| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
McGill Nutrition and Food Science Center, Royal Victoria Hospital (E.B.M.), Montreal, Quebec, Canada H3A 1A1; the Departments of Physiology and Medicine, University of Toronto (S.J.F., M.V.), Toronto, Ontario, Canada M5S 1A8; the Department of Internal Medicine and Institute of Gerontology, University of Michigan and Veterans Affairs Medical Center (J.B.H.), Ann Arbor, Michigan 48109; and the Department of Medicine and Loeb Health Research Institute, University of Ottawa (R.J.S.), Ottawa, Ontario, Canada K1Y 4E9
Address all correspondence and requests for reprints to: Dr. Errol B. Marliss, McGill Nutrition and Food Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: emarliss{at}rvhmed.lan.mcgill.ca
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-adrenergic stimulation to this Ra effect. |
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
O2max), with the increment of uptake (Rd)
precisely matched by that of production (Ra). It is generally held that
this Ra response is due to the increase in the portal vein
glucagon/insulin ratio (1). It has been postulated that the afferent
signals for the neurally mediated increase in glucagon and decrease in
insulin arise from the exercising muscle itself (1, 2, 3), constituting a
feedback mechanism. In contrast, intense exercise (
80%
O2max) is associated with changes in peripheral
plasma glucagon and insulin that would be of insufficient magnitude to
stimulate the up to 8-fold increase in Ra that occurs (4–7; reviewed
in Refs. 8, 9). Even extrapolated to probable portal venous
concentrations, such changes would not be able to stimulate such a
large increase in Ra. Furthermore, in islet cell clamp experiments, the
catecholamine response to exercise was intact, and even a substantial
rise in immunoreactive insulin (IRI) did not attenuate the Ra response
(10, 11).
Therefore, a signal for rapid and marked hepatic glycogenolysis
(apart from glucagon/insulin ratio responses) is required, anticipating
the need for an increase in Ra during intense exercise. This has been
suggested to be feedforward and centrally originated (12, 13). We
(4, 5, 6, 8, 9, 10) and others (12, 14) have proposed that it is the
catecholamine response that is the primary regulator of Ra under these
conditions. Circulating plasma norepinephrine (NE) and epinephrine
(EPI) increase at least 14-fold at nearly 100%
O2max exercise (4, 5, 6, 8, 9, 10, 12). Highly
significant correlations between the individual catecholamines and the
corresponding values of Ra during intense exercise and early recovery
(4, 5, 6, 8, 9, 10) support such a regulatory mechanism, but do not prove
it.
One approach to test this hypothesis is to observe the alterations in
glucoregulation during intense exercise in which the sympathetic
response is altered. We have tested the roles of ß-adrenergic
receptors during and after intense exercise with propranolol infusion
(15). Whereas stimulation of hepatic glucose production has been
considered to be primarily ß-receptor mediated, ß-blockade of these
receptors in our subjects surprisingly resulted in a greater Ra
response than control subjects exercised at the same
%O2max. However, the ß-blockade was
accompanied by a substantial decrease in IRI, presumably from unmasking
of -receptor-mediated inhibition of insulin secretion, and this led
to a greater increase in the glucagon/insulin ratio, which could have
contributed to the greater Ra.
Furthermore, ß-blockade increased Rd during both exercise and early recovery. Thus, the sustained hyperglycemia that usually occurs for up to 60 min of recovery was shortened. The substantial hyperinsulinemia of early recovery was the same with and without ß-blockade, so the enhanced Rd was due to the adrenergic blockade. In unblocked subjects with type 1 diabetes mellitus, plasma glucose remained elevated for at least 2 h postexercise (6) unless the exogenous insulin infusion rate was increased at exhaustion to mimic the normal response (7). Thus, type 1 diabetic subjects provide a model for testing the relative importance of islet hormones vs. catecholamines on both Ra and Rd during both exercise and recovery.
The present study was therefore undertaken in such subjects, during euglycemia attained by overnight insulin infusion, in whom the infusion rate was kept constant throughout the exercise and recovery periods. This report compares their responses principally to those of previously reported nondiabetic control subjects who received the same propranolol infusion and were exercised at the same high intensity and, where pertinent, to the responses of control subjects exercised at the same intensity without adrenergic blockade (15).
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
.
None had evidence of cardiovascular, pulmonary, hepatic, hematological,
renal, or other systemic disease. All were nonsmokers, and the control
subjects were taking no medications. The diagnosis of type 1 diabetes
mellitus was based on the onset of classical symptoms in youth, with
marked hyperglycemia, and the absence of measurable C peptide in
plasma. There was no clinical or laboratory evidence of complications
of diabetes. All received at least twice daily injections of insulin.
Subjects were informed of the purpose of the study and the possible
risks of the exercise, propranolol, cannulations, blood sampling, and
tritiated glucose administration. They gave consent as prescribed by
the institutional human ethics committee. Screening before the study
included medical history, physical examination, hemogram, blood
biochemistry, hepatitis B serology, urinalysis, electrocardiogram, and
chest roentgenogram. TSH and hemoglobin A1 were
measured in the diabetic subjects. All studies took place in the
exercise physiology laboratory of the McGill Nutrition and Food Science
Centre at the Royal Victoria Hospital.
|
O2max was determined with continuous
breath by breath analysis during an incremental workload test in the
sitting upright position on an electrically braked cycle ergometer
(Collins Metabolic Cart, Warren E. Collins, Inc., Braintree, MA).
Resistance was increased by 20 watts each minute until exhaustion. In
this and the subsequent tests, exhaustion was defined by the subject as
the time at which he was unable to continue cycling, uniformly reported
as due to leg muscle fatigue. The same investigators used the same
approach with verbal encouragement to the subjects to exercise to
their individual limits. Oxygen uptake
(O2, standard temperature, pressure, dry
gas; liters per min), carbon dioxide output
(CO2, standard temperature, pressure, dry
gas), ventilation (liters per min), and respiratory
exchange ratio were acquired and recorded at 30-s intervals. Heart rate
was displayed electro-cardiographically.
On a separate occasion at least 2 days after the
O2max test, each subject underwent a
second test without blood sampling, at 50% for 30 s, followed by
70–80% of the previously established maximum workload. This test was
performed to familiarize the subjects with the workload protocol, to
determine that the time to exhaustion would be 12–15 min, and to
assure intersubject uniformity in endurance. The third exercise study
was performed after an interval of at least 2 days from the second test
and in most cases after an interval of more than 1 week. Seven control
(CP) and six diabetic subjects (DM) underwent ß-blockade with
propranolol (Inderal, Wyeth-Ayerst Laboratories, Inc.,
Montreal, Canada), whereas the seven other control (C) subjects
received no propranolol. This study began at 0800–0900 h with subjects
in the 12-h overnight fasted (postabsorptive) state, without having
undergone any significant exercise in the preceding 24 h. In the
diabetic subjects, intermediate and long acting insulin treatments were
stopped 48 h before the study, and glucose control was obtained by
frequent injections of regular insulin, as previously described (6, 7).
Their glycemias were brought to normal and maintained overnight by
continuous iv insulin infusions (Humulin R, Eli Lilly Canada, Scarborough, Canada), adjusted every 30 min. The rates
that achieved euglycemia were kept constant for the rest, exercise, and
recovery periods.
A 20-gauge Cathlon IV cannula (Critikon Canada, Inc., Markham, Canada) was inserted into one antecubital vein for blood sampling, and another was inserted into a forearm vein of the other arm for infusion. The subjects remained sitting, with the catheters kept patent by a slow infusion of physiological saline. After 20–30 min, a preinfusion blood sample was drawn, and the infusion of high performance liquid chromatography-purified [3-3H]glucose tracer (NEN Life Science Products, Billerica, MA) was begun. A priming bolus at time zero of 11 mL was followed by a constant infusion at 0.109 mL/min (of a solution containing 2 µCi/mL in 0.9% saline) for 150 min. Blood was sampled at 90, 100, 110, 120, 130, 140, and 150 min to assure a near steady state enrichment of plasma [3H]glucose. In the ß-blocked subjects, 30 min before exercise, iv propranolol was started. A dose of 150 µg/kg was given over 20 min, followed by a continuous infusion of 80 µg/min that was continued through exercise and stopped at 60 min of recovery. The rate of tracer infusion was increased stepwise during exercise and returned stepwise to the original rate during recovery, a method that attenuates changes in [3H]glucose specific activity during the rapid changes in glucose kinetics and thereby assures the validity of glucose turnover calculations (16). The [3H]glucose infusion was continued for the 2 h of recovery. During exercise, blood was sampled at 2-min intervals. A sample was drawn at exhaustion, and this time was defined as time zero of recovery, such that samples were drawn at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 80, 100, and 120 min thereafter for glucose and radioactivity measurements. Samples for all other measurements were drawn at 0 and 10 min before exercise, at 4 and 10 min of exercise, at exhaustion, and at 4, 8, 10, 15, 20, 30, 40, 60, and 100 min during recovery.
Samples for glucose turnover measurements were placed into tubes that contained heparin and sodium fluoride and were processed as described previously (5). Heparinized plasma was collected with aprotinin (10,000 kallikrein inhibitor units/mL; Trasylol, FBA Pharmaceuticals, New York, NY) in volume 1/10th that of the added blood, for subsequent IRI, immunoreactive glucagon (IRG), and free fatty acid (FFA) assays. For catecholamine measurements, blood was added to ethyleneglycol-bis-(ßaminoethyl ether)-N,N,N',N'-tetraacetic acid- and reduced glutathione-containing tubes, and the plasma was frozen at -70 C until assay. One aliquot of whole blood was immediately deproteinized in an equal volume of cold 10% (wt/vol) perchloric acid and kept on ice until centrifuged at 4 C, then frozen at -20 C for later lactate, pyruvate, and glycerol assays.
Glucose was measured by the glucose oxidase method using a Glucose Analyzer II (Beckman Coulter, Inc., Fullerton, CA). Blood lactate, pyruvate, and glycerol were measured by two-channel automated enzymatic microfluorometric methods, enabling assay of replicate 5- or 10-µL aliquots of the perchloric acid supernatants and using two Turner model 430 spectrofluorometers (Sequoia-Turner Corp., Mountain View, CA) by methods previously detailed (10). Plasma insulin was determined by RIA using an antibeef insulin antiserum, purified human insulin standard (27.3 µU/ng), and125I-labeled human insulin (Linco Research, Inc., St. Louis, MO). Free insulin was measured in the diabetic subjects on polyethylene glycol extracts of plasma after 1-h incubation in vitro for 37 C before storage at -20 C. IRG was measured in plasma by either single (in C and CP) or double (DM) antibody RIA using purified porcine glucagon for standard and as 125I label, and a pancreatic glucagon-specific antibody [Novo Research Institute (Copenhagen, Denmark) and Linco Research, Inc., respectively]. Plasma C peptide was measured by double antibody RIA in the DM subjects (Linco Research, Inc.). FFA were estimated using a radiochemical method. All assays performed on aprotinin-containing plasma were corrected for the plasma dilution introduced, using the concurrently obtained hematocrit. Plasma NE and EPI concentrations were measured using a radioenzymatic technique (17). The sensitivity of this method is less than 50 pmol/L. The intra- and interassay coefficients of variation for all assays were <10%; for the enzymatic assays, they were less than 5%. Glucose production (appearance, Ra) and utilization (disappearance, Rd) were calculated from the variable isotope infusion protocols according to the one-compartment model with a pool fraction of 0.65 (18), with data systematically smoothed using the Optimized Optimal Segments program (19). The glucose MCR was calculated by dividing Rd by the plasma glucose concentration at each time point.
Baseline characteristics were analyzed using one-way ANOVA. Study
workload was calculated as the mean workload for all but the first
30 s of exercise. Study O2 was
calculated as the mean O2 during the last
half of exercise. Glucose, glucose turnover, and other metabolite and
hormone results were analyzed by ANOVA for repeated measures. Separate
analyses were performed between CP and DM and to compare all three
groups. Intergroup differences found to be significant
(P < 0.05) were subsequently analyzed by the
Student-Newman-Keuls test. Linear correlations were calculated using
the Pearson correlation coefficient. Individual correlation
coefficients were calculated using all data points for each individual
at which catecholamines were measured. This correlation coefficient was
then treated as a continuous variable on which the mean and
SE were calculated, and intergroup differences
were assessed using one-way ANOVA. The SAS-STAT software package
(SAS Institute, Inc., Cary, NC), SPSS-Windows release 6.0
software package (SPSS, Inc., Chicago, IL), Microsoft
Excel 5.0 Analysis ToolPak (GreyMatter International, Inc., Cambridge,
MA), and Primer Biostats (McGraw-Hill, New York, NY) were used. Data
are presented as the mean ± SE.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
),
although it was set at about 14 min in C. It was necessary to exercise
the C subjects with both the same duration and percentage of their
individual O2max levels as the ß-blocked
subjects, because of the limitation in increase in heart rates due to
propranolol in the latter. Thus, the C subjects did not work to
exhaustion, but the CP and DM subjects did. The anthropometric data,
relative fitness (indicated by similar O2
per kg/min), and the key exercise end point (study
O2/O2max) did
not differ among the three groups (Table 1). Interestingly, the heart
rate at the end of exercise was lowest in CP and intermediate in DM
subjects (P = 0.0005 among the three groups). The
hemoglobin A1 values in the DM subjects indicated
excellent diabetes control.
Plasma glucose (Fig. 1A) was
not different in the groups before exercise and increased significantly
during exercise to the same peak values at 2 min of recovery (6.8
± 0.7 mmol/L in DM and 6.5 ± 0.4 mmol/L in CP; P
= NS). Glycemia returned rapidly to baseline levels in CP subjects, but
more slowly in DM (P = 0.049 from 8–60 min). The
hyperglycemic response was smallest in C subjects (P =
0.035). The plasma glucose specific activities did not vary by greater
than 25% over time within each subject despite rapid changes in
glucose turnover (data not shown). The baseline Ra was the same, as
were exercise responses in CP and DM. Peak values at the end of
exercise were 13.3 ± 1.6 mg/kg·min in CP and 11.6 ± 1.0
mg/kg·min in DM. Although declining rapidly in early recovery, Ra
remained higher in DM than CP from 2–15 min (P =
0.013). Baseline levels were reached by 20 min, but CP subjects showed
a small, but significant, later increment (P = 0.038)
to rates above DM from 25–120 min of recovery. Notably, the exercise
Ra response was considerably smaller in C subjects (P
< 0.001).
|
) did not differ significantly between CP and DM
before or during exercise or in early recovery. Peak rates at
exhaustion were 10.6 ± 0.9 mg/kg·min in CP and 9.2 ± 1.0
mg/kg·min in DM. The mean Rd was higher in CP than DM from 50–100
min of recovery (P = 0.050). Thus, in DM the
combination of the slower Ra decline in early recovery and the lower Ra
and Rd in later recovery accounts for the slower decline in glycemia.
As with Ra, the Rd response was considerably less in C subjects
(P = 0.032). The MCR (Fig. 1D) increased comparably by
the end of exercise in CP and DM subjects and did not differ
significantly during recovery. The response in C was again less than
those in CP and DM both during exercise (P = 0.030) and
until 15 min of recovery.
IRI was higher (P = 0.011) in DM than in CP
subjects before exercise (Fig. 2A). The
responses during exercise were opposite (P = 0.003),
with a small, but significant (P < 0.05), decline in
CP and a rise in DM subjects. In recovery, a rapid and significant rise
to a peak at 4 min in CP subjects was followed by sustained elevations
above the values at the end of exercise for 20 min before returning to
baseline values thereafter. Because of this rise, their values were not
different from those in DM subjects in the first 30 min of recovery.
However, because in DM, once returning to baseline, plasma IRI remained
unchanged thereafter, its levels were higher than those in CP subjects
for the remainder of recovery (P = 0.008). With the
exception of no significant change during exercise, responses in C were
not different from those in CP.
|
). Although
a trend toward an increase during exercise in all groups was present,
this did not reach statistical significance, nor were there significant
intergroup differences during or after exercise. The mean
glucagon/insulin ratio (Fig. 2C) was lower in DM than in CP subjects
before exercise (but P = 0.104), related to their
higher IRI. A significant increase (P = 0.002) occurred
in the CP subjects (whose IRI declined), but there was no change in DM
subjects, although by ANOVA the exercise responses were not
significantly different (P = 0.069). In recovery, the
ratio decreased in CP for a duration corresponding to that of the
increase in IRI levels, whereas in DM subjects it remained constant. In
C, there was no significant change in exercise.
The catecholamine responses (Fig. 3) did
not differ by ANOVA between CP and DM subjects, although the timing of
the responses varied. The NE (Fig. 3A) increased to a peak of 23.7
± 3.6 nmol/L at 4 min of exercise in CP, but increased progressively
during exercise to a peak of 25.7 ± 3.0 nmol/L at exhaustion, in
DM subjects. NE returned promptly in both CP and DM to baseline
concentrations not different from one another by 20 min of recovery.
The exercise responses of C were less (incremental area under the curve
was less than that in CP, P < 0.05), with peak at
exhaustion of 15.2 ± 2.9 nmol/L. A similar pattern of responses
to exercise occurred in EPI levels (Fig. 3B). In CP, the peak of
7050 ± 2200 pmol/L was at 4 min, and levels were still at
5600 ± 1530 pmol/L at the end of exercise. In the DM, the peak
EPI of 4700 ± 1650 pmol/L was reached at the end of exercise.
Because of interindividual variability, responses during exercise were
not significantly different (P = 0.180). Once again,
responses of C subjects were considerably less than those of CP and DM
subjects (P = 0.026); the peak value reached was
1720 ± 340 pmol/L. Although in all subjects, the return to
baseline values was rapid, by ANOVA a difference (P =
0.002) persisted from 4–100 min, with concentrations in CP being
higher than those in C throughout and higher than those in DM subjects
from 60–100 min. The correlation coefficients of NE and EPI with Ra
were highly significant in all three groups of subjects (Table 2).
|
|
.
Lactate responses (Fig. 4A) differed somewhat during exercise. CP
increased earlier, but DM reached peak values at the end of exercise
(10.6 ± 0.8 mmol/L) that were higher than those in CP (7.8
± 0.6 mmol/L) and C (5.7 ± 0.6 mmol/L; P =
0.003). However, by repeated measures ANOVA, the differences for the
whole exercise period were not significant. The decline during recovery
was such that lactate levels in DM subjects were significantly higher
than those in CP throughout (P = 0.023). In C during
both exercise and recovery, concentrations were lower
(P = 0.001). In contrast, the marked increments in
pyruvate (Fig. 4B) during exercise were not different among the three
groups. Peak values occurred at 4 min of recovery, with those in DM
higher (P = 0.008) than values in the other groups and
remaining higher (P = 0.008) until 100 min of recovery
(P < 0.001).
|
) were suppressed
comparably before exercise and did not change during or after exercise.
In C, levels were higher at baseline (P < 0.015),
decreased to the same levels as in CP and DM during exercise, rebounded
transiently at 4 min of recovery, then declined again by 40 min. Blood
glycerol (Fig. 4D) levels were suppressed more by propranolol at rest
in DM than in CP subjects (P < 0.001) and remained
lower during exercise (P = 0.002) and recovery
(P = 0.049). Although concentrations rose slightly in
DM with exercise, the response was not significant. In contrast,
glycerol increased substantially in C during exercise
(P < 0.001) vs. levels in CP and DM. |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The greater Ra responses we previously reported in these CP compared to
C subjects (15) could not be proven to be due only to the greater
catecholamine responses, acting via an -adrenergic receptor
mechanism, because the fall in IRI and the rise in the glucagon/insulin
ratio might have contributed. Thus, the DM subjects add further
evidence in support of the proposed mechanism. That they had the same
Ra response during exercise in association with a rise in IRI and no
change in glucagon/insulin ratio constitutes strong evidence that
neither suppression of insulin release nor stimulation of glucagon
secretion contributes to the marked Ra response. We previously reported
such increments in IRI in type 1 diabetic subjects using the same
paradigm but at even more intense exercise (6, 7), yet with normal Ra
and catecholamine responses. Furthermore, in islet cell clamp
experiments with basal hormone replacements kept at constant rates
during exercise, the IRI also increased, the glucagon/insulin ratio
decreased, yet the Ra and catecholamine responses were identical to
those in control subjects (10, 11). During exercise with -blockade
by iv phentolamine, there was a 3-fold rise in IRI that did not
attenuate the Ra response, (32) (our unpublished data). Only if the
rise in IRI precedes the exercise does partial attenuation of the Ra
response occur (33).
Previous studies of the roles of - vs. ß-adrenergic
activation of Ra yielded differing results both within and between
species (23), at rest during catecholamine infusions, and during
exercise of different intensities. The following have been observed at
rest. In rats, -receptors are most important (34), whereas in dog
hepatocytes, ß-receptors are dominant, and both play roles in cats
(reviewed in Ref. 23). Some human studies have suggested the
predominance of ß-receptors (22, 23, 32), whereas others both do (24, 26, 35, 36) and not do not (22, 25, 37) support a role for
stimulation of Ra. Interestingly, NE infusion has been shown to
increase Ra only at or above plasma levels of about 10.6 nmol/L (35).
Although NE activates both - and ß-receptors, it appears to act
mainly via -receptors. One possibility is, therefore, that
-adrenergic stimulation of Ra occurs only when the level exceeds
such a threshold. As NE is released at sympathetic nerve endings in the
liver, levels exceeding these could well occur without being reflected
in the circulation. Intraportal catecholamine and adrenergic blocker
infusions in dogs suggest that NE stimulation of Ra is mainly via
1 and EPI is mainly via ß2-adrenergic
receptors (38). Taking all such results together, there is probably an
important Ra effect of both main classes of receptors that may
contribute differently according to the nature and intensity of the
stimulus, i.e. some redundancy exists.
This could explain results obtained at lower intensities of exercise
than the present study. Normal subjects had increased Ra during
moderate intensity exercise with propranolol infusion (27), consistent
with ß-blockade unmasking -adrenergic stimulation. The same study
presented data that raise the possibility of attenuation of the Ra
increase by the -blocker phentolamine. The paradigm of clamping
insulin and glucagon and combined - and ß-adrenergic blockade
during moderate exercise brought out a role for catecholamines in Ra
regulation; Ra failed to increase, and hypoglycemia ensued (28).
Interestingly, propranolol and phentolamine infused together directly
into the portal vein of dogs were able to block the Ra effects of
portally infused NE and EPI at rest, but not a 4-fold Ra increment
during exercise (39). These results at lower intensity are consistent
with 1) the magnitude of the need for stimulation of Ra being the key
factor in determining which mediators are most important, 2) unmasking
a role for catecholamines when the principal regulators are prevented
from responding normally, and 3) a role for locally released NE in the
liver in stimulation of Ra.
The present Rd data support a key role for ß-receptors in restraining the increment in glucose uptake by the exercising muscles. Compared with C subjects, both DM and CP subjects demonstrated markedly enhanced Rd in the presence of both increased and decreased IRI during exercise. ß-Adrenergic receptor stimulation causes muscle glycogenolysis, thereby decreasing the uptake of glucose because of the increase in intracellular glucose-6-phosphate (40). ß-Blockade attenuates the increase in glycogenolysis, resulting in a major increment in glucose Rd. This is of particular interest in the DM subjects. Our previous studies in such subjects in whom insulin infusion rates were held constant during exercise and recovery showed a sustained rise in plasma glucose throughout recovery (6, 7). Doubling the insulin infusion rate to mimic normal physiology restored glycemia to the resting level (7). Although these studies were at higher intensity, the rise in Rd was the same as that observed in the present DM subjects. Therefore, this implies that the rate of ß-receptor-mediated muscle glycogenolysis has an inverse effect on muscle glucose uptake in this special setting, which can be overcome by increasing the insulin infusion during recovery (7). ß-Blockade doubtless also contributed to the shortened duration of the hyperglycemic response during recovery in the CP subjects.
This return to baseline glycemia in the DM subjects in the absence of a sustained increase in IRI has implications for persons with diabetes treated with ß-blocking drugs. Hypoglycemia in such persons poses greater risks due to attenuation of adrenergic symptoms and to impairment of counterregulation. The present results suggest that a major component of the regulation of plasma glucose is related to enhanced glucose disposal. Thus, a person taking such medication would have yet another mechanism that could contribute to postexercise hypoglycemia after exercise that would ordinarily produce glycogen depletion. Studies at lower intensity gave results consistent with this (27, 28). In patients receiving sc insulin, the problem might be further amplified if they are tightly controlled. On the other hand, if the patient was hyperglycemic before intense exercise, propranolol might shorten and/or attenuate the usual hyperglycemic effect (6).
A number of differences between the responses of our DM and CP subjects are noteworthy. Baseline free IRI levels were higher in the DM subjects. This implies that peripheral insulin resistance might be present. We have no direct data on insulin sensitivity in our subjects, but none was unduly insulin resistant. Their usual daily insulin doses were 40 ± 5 U, and the mean rate of insulin infusion to maintain euglycemia at the onset of the experiment was only 0.73 ± 0.08 U/h. Furthermore, the circulating IRI of 70 ± 7 pmol/L at rest in DM, compared with 49 ± 1 pmol/L in CP, would not be an excessive portal vein level to achieve normal glucose turnover. Thus, the liver is probably not insulin resistant. This combined with the IRI rise with exercise permits us to draw conclusions about the role of catecholamines in Ra, comparing the responses of DM and CP. A role of insulin resistance in the Rd responses cannot be excluded, however.
The mechanism(s) responsible for the different blood lactate responses
in DM is not apparent from the data available. Despite the fact that
O2 responses were comparable (data not
shown), the greater hyperlactatemia developed at the end of the
exercise and persisted throughout recovery. That the same pyruvate
response occurred in all groups during exercise meant that the
lactate/pyruvate ratio was higher in the DM subjects at the end of
exercise, but there was also a sustained greater pyruvate response
during recovery.
The differences in FFA response during exercise and recovery are consistent with the known effects of the catecholamines and insulin. The suppressed FFA with propranolol is expected as lipolysis is ß-receptor mediated, and in the DM subjects IRI was elevated at rest. The failure of FFA to increase after exercise in the CP and DM groups was probably due to the ongoing effects of propranolol and the sustained higher IRI in DM. The blood glycerol responses can be explained largely by the considerations applicable to FFA.
In summary, the present study further implicates the catecholamine
responses to intense exercise as the principal mediators of the Ra
response. With ß-blockade, the marked increment in Ra is consistent
with -adrenergic receptor activation in intense exercise in both
nondiabetic and diabetic subjects. This similar response despite no
increase in the glucagon/insulin ratio in DM subjects implies that the
pancreatic hormones have a minor role if any in the Ra increment. The
marked increase in Rd with ß-blockade supports a key role for
ß-receptors in muscle glycogenolysis, such that if it proceeds at a
lesser rate, more circulating glucose is taken up. The greater lactate
response together with other differences in the metabolic and heart
rate responses suggest different effects of propranolol in diabetic
subjects. The plasma glucose decline in recovery in the DM subjects
suggests that ß-adrenergic regulation of muscle glycogenolysis is a
powerful controller of rate of glucose uptake in this setting. This may
either be beneficial in reducing elevated glycemia or constitute a risk
for hypoglycemia after glycogen-depleting exercise. The slower rate of
decline in glycemia during recovery in DM than CP subjects despite
somewhat higher IRI might be attributable to some degree of peripheral
insulin resistance.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Supported by postdoctoral fellowships from the Canadian Diabetes
Association and the Juvenile Diabetes Foundation International.
Received May 6, 1999.
Revised June 30, 1999.
Accepted July 26, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-adrenergic stimulation and its
blockade on glucose turnover in man. Am J Physiol.
238:E467–E472.
-adrenergic effect of epinephrine on glucose production
in human subjects. Am J Physiol. 246:E271–E276.
-adrenergic stimulation of hepatic glucose
production in human subjects. Am J Physiol. 245:E616–E626.
-adrenergic effect of epinephrine on glucose production
in human subjects. Am J Physiol. 246:E271–E276.
-Adrenergic mechanisms in glucoregulation in intense
exercise. Proc of the 15th Int Diabetes Fed Congr. 1994; 399.
1- and ß2-adrenergic receptors in male
rats. J Biol Chem. 258:5103–5109.- and ß-adrenergic receptor
stimulation on hepatic glucose production during heavy exercise.
Am J Physiol. 273:E831–E838.
This article has been cited by other articles:
 |
|
 |
|
  V. A. Bussau, L. D. Ferreira, T. W. Jones, and P. A. Fournier The 10-s Maximal Sprint: A novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes Care, March 1, 2006; 29(3): 601 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Sigal, G. P. Kenny, D. H. Wasserman, and C. Castaneda-Sceppa Physical Activity/Exercise and Type 2 Diabetes Diabetes Care, October 1, 2004; 27(10): 2518 - 2539. [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Hoffman, C. A. Sinkey, J. M. Dopp, and B. G. Phillips Systemic and Local Adrenergic Regulation of Muscle Glucose Utilization During Hypoglycemia in Healthy Subjects Diabetes, March 1, 2002; 51(3): 734 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Marliss and M. Vranic Intense Exercise Has Unique Effects on Both Insulin Release and Its Roles in Glucoregulation: Implications for Diabetes Diabetes, February 1, 2002; 51(90001): S271 - 283. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
; n
= 7) are compared to those from propranolol-infused DM subjects (
;
n = 6). Results from C subjects without propranolol are shown in
shaded area with the mean ± SE (n = 7). C and CP
data are from Ref. 15. The propranolol infusion, indicated by the
horizontal bar, was begun 30 min before exercise and
ended at 60 min of recovery. Data are presented as the mean ±
SE. Where SE bars are not present, they are
smaller than the symbol. Significant differences are specified in the
text.
