A P value of less than 0.05 indicated significant difference.
Results
Insulin, glucose and counterregulatory hormone levels
Glucose levels were similar between groups at the start of exercise and were maintained at baseline levels throughout the experiment, with no difference between genders (Fig. 1). Before exercise was started, plasma insulin levels were 72 ± 12 pM in men and 66 ± 15 pM in women; these levels remained unchanged through the exercise bout (last 30 min, men, 72 ± 12 pM; women, 60 ± 6 pM; Fig. 1).
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). Norepinephrine also increased by a greater extent during exercise in men (from 1.9 ± 0.3 to 5.9 ± 0.8 nM) compared with women (from 2.0 ± 0.3 to 4.0 ± 0.7 nM; P < 0.05). Circulating levels of GH increased in men during exercise from 1 ± 0.4 µg/liter to 24 ± 9 µg/liter; a significantly smaller increase was observed in women (from 4 ± 2 to 14 ± 3 µg/liter; P < 0.05; Fig. 2).
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). The exercise-induced increases in cortisol and PP were also not different between the two experimental groups (cortisol, from 331 ± 55 to 607 ± 110 nM in men and from 414 ± 110 to 662 ± 110 nM in women; PP, from 19 ± 5 to 32 ± 8 pM in men and from 14 ± 3 to 41 ± 14 pM in women). Glucose kinetics and gas exchange measurements
Despite sizable gender differences in key neuroendocrine responses to exercise, the incremental response in EGP was not different between genders during the last 30 min of exercise (18 ± 6 µmol·kg-1·min -1 in men and 14 ± 3 µmol·kg-1·min-1 in women; Fig. 3). Similarly, the infusion rate of exogenous glucose required to maintain euglycemia during the last 30 min of exercise was comparable in men (8.9 ± 3.9 µmol·kg-1·min-1) and women (10.0 ± 3.9 µmol·kg-1·min-1; Fig. 3). The glucose Rd (Fig. 3) and specific activity (Table 2) were also not different between genders.
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). During the last 15 min of exercise, although carbohydrate oxidation tended to be higher in men compared with women, no significant gender differences in these variables were measured (Table 3).
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Blood lactate levels, similar at baseline in the two groups, increased similarly in men and women during exercise (Table 4). Basal levels of blood glycerol were similar between genders; the exercise-induced increase in this metabolite, however, was significantly greater in women (from 46 ± 7 to 188 ± 40 µM) compared with men (from 31 ± 5 to 131 ± 10 µM; P < 0.05 area under the curve; Fig. 4). Circulating levels of free fatty acids (FFA) on one hand and the ketone body ß-hydroxybutyrate on the other hand were not different between genders at baseline or during exercise (Table 4). No difference in the circulating levels of alanine was measured between the two groups at baseline or during exercise.
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Systolic and mean arterial blood pressure readings were higher in men, compared with women, throughout the study (Table 5). Exercise-induced increases in heart rate and systolic, diastolic, or mean arterial pressure, however, were similar between genders.
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In this study, a comprehensive evaluation of neuroendocrine and metabolic counterregulatory responses was performed during 90 min of moderate exercise in a group of adult patients with T1DM matched for age, body mass index, glycemic control, and levels of physical fitness. To prevent the confounding effect of hyperglycemia/hypoglycemia before and during exercise, euglycemia was strictly controlled. To reproduce the standard insulin profile of the average T1DM patient, who is likely to administer one or two injections per day of long-acting insulin, basal insulin levels were maintained via constant infusion of 1 U/h of insulin. Under these conditions, a clear sexually dimorphic pattern of counterregulatory responses to exercise was revealed. The epinephrine, norepinephrine, and GH responses to exercise were greater in men compared with women. EGP and exogenous glucose infusion rates, however, were similar between sexes, whereas lipolysis was increased in women.
Despite similar experimental conditions during exercise (identical insulin and glycemic levels, relative exercise intensity, and degree of individual fitness), the epinephrine and norepinephrine responses were significantly increased in men compared with women, suggesting a gender difference in sympathetic nervous system (SNS) activity during exercise. The effect of greater SNS activity may also have been reflected in our patients’ cardiovascular adaptation to exercise. Although incremental responses in measured cardiovascular parameters were not significantly different between genders, men displayed consistently higher systolic and mean arterial blood pressures compared with women. A condition of greater SNS activation in men during exercise is consistent with previous reports from our laboratory (13, 31) and other laboratories (10). It has also been previously hypothesized that during exercise, male subjects may display a more generalized increase in autonomic nervous system (ANS) activation, including a parasympathetic component. Indeed, our laboratory has previously reported a significantly greater PP response to exercise in healthy men compared with women (13). PP, although not a direct measurement of parasympathetic activity, is considered a reliable marker of vagal efferent input to the pancreas. In the present study, no gender difference was apparent in the PP response to exercise. It should be noted, however, that diabetes per se has been determined to reduce the magnitude of the PP response to other stress (hypoglycemia; Ref. 32). Furthermore, in nondiabetic subjects, induction of acute autonomic failure resulted in severely reduced PP responses to hypoglycemia of identical magnitude in men and women (31). Therefore, an inherent, subtle inability to appropriately increase PP secretion during exercise (due to prolonged diabetes) may have contributed to the lack of gender differences observed in our diabetic patients.
Among other neuroendocrine responses to exercise, GH was reduced in women compared with men, but cortisol and glucagon were similar in both genders. A nonhomogeneous pattern in hormonal responses to stress is not unusual. A recent study has shown that plasma cortisol responses to hypoglycemia, for instance, were the only hormonal response not reduced by 3 h of antecedent exercise (31); furthermore, healthy men and women with significant differences in catecholamine and ANS responses to exercise displayed similar cortisol elevations (13). The glucagon response to exercise deserves particular attention. During the first few years after the onset of T1DM, pancreatic 
-cells become permanently unable to increase glucagon secretion in response to hypoglycemia (14). T1DM patients, however, maintain a normal ability to produce a full glucagon response to exercise. The preservation of this response may be crucial in preventing or limiting exercise-associated hypoglycemia in later stages of the disease, when the onset of diabetic autonomic neuropathy may impair other counterregulatory mechanisms (33). The characteristics of the glucagon response to exercise in the present study (magnitude and lack of gender difference) paralleled the glucagon response reported in healthy men and women during similar experimental conditions.
Despite the reported differences in neuroendocrine counterregulatory responses, the amount of exogenous glucose needed to maintain euglycemia during exercise and the rate of EGP were similar in men and women. It should be noted that the reported rates of exogenous glucose infusion are substantially higher that expected for this level of exercise intensity. This was probably due to the fact that the basal insulin levels maintained during exercise represented a state of relative hyperinsulinemia when compared with the physiological fall in insulin occurring during exercise in nondiabetic patients. The main determinants of EGP during moderate intensity exercise are believed to be the decrease in insulin and the increase in glucagon levels (34). In nondiabetic subjects, insulin typically decreases by 40–50% below basal levels during euglycemic exercise of intensity and duration comparable to the experimental protocol used in the present study. The modulation of this exercise-induced fall in insulin is considered one of the factors affecting adequate counterregulation during exercise. Insulin suppression during exercise is mainly mediated via -adrenergic activity (34). In situations of altered autonomic response to stress, therefore, such as the acute condition known as hypoglycemia-associated autonomic failure, a smaller reduction in insulin levels is one of several blunted responses to exercise, contributing to a generalized counterregulatory failure (35). Furthermore, the exercise-induced fall in insulin appears to be more pronounced in healthy men compared with women, possibly as part of greater systemic ANS activation (13). In our study, however, in the absence of endogenous insulin secretion and with a constant rate of exogenous insulin replacement of 1 U/h, basal insulin levels were maintained through exercise. Because the glucagon response to exercise was similar in both genders, the glucagon to insulin ratio was also similar. Therefore, the finding of identical rates of EGP during exercise in our T1DM men and women supports a pivotal role of insulin and glucagon levels in the control of EGP during exercise.
In the present study, male patients displayed a greater increase of indexes of SNS activity during exercise. This was not paralleled, however, by a proportionally greater lipolytic response. Circulating levels of glycerol, in fact, increased significantly more in women compared with men during exercise. This is consistent with several previous reports of increase lipolytic responses in women during stress (6, 8, 9, 11, 12). The underlying mechanisms for this phenomenon remain partly speculative and include gender differences in fat mass, regional lipolysis, sensitivity to ß-adrenergic effects, and relative stimulation of - and ß-adrenoreceptors (12, 36). In our study, a significant increase in circulating FFA did not parallel, in female patients, the increase in glycerol levels. The pattern of peripheral substrate oxidation, however, as detected by gas exchange, although not statistically different between genders, supports a shift toward greater usage of fats in women. Fat oxidation was 20% higher, and carbohydrate oxidation was 20% lower compared with men. Furthermore, a previous study reported a gender-related discrepancy in glycerol and FFA incremental responses during exercise (37). In this study, healthy men and women displayed a similar glycerol, but not FFA, increase during prolonged submaximal exercise, raising the speculation of gender-specific regional adipose tissue hypersensitivity to insulin. Insulin, indeed, may have played a role in the present study, because it should also be noted that our experimental design required basal insulin levels to be maintained through the exercise bout. This choice was meant to reproduce the standard insulin profile of T1DM patients on multiple daily insulin injections, rendering our findings more clinically applicable to everyday diabetes life. However, a possible drawback is the potential confounding effect of relative hyperinsulinemia on lipid metabolism during exercise. A relatively increased antilipolytic effect of insulin, particularly in our female patients, may have masked a greater gender difference in lipolysis and possibly affected circulating FFA levels via a gender-specific effect on reesterification.
In summary, our study demonstrated that in patients with T1DM, a marked sexual dimorphism exists in the pattern of counterregulatory responses to moderate, prolonged euglycemic exercise. These differences, including reduced catecholamine and GH responses in women and reduced lipolysis in men, were not paralleled by gender differences in EGP or the need for exogenous glucose.
We conclude that a greater SNS drive is present in male T1DM patients during moderate exercise. Despite reduced plasma levels of epinephrine, norepinephrine, and GH, T1DM women have a greater lipolytic response, possibly reflecting greater tissue sensitivity to one or all of these hormones during exercise. The glucagon response and the glucagon to insulin ratio, however, were similar between genders and appear to be the main modulator of EGP during moderate intensity exercise in T1DM.
Acknowledgments
We thank Eric Allen, Angelina Penalosa, and Wanda Snead for expert technical assistance. We also appreciate the skill and help of the nurses of Vanderbilt General Clinical Research Center in the performance of the studies included in this report.
Footnotes
This work is supported by a grant from the Juvenile Diabetes Research Foundation International (JDRFI), National Institutes of Health Grant R01 DK45369, Diabetes Research and Training Center Grant 5P60-AM20593, Clinical Research Center Grant M01-RR00095, and a Veterans Affairs/JDRFI Diabetes Research Center grant. P.G. was supported by a JDRFI research fellowship grant.
Present address for P.G.: University of California, Irvine, General Clinical Research Center Bionutrition/Metabolism Core, Orange, California 92868.
Abbreviations: ANS, Autonomic nervous system; AT, anaerobic threshold; EGP, endogenous glucose production; FFA, free fatty acids; PP, pancreatic polypeptide; Ra, rate of appearance; Rd, rate of disappearance; SNS, sympathetic nervous system; T1DM, type 1 diabetes mellitus; VO2 max, maximum rate of O2 consumption.
Received May 15, 2002.
Accepted August 14, 2002.
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