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Reduced counterregulatory responses to a next-day hypoglycemic challenge and hypoglycemia result from two spaced episodes of moderate-intensity exercise and have been characterized as exercise-associated autonomic failure. We hypothesized that this phenomenon is caused by postabsorptive state at the time of exercise rather than by autonomic failure. Participants were nine healthy postmenopausal women in a crossover study. Two hours of treadmill exercise at 43% of maximal effort were performed twice a day, separated by 5 h, either 1 h before (Before-Meals trial) or 1 h after a meal (After-Meals trial). Plasma insulin, counterregulatory hormones (glucagon, growth hormone, cortisol), and metabolites (glucose, free fatty acids, ketones) were measured to evaluate the effects of nutritional timing. Analyses of HR and vagal tone were measured to assess autonomic function. Before-Meals exercise, but not After-Meals exercise, reduced postabsorptive plasma glucose by 20.2% during a 16-h period, without a change in counterregulatory response, and elicited postexercise ketosis. A 49% increase in insulin-glucagon ratio during meals, a 1 mM decline in glucagon glycemic threshold, and a reduced vagal tone during exercise were associated with Before-Meals but not with After-Meals trials. These results demonstrate that exercise performed in postabsorptive, but not in postprandial state, lowers glucoregulatory set point and glucagon glycemic threshold and is accompanied by reduced vagal tone, counterregulatory responses, and glucagon glycemic threshold and by increased insulin-glucagon ratio. Reduced counterregulatory response, altered neuroendocrine function, and sustained lowering of blood glucose are most likely the consequences of reduced carbohydrate availability during exercise.
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Two Bouts of Exercise before Meals, but Not
after Meals, Lower Fasting Blood Glucose
KATARINA T. BORER
1
, ELIZABETH C. WUORINEN
1
, JAMIE R. LUKOS
1
, JOHN W. DENVER
3
,
STEPHEN W. PORGES
3
, and CHARLES F. BURANT
1,2
1
School of Kinesiology, University of Michigan, Ann Arbor, MI;
2
Department of Internal Medicine,
University of Michigan, Ann Arbor, MI; and
3
Brain-Body Center, Department of Psychiatry, University of
Illinois at Chicago, Chicago, IL
ABSTRACT
BORER, K. T., E. C. WUORINEN, J. R. LUKOS, J. W. DENVER, S. W. PORGES, and C. F. BURANT. Two Bouts of Exercise
before Meals, but Not after Meals, Lower Fasting Blood Glucose. Med. Sci. Sports Exerc., Vol. 41, No. 8, pp. 1606–1614, 2009.
Introduction: Reduced counterregulatory responses to a next-day hypoglycemic challenge and hypoglycemia result from two spaced
episodes of moderate-intensity exercise and have been characterized as exercise-associated autonomic failure. We hypothesized that this
phenomenon is caused by postabsorptive state at the time of exercise rather than by autonomic failure. Methods: Participants were nine
healthy postmenopausal women in a crossover study. Two hours of treadmill exercise at 43% of maximal effort were performed twice a
day, separated by 5 h, either 1 h before (Before-Meals trial) or 1 h after a meal (After-Meals trial). Plasma insulin, counterregulatory
hormones (glucagon, growth hormone, cortisol), and metabolites (glucose, free fatty acids, ketones) were measured to evaluate the
effects of nutritional timing. Analyses of HR and vagal tone were measured to assess autonomic function. Results: Before-Meals
exercise, but not After-Meals exercise, reduced postabsorptive plasma glucose by 20.2% during a 16-h period, without a change in
counterregulatory response, and elicited postexercise ketosis. A 49% increase in insulin–glucagon ratio during meals, a 1 mM decline in
glucagon glycemic threshold, and a reduced vagal tone during exercise were associated with Before-Meals but not with After-Meals
trials. Conclusions: These results demonstrate that exercise performed in postabsorptive, but not in postprandial state, lowers
glucoregulatory set point and glucagon glycemic threshold and is accompanied by reduced vagal tone, counterregulatory responses, and
glucagon glycemic threshold and by increased insulin–glucagon ratio. Reduced counterregulatory response, altered neuroendocrine
function, and sustained lowering of blood glucose are most likely the consequences of reduced carbohydrate availability during
exercise. Key Words: RESPIRATORY SINUS ARRHYTHMIA, COUNTERREGULATION, HYPOGLYCEMIA, GLUCAGON
GLYCEMIC THRESHOLD, POSTEXERCISE KETOSIS, VAGAL TONE
Diet and exercise are integral to the prevention of
type 2 diabetes (16) by normalizing blood glucose
level and preventing damage to peripheral organs
that results from chronic hyperglycemia. When diet and ex-
ercise fail to reduce persistent hyperglycemia, pharmaco-
logical agents such as metformin (35) are added to increase
peripheral insulin sensitivity, to enhance insulin secretion,
or to reduce elevated hepatic glucose production. Improve-
ments in the efficacy of diet and exercise could aid the pre-
diabetic without the side effects of medication and with
additional health benefits of exercise.
Dysregulation of insulin action entails reduction in the
insulin-stimulated glucose uptake and increase in hepatic glu-
cose output (5,29). Hepatic glucose output is increased by
glucagon, epinephrine, growth hormone (GH), and cortisol,
and this provides adequate circulatory glucose supply dur-
ing fasting and during up to 3 h of continuous moderate-
intensity exercise. Exercise causes faster glucose clearance
from plasma owing to increased insulin-independent mus-
cle glucose uptake (27) even when additional glucose is
concurrently introduced through food or drink (22). After
4 h of continuous low-intensity exercise (3) or 3 h of
moderate-intensity exercise (2), plasma glucose gradually
declines toward the hypoglycemic level, despite robust in-
creases in counterregulatory response. This likely reflects a
limit in hepatic glucose production capacity rather than an
altered neuroendocrine response, as supplying glucose orally
(6) or intravenously (10,12) normalizes plasma glucose and
appropriately suppresses counterregulatory response.
Glucoregulation is altered when moderate-intensity exer-
cise of 90-min duration is repeated after 3 h of rest. This
treatment reduces or eliminates counterregulatory response
to a hyperinsulinemic hypoglycemic challenge reducing plas-
ma glucose to 2.8 mM administered 6 to 24 h later (8,9,
30–33). Hepatic glucose output declines, and plasma glucose
concentration declines toward hypoglycemic levels in both
healthy (8,9,32,33) and type 1 diabetic subjects (30,31). This
Address for correspondence: Katarina T. Borer, Ph.D., Division of Kine-
siology, University of Michigan, Ann Arbor, MI 49109-2214; E-mail:
Katarina@umich.edu.
Submitted for publication September 2008.
Accepted for publication December 2008.
0195-9131/09/4108-1606/0
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DOI: 10.1249/MSS.0b013e31819dfe14
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phenomenon has been characterized as exercise-associated
autonomic failure (EAAF) because of reduced of absent
counterregulatory response (33). A postabsorptive state in
combination with an extended interval between two exercise
bouts seems to be necessary for the appearance of sustained
hypoglycemia and the reduction in counterregulation be-
cause neither continuous exercise after a 72-h fast (11) nor
repeated exercise bouts of 30-min duration at 30-min in-
tervals (18) suppress vigorous counterregulatory response in
the face of plasma glucose declines.
We hypothesized that sustained hypoglycemia seen in
the spaced exercise studies is an adaptation to reduced cir-
culating carbohydrate availability during exercise. The pref-
erential glucose uptake into the exercising and postexercise
muscle does not allow adequate glucose flux to restore liver
glycogen when exercise is carried out in fasted or in post-
absorptive state (7). Increased non–insulin-dependent muscle
glucose uptake during exercise (27) and substantial depen-
dence on carbohydrate fuel during moderate-intensity ex-
ercise (28), combined with sustained increases in muscle
insulin sensitivity after exercise (13,39), channel ample
amounts of carbohydrate to muscle for glycogen synthe-
sis. Postexercise muscle glycogen synthesis is further facil-
itated by the activation of glycogen synthase in proportion
to the level of muscle glycogen depletion (17) and of the
enzyme hexokinase that is capable of sequestering glucose
at hypoglycemic concentrations so long as it is used for
glycogen synthesis (25). Because of the difference in the
K
m
of muscle hexokinase and liver glucokinase, muscle
takes precedence over liver in glucose uptake and gly-
cogen resynthesis for between several hours (7) and for
upto3dafteraglycogen-depletingexercise.Thisproduces
not only compensation but also supercompensation of
muscle glycogen stores (4) before the full recovery of
liver glycogen.
To test the hypothesis that sustained lowering of blood
glucose after two spaced bouts of exercise performed in
postabsorptive state is due to inadequate circulating carbohy-
drate availability rather than to autonomic failure, we sched-
uled exercise either 1 h before (Before-Meals) or 1 h after
(After-Meals) a meal containing 63% carbohydrate. We also
measured plasma ketone body formation after exercise
to functionally evaluate hepatic carbohydrate depletion
(1,19–21). Finally, to assess whether the reduced carbohydrate
availability was responsible for autonomic failure, we exam-
ined changes in global autonomic function during exercise
under differing prandial states by measuring HR and its var-
iability. Our aim was to gain a better understanding of the
mechanism of exercise-associated blood lowering in healthy
subjects before such lifestyle strategy could be tested in pre-
diabetic and type 2 diabetic subjects.
MATERIALS AND METHODS
The study was approved by the University of Michigan
Medical School Institutional Review Board, and all subjects
provided informed consent. Subjects were nine postmeno-
pausal women, seven white and two African American.
Eight were nondiabetic, and one African American sub-
ject was prediabetic. They were 58.5 T1.7 yr of age, with
body mass of 74.9 T4.3 kg, body mass index of 27.0 T
1.4 kgIm
j2
, and 37.3 T2.7% body fat, and four were on
hormone replacement therapy. All engaged in less than
60 min of exercise per week. Their maximal oxygen
consumption was 1.9 L O
2
Imin
j1
or 25.1 T1.5 mL
O
2
Ikg
j1
Imin
j1
. A health questionnaire, that is, and a de-
tailed physical examination that included measurements of
weight, height, body fat by a bioimpedance apparatus (RJL
Quantum II, Clinton, MI), laboratory chemistries, and
thyroid function, constituted a health screen. An exer-
cise screen consisted of indirect calorimetric measurements
(Physio-Dyne, Quoque, NY) during a treadmill test con-
sisting of 0.64-kmI3 min
j1
speed increments until maximal
effort was achieved on the basis of the respiratory quotient,
RQ of 1 as the criterion.
Study protocol. Subjects participated in two trials that
were assigned in a random order and separated by at least
1 wk (Fig. 1). After admission to the General Clinical Re-
search Center at 1800 h on the day before a trial, sub-
jects were provided at 1900 h with a standardized meal
consisting of 63% carbohydrates, 23% fat, and 14% pro-
tein that provided 25 kcalIkg
j1
body weight. A chest elec-
trode below the right clavicle and another one at the left
lower rib cage were connected to a Polar HR receiver and
a Mini-Logger2000 recorder (Respironics, Inc, Bend, OR),
worn around the waist, for measurement of HR and its var-
iability. At 0545 h the following morning, an indwelling
Teflon catheter was inserted into a forearm vein.
Meals. Two meals containing 22.7 T0.9 kcalIkg
j1
body
weight and consisting of 63% carbohydrates, 23% fat,
and 14% protein were provided at 1000 and at 1700 h of
the study day. The food provided and any food left uneaten
were weighed to allow calculation of macronutrient energy.
Exercise. Two 2-h bouts of treadmill walking at 43 T
2.5% of V
˙O
2max
were completed by each subject. The times
of Before-Meals exercise were 0700 to 0900 h and 1400
to 1600 h, and those of After-Meals exercise were 1100
to 1300 h and 1800 to 2000 h.
Metabolic measurements. RMR was measured be-
tween 0600 and 0630 h at the start and the end of the
24-h trials with a Delta Trac II metabolic cart (SensorMedics,
Yorba Linda, CA). Metabolism was also measured immedi-
ately after exercise and meals and at midnight and 0400 h.
Exercise metabolism was measured (Physio-Dyne, Quoque,
NY) during minutes 0 to 30 and minutes 60 to 90 of
each exercise bout. Energy cost of exercise and relative
use of carbohydrates and lipids were estimated using the
Weir equation (38).
Blood collection. Serial blood samples (3 to 5 mL,
n= 42) were collected into ice-chilled EDTA-coated tubes
containing 50 KLImL
j1
blood of aprotinin (Sigma Chem-
ical, St. Louis, MO) at hourly intervals except for 15- and
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30-min intervals at the start of meals and exercise. Plasma
was kept frozen at j80-C.
Hormone and metabolite measurements. Con-
centrations of insulin, glucagon (Linco Research, St. Louis,
MO), and cortisol (Diagnostic Systems Laboratories, Web-
ster, TX) were measured with radioimmunoassays. Mea-
surements for both trials were performed in the same assay.
The intra- and interassay coefficients of variation (CV)
were 2.2% and 20% for insulin, 10.1% and 11.8% for
glucagon, and 9.1% and 14.2% for cortisol, respectively.
GH was measured with a chemiluminescent immunoassay
(Nichols Institute Diagnostics, St. Juan Capistrano, CA)
with intra- and interassay CV of 10.7% and 15.9%, respec-
tively. Plasma glucose, nonesterified free fatty acid (FFA),
and the ketone body 3-D-hydroxybutyrate concentrations
were measured with enzymatic spectrophotometric pro-
cedures provided by Thermo DMA (Arlington, TX),
WACO Diagnostics (Richmond, VA), and RANDOX
(Ardmore, Antrim, United Kingdom; Randox Laboratories,
Oceanside, CA), respectively.
Assessment of autonomic function. This used
measurement of HR and respiratory sinus arrhythmia
(RSA). HR acceleration during exercise is caused by vagal
withdrawal and sympathetic stimulation of A
1
-adrenergic
receptors and thus reflects global sympathetic function. RSA
reflects spontaneous HR oscillations at the frequency of
breathing, and its amplitude is a component of the beat-to-
beat HR variability. It is controlled by the parasympathetic
vagal tone (23). Duration of interbeat (R-wave) intervals was
timed by the Mini-Logger2000 in milliseconds and stored as
sequential heart periods. A 250-s series of interbeat intervals
during the last 5 min of each hour were analyzed by MxEdit
software (Brain–Body Center, Chicago). MxEdit applied
time series analyses to the interbeat interval data to extract
the HR variability in the frequencies of spontaneous
breathing during resting and exercise conditions (0.12–1.00
Hz) after removing lower-frequency trends and periodicities.
The natural log of the variance of the HR data was a measure
of cardiac vagal tone (14,26).
Statistical analysis. A two-way mixed-model repeated-
measures ANOVA (factors: trial and time) was performed
with SAS software version 9.1 (SAS Institute, Cary, NC) for
hormone and metabolite areas under the curve (AUC) cal-
culated with trapezoidal rule. AUC were calculated for insulin
and insulin–glucagon ratio during the 4.5-h postprandial
periods, for GH and cortisol during exercise-associated hor-
mone surges, and for FFA and ketone bodies during 2 h before
and 2 h after the meals. Glucose concentrations, energy ex-
penditure, use of carbohydrates and fats, HR, and RSA were
averaged during the 2 h of exercise. Mixed-model repeated-
measures ANOVA was performed on all time points for
glucagon and postabsorptive glucose concentrations during
the entire period and the final 16 h of study. Glucagon gly-
cemic threshold was identified at glucose concentrations that
elicited increases in hormone concentration. RMR and total
nonexercise metabolism also were analyzed. Data are pres-
ented as means and SEM. >e0.05 was the criterion of
significant difference.
RESULTS
All subjects had normal hemoglobin (13.1T0.3 gIdL
j1
),
hematocrit (38.0 T1%), fasting insulin (10.3 TUImL
j1
),
and TSH (2.4 T0.3 mUIL
j1
). Eight subjects had normal
fasting glucose (4.1 T0.2 mM) and total–HDL cholesterol
ratio (2.9 T0.3), whereas one subject was prediabetic with
above-normal fasting glucose (7.5 mM) and total–HDL
cholesterol ratio (4.7).
Energy metabolism. No between-trial differences were
found for any measures of energy expenditure or intake
(Table 1). In both trials, RMR was 53.3 T2.5 kcalIh
j1
, total
24-h nonexercise energy expenditure ranged between 1570 T
82 and 1475 T76 kcal, and exercise energy expenditure
above the RMR was between 761.5 T37 and 762.1 T25
kcal in each trial. Carbohydrate use during exercise was the
same in the two trials but was significantly lower in the
morning (43% to 48% of total) compared with that in
the afternoon (approximately 53% of total; F
1,8
= 13.31,
FIGURE 1—Experimental design showing times of exercise in Before-Meals trial (first row) and After-Meals trial (second row) relative to the times
of meals at 1000 and 1700 h. Times of metabolic measurements (third row) and of blood sampling (fourth row) are also shown.
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P= 0.007). There also were no between-trial differences in
energy intake (752 to 785 kcal per meal) or in carbohy-
drate intake. Carbohydrate intake (462 to 488 kcal per meal)
matched carbohydrate use during exercise (463.9 T28.5 kcal
in Before-Meals and 516.6 T37.7 kcal in After-Meals trials).
Total daily energy intakes were 1542.4 T79 and 1508.4 T
71 kcal in the Before-Meals and After-Meals trials, respec-
tively. Daily energy intake matched the total sedentary
energy expenditures of between 1475 and 1570 kcal but did
not replace the 762 kcal energy cost of exercise.
Plasma glucose, insulin, FFA, and ketone bodies.
The pattern of changes in one prediabetic subject was
comparable to that in eight nondiabetic subjects and was in-
cluded in data analysis. There was no between-trial differ-
ence in fasting glucose concentration (4.5 mM) or the initial
postprandial rise in plasma glucose (Fig. 2A), but differ-
ences appeared during the postabsorptive state. Postab-
sorptive glucose levels remained between 4.0 and 5.5 mM
in the After-Meals trial. In contrast, plasma glucose
decreased to approximately 3.7 mM after both meals in the
Before-Meals trial and remained at between 3.8 and 4 mM
throughout the night. Between-trial difference in plasma glu-
cose concentration was significant during 2 h of exercise
(F
1,8
=6.66,P= 0.03). Postabsorptive plasma glucose in
the Before-Meals trial was 16.4 T0.2% lower than that
in the After-Meals trial when the entire 24-h period was
considered (4.0 T0.1 vs 4.8 T0.1 mM, F
1,520
=22.47,
PG0.0001) and 20.2 T0.2% lower during the final 16 h
of the study (F
1,376
=25.98,PG0.0001). A greater between-
trial difference in glucose concentration during the second
compared with the first exercise bout (F
1,8
=12.9,P=0.007)
caused a significant interaction between meals and trials
(F
1,8
=8.32,P= 0.02). Thus, postabsorptive plasma glucose
was approximately 20% lower in the Before-Meals com-
pared with that in the After-Meals trials and was maintained
at this reduced level throughout the night.
Postprandial insulin AUC in the Before-Meals trial was
48% and 52% higher compared with the After-Meals trial
despite similar initial rises (Fig. 2B). In addition to the
overall between-trial difference in insulin AUC (F
1,8
= 6.67,
P= 0.03), the interaction between trials and meals was sig-
nificant after both meals (morning, F= 6.28, P= 0.037 and
afternoon, F= 5.39, P= 0.049).
There was no between-trial difference in FFA AUC
(Fig. 2C), but exercise caused significant premeal FFA rises
(F
1,8
= 5.21, P= 0.048). A smaller morning rise in FFA
concentration during the After-Meals trial contributed to a
significant interaction between the trials and time (F
1,8
=
6.36, P= 0.03).
An increase in the AUC of the 3-D-hydroxybutyrate
(Fig. 2D) was 137% greater after the morning exercise bout
and 314% greater after the afternoon exercise bout in the
Before-Meals trial than in the After-Meals trial (F
1,8
= 13.39,
P= 0.005). A disproportionate increase in ketone body AUC
after the afternoon exercise trial (F
1,8
=9.01,P=0.015)
accounted for a significant interaction between the trials
and exercise. Thus, a significant postexercise ketosis, espe-
cially after the second exercise bout, occurred in the Before-
Meals but not in the After-Meals trials.
Counterregulatory hormone response. No overall
between-trial difference was found in the counterregulatory
response to exercise despite a between-trial difference in
plasma glucose (Fig. 3). There only was a significant effect
of time for glucagon (F
21,344
=2.26,P= 0.001) and cor-
tisol AUC (F
2,16
=7.45,P= 0.005). GH secretory pulses
were amplified by exercise, and an interaction between the
trials and exercise was of borderline significance (F
1,8
=5.3,
P=0.05).
Insulin–glucagon ratio and glucagon glycemic
threshold. The AUC for the postprandial insulin–glucagon
ratio (Fig. 4A) after the morning and afternoon meals were
50% and 48% greater, respectively, in the Before-Meals
trials compared with the After-Meals trials (F
1,8
= 8.01,
P= 0.02). This effect was significant at both times (morn-
ing, F= 6.74, P= 0.03 and afternoon, F= 8.33, P= 0.02).
Glucagon glycemic threshold was approximately 1 mM
lower in the Before-Meals compared with the After-Meals
trial. In the After-Meals trial, declines in glucose below 5.5
to 5.3 mM during both morning and afternoon exercises
(Fig. 4B, right) triggered increases in glucagon concentra-
tion. Plasma glucagon concentration was unaffected during
the first Before-Meals exercise bout with plasma glucose
at 4.3 to 4 mM. It increased during the second exercise bout
(Fig. 4B) when plasma glucose declined below 4.3 mM.
Increased insulin–glucagon ratio and reduced glucagon
glycemic threshold indicate reduced contribution of glu-
cagon to glucose counterregulation during Before-Meals
compared with After-Meals trials.
Assessment of autonomic function. There was no
between-trial difference in HR during exercise, reflecting
equal sympathetic activation of the heart (Fig. 5A). How-
ever, vagal tone during exercise was significantly lower in
TABLE 1. Energy intake and expenditure.
Energy Intake (Meal) Resting Metabolism (2 h) Exercise Metabolism (2 h)
Energy (kcal) Before-Meals Trial After-Meals Trial Before-Meals Trial After-Meals Trial Before-Meals Trial After-Meals Trial
Morning Total 757.8 T43 751.8 T33 106.3 T5 106.9 T5 475.7 T20 474.6 T19
Carbohydrates 466.2 T22 462.5 T20 51.0 T8 41.7 T7 202.1 T14* 229.3 T16*
Fat 76.1 T1 75.9 T1 55.4 T8 65.2 T8 273.7 T24 245.4 T22
Afternoon Total 784.6 T36 756.6 T38 498.4 T27 501.3 T16
Carbohydrates 487.9 T18 470.1 T22 261.9 T16* 266.1 T26*
Fat 77.0 T1 77.2 T1 236.5 T40 235.2 T42
* Different from afternoon values (F
1,8
= 13.31, P= 0.007).
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Before-Meals trial compared with the After-Meals trial
(F
1,8
= 75.63, PG0.0001), and the effect was seen during
both exercise bouts (bout 1, F=40.93,P= 0.001 and bout 2,
F=17.67,P= 0.0023; Fig. 5B). Thus, the two trials did
not differ in the sympathetic activation of the heart, whereas
the parasympathetic influence only declined during post-
absorptive exercise.
DISCUSSION
In this study, we tested the hypothesis that a previously
described reduction in counterregulatory response and a sus-
tained decline in plasma glucose after two bouts of spaced
exercise in postabsorptive state in EAAF studies (8,9,30–33)
was due to reduced circulating carbohydrate availability ra-
ther than to autonomic failure. By manipulating the timing of
FIGURE 2—Effect of Before-Meals exercise (horizontal solid bar) and
After-Meals exercise (horizontal open bar) on plasma concentrations of
glucose (A), insulin (B), FFA (C), and ketone bodies (D). Solid circles,
Before-Meals trials; open circles, After-Meals trials.
FIGURE 3—Effect of Before-Meals and After-Meals exercises
(horizontal solid and open bars, respectively) on plasma concentrations
of counterregulatory hormones glucagon (A), GH (B), and cortisol (C).
Solid circles, Before-Meals trials; open circles, After-Meals trials.
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meals and exercise and thus changing the abundance of cir-
culating nutrients, we demonstrated that a postabsorptive
state was a necessary condition for sustained 20% reduction
in plasma glucose. In the spaced EAAF studies (8,9,30–33),
exercise was performed after a 10-h overnight fast, and in
some of them (8,9), glucose was provided in the amount of
1.5 gIkg
j1
body weight 30 to 45 min after exercise, the
condition that, as demonstrated by our Before-Meals trial,
does not prevent the decline in plasma glucose. Four- to
sixfold increases in glucose infusion rates were required
24 h after exercise in spaced EAAF studies to maintain
euglycemia during the hyperinsulinemic euglycemic clamps.
The sustained reductions in plasma glucose and increases in
glucose infusion rate required to maintain euglycemia are
consistent with a downward shift in glucoregulatory set
point in both the spaced exercise studies and our Before-
Meals trials.
Dramatic increases in postexercise ketosis in the Before-
Meals trial support the inference that deficiencies in circu-
lating carbohydrates were critical in precipitating sustained
lowering of plasma glucose. Postexercise ketosis is an indi-
cator of hepatic glycogen depletion because it develops
when liver glycogen declines in response to dietary carbo-
hydrate scarcity (1,19–21). Postexercise ketosis is prevented
by postexercise glucose ingestion or preexercise carbohy-
drate intake (20,21). Liver biopsies (15) or nuclear magnetic
resonance measurements (36) reveal liver glycogen to
contain approximately 90 gI1.4 kg
j1
liver weight approx-
imately 5 h after a meal. Hepatic glycogen declines at a rate
of 4.5 to 5 gIh
j1
during fasting. Therefore, at the start of
both Before-Meals and spaced exercise studies (8,9,30–32),
liver glycogen was probably reduced by approximately 33 g
or was approximately 37% depleted. At exercise intensities
where approximately 40% of energy cost of exercise is
supplied by carbohydrates as was the case in this study,
20% of glucose is supplied by the liver and 80% by muscle
glycogen (28). Therefore, oxidation of approximately 51 to
FIGURE 4—Effect of Before-Meals and After-Meals exercises
(horizontal solid and open bars, respectively) on the insulin–glucagon
ratio (A) and glucagon glycemic threshold (B) during the Before-Meals
trial (center) and during the After-Meals trial (C; bottom). A. Solid
circles, Before-Meals trials; open circles, After-Meals trials. C. Open
symbols, morning values; solid symbols, afternoon values.
FIGURE 5—Effect of Before-Meals and After-Meals exercises
(horizontal solid and open bars, respectively) on the HR (A) and vagal
tone (B), as assessed by analysis of HR and its variability.
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65 g of carbohydrates during exercise in fasted state
(Table 1) could have produced further liver glycogen deple-
tion possibly by between 48% to 51%. An acute postexer-
cise increase in muscle insulin sensitivity (13,39), reduction
in muscle glycogen concentration, and activation of the
low-K
m
hexokinase should have secured abundant glucose
uptake and glycogen resynthesis in the muscle after exercise
in the postabsorptive state. This is likely to have left liver
deprived of glucose and glycogen depleted for the remain-
der of the experimental period (7). In contrast, during the
After-Meals trial, absorption of 116 to 122 g of carbohy-
drates into circulation was sufficient to support the oxida-
tion of 57 to 67 g of glucose during postprandial exercise.
Finally, we show a significantly lower cardiac vagal tone
and changed neuroendocrine function during exercise carried
out in the postabsorptive state. Thus, selective suppression of
parasympathetic, but not sympathetic function during post-
absorptive exercise, is associated with two bouts of spaced
exercise in the postabsorptive but not in the postprandial
state. An increase in the insulin–glucagon ratio and a 1-mM
decline in glucagon glycemic threshold during spaced exer-
cise in postabsorptive state are consistent with a downward
shift in neuroendocrine glucoregulatory set point in response
to inadequate circulating carbohydrate availability. Plasma-
lowering effect may be an adaptive process to reduce the
autonomic and neuroendocrine drive for hepatic glucose pro-
duction when liver remains glycogen-depleted during post-
exercise replenishment of muscle glycogen stores.
Two concerns specific to this study need to be addressed
to determine whether the results can be generalized to a
wider range of subjects and conditions. An additional con-
cern addresses the possibility that the phenomenon de-
scribed could be attributed entirely or in part to circadian
effects on the endocrine and autonomic functions. The first
concern is whether the age or the postmenopausal status of
our subjects would make the results less applicable to
younger individuals of both gender. This concern is allayed
by EAAF studies that show similar blood glucose lowering
to two bouts of spaced exercise in 27- to 30-yr-old indivi-
duals of both gender (8,9,30,31) indicating that the phe-
nomenon is not limited to a particular age range or gender.
The second concern is the approximately 500 kcal daily ne-
gative energy balance under which our study was conducted.
This concern would be minimized if the spaced EAAF
studies that reported glucose lowering were also conducted
under negative energy balance. The assessment of energy
balance in EAAF studies is uncertain because the subject’s
weight, exercise energy expenditure, and postexercise meal
energy were not reported. Some estimates can be made from
the reported exercise intensity, infusion rates of glucose, and
occasional oral glucose supplementation in those studies.
Their subjects entered their studies after a 10-h overnight fast
and an additional 3-h equilibration period, which should
have depleted approximately 69% of liver glycogen (8,9,
30,31). In three of these studies, energy balance cannot be
estimated further because an evening meal and an additional
snack of unspecified caloric content were given (8,30,31).
However, an estimate of energy balance can be made for
one EAAF study where exercise was applied in the morning
and a hyperinsulinemic hypoglycemic clamp was applied in
the afternoon (9). In this study, total provision of energy is
estimated to include 538 kcal in the form of carbohydrate:
105 g of oral carbohydrate after morning exercise, 7.9 g of
glucose infused during morning exercise, and 21.5 g of glu-
cose infused during the afternoon hyperinsulinemic hypo-
glycemic clamp. We estimate that the subjects expended
approximately 750 kcal during 90 min of morning exercise at
50% of maximal effort and approximately 600 kcal in RMR
and were therefore in approximately 800 kcal negative
energy balance. Whether spaced exercise in postabsorptive
state produces glucose-lowering effect only if a negative
energy balance is maintained requires further examination.
The third concern addresses the possibility that the pheno-
menon we described in this study could be attributed entirely
or in part to circadian effects on the endocrine and autonomic
functions. Constant routine experiments, where masking and
confounding influences of meal eating or lighting are re-
moved, are appropriate tests of the contribution of endoge-
nous rhythms to physiological processes. One such study
addresses the role of circadian rhythms in glucoregulation
(37). When the nutrient energy was provided through a
continuous glucose infusion during a 24-h period at two
rates, 5 and 8 gIkg
j1
Ih
j1
(corresponding to daily energy
intakes of between 1000 and 2500 kcal), a distinct increase
in plasma glucose was seen between 2300 and 0700 h, with a
peak at 0300 h. Because no distinct circadian change in in-
sulin concentration was seen, this circadian effect on gluco-
regulation in healthy subjects is more likely a result of
reduced muscle glucose uptake during sleep rather than a
result of reduced insulin sensitivity. This circadian effect
could not have affected the changes in plasma glucose in our
study because both bouts of exercise occurred before its
onset. Further, sustained overnight reduction in plasma glu-
cose in the Before-Meals trial and no elevation in plasma
glucose at night in the After-Meals trial demonstrate that
timing of meals and exercise overrode the nocturnal circadian
effect on glucoregulation. The second study (34) exposed
subjects to 8 h of darkness and 16 h of light under otherwise
controlled conditions during which sympathetic and parasym-
pathetic activities were assessed with power spectral analysis
of HR variability at 4-h intervals. Within 4 h of light onset,
the vagal tone declined and remained at reduced level during
the next 8 h. Within 4 h of the light offset, the vagal tone
increased and remained elevated during the remaining 4 h of
darkness. The change in HR, a measure of sympathetic acti-
vation, followed a reciprocal pattern. In our study, the timing
of morning exercise coincided with the last 2 h of autono-
mic shift toward diurnal function and that of our afternoon
exercise coincided with the first 2 h of autonomic shift to-
ward nocturnal function. Therefore, any contribution of
circadian rhythms to the observed changes in vagal function
would have been similar during both morning and afternoon
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Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
9
exercises and could not have accounted for the differences in
vagal tone observed between Before-Meals and After-Meals
trials. Finally, a circadian influence has also been reported for
counterregulatory hormones (24). The counterregulatory hor-
mones epinephrine, cortisol, and glucagon were all more re-
sponsive to hypoglycemia at night than during the day. Our
exercise and meal manipulations were carried out during
the day, but the sustained reduction in plasma glucose was
observed throughout the night. The circadian shift toward
stronger nocturnal counterregulation at night cannot account
for the selective reduction in nocturnal counterregulation in
the Before-Meals trial.
This study shows that a behavioral strategy consisting of
exercising twice a day before the meals in nondiabetic
subjects can achieve a sustained reduction in fasting plasma
glucose of comparable magnitude to that achieved by phar-
macological approaches in type 2 diabetic subjects (33).
Inclusion of one prediabetic subject in the study suggests
that this behavioral strategy is likely to be effective not only
in nondiabetic but also in prediabetic subjects. Because the
present exercise paradigm requires exercise in excess of the
amount likely to be acceptable to average individuals, it will
be important in future studies to characterize the threshold
amount of exercise sufficient for the glucose-lowering
effect, the extent to which reduced dietary carbohydrates
can substitute for exercise, and the mechanism through
which reduced circulating carbohydrate availability during
exercise affects neuroendocrine control of glucoregulation.
This study was supported in part by the NIDDK grant 1R15-
DK066286 to K.T.B. and the NIH grant M01-RR00042 to the
University of Michigan Clinical Research Unit (MCRU). The authors
thank the study volunteers and MCRU nursing staff and dieticians for
their help in the execution of the study, Ariel Barkan for the help in GH
measurements, Jean Hunt for help with illustrations, Kathleen Welch
for statistical analyses, and Lauren Weddell and Keri Kirk for technical
assistance. The results of the present study do not constitute
endorsement by the American College of Sports Medicine.
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... Since 2001, some studies [8,12,23,33,34,36,41,43] have highlighted the potential importance of activity-meal timing in relation to blood glucose control (reviewed in [39]). However, the number of studies is sparse and the sample sizes are small. ...
... Some studies have no control [41] or pre-meal activity group [36], and some are retrospective diet and exercise log analyses [34,41]. Other studies have used either long duration (2 h) [8] or vigorous [23,41,43] activities that are effective in reducing postprandial glucose but not always feasible in the real-world. Consequently, outcomes from these studies are equivocal. ...
... However, vigorous intensity is not always feasible at meal times; it often requires specialized equipment, is not desirable for all people, is precluded in the presence of some chronic conditions, and is initially inappropriate for inactive people [20]. Longer duration activity may also have been advantageous as studies of activity lasting for 2 h post-meal show improved glucose control [8]. Yet, for most people, 2 h of Fig. 3 The effect of walking on glucose control. ...
Article
Full-text available
The optimal timing between meal ingestion and simple physical activity for improving blood glucose control is unknown. This study compared the effects of physical activity on postprandial interstitial glucose responses when the activity was conducted either immediately before, immediately after, or 30 min after breakfast. Forty-eight adults were randomized to three separate physical activity interventions: standing still (for 30 min), walking (for 30 min), and bodyweight exercises (3 sets of 10 squats, 10 push-ups, 10 lunges, 10 sit-ups). In each intervention, 16 participants completed four trials (A to D) during which a 500 kcal mixed nutrient liquid breakfast meal was consumed. Interstitial glucose responses were recorded using continuous glucose monitoring for 2 h after the meal. The activity was completed either after the glucose monitoring period (trial A; control) or immediately before (trial B), immediately after (trial C), or 30 min after (trial D) the breakfast. Mean, coefficient of variance (CV), and area under the curve (AUC) for glucose were calculated and compared between the four trials. Walking and bodyweight exercises immediately after the meal improved mean, CV, and AUC glucose (P ≤ 0.05 vs. control), while standing immediately after the meal only improved AUC glucose (P ≤ 0.05 vs. control) and nearly improved mean glucose (P = 0.06). Mean, CV, and AUC glucose were not affected by standing, walking, or bodyweight exercise conducted immediately before, or 30 min after the meal (all P > 0.05 vs. control). Energy intake (diet records) and energy expenditure (Actigraph) were consistent throughout the studies and did not influence the findings. Low- to moderate-intensity activity should be implemented soon after eating to improve glucose control following breakfast. The type of activity appears less important than the timing. These findings will help optimize exercise-meal timing in general health guidelines. ClinicalTrials.gov Identifier: NCT03730727
... On the other hand, postmeal exercise does not improve glucose tolerance for subsequent meals (56). It also does not improve fasting glucose (75); improvement in insulin sensitivity, if any, is short-lived, as demonstrated by Nygaard et al. (76) in training studies lasting 12 weeks in hyperglycemic individuals. Although long-duration, highintensity interval exercise (HIIE) before meals is better than its postmeal counterpart for improving glycemia (49), long-duration (45 minutes) resistance exercise performed 45 minutes after meals is better than similar premeal exercise for improving glycemia and triglycerides (77). ...
... Glycogen depletion brings on delayed insulin sensitivity improvement during glycogen repletion (27,41,42). Borer et al. (75) showed that longduration premeal exercise improved fasting glucose in post-menopausal women. HIIE before meals has been found to be very beneficial for glycemia (49). ...
... On the other hand, premeal exercise is effective in increasing insulin sensitivity prospectively for the rest of the day and beyond ( Figure 3B). Additionally, premeal exercise has salutary effects on fasting glucose (75), glycogen content, and GLUT-4 protein levels (43-46). These mixed results make the utility and efficacy of premeal exercise unclear for people with diabetes. ...
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Full-text available
Several evidence-based lifestyle habits focusing on the composition, timing, and sequence of meals and on pre- and postmeal exercise can improve diabetes management. Consuming low-carbohydrate, balanced meals and eating most carbohydrates early in the day are helpful habits. Eating the protein and vegetable components of a meal first and consuming the carbohydrates 30 minutes later can moderate glucose levels. Postmeal glucose surges can be blunted without precipitating hypoglycemia with moderate exercise 30-60 minutes before the anticipated peak. Short-duration, high-intensity exercise could also be effective. Premeal exercise can improve insulin sensitivity but can also cause post-exertion glucose elevations. Moreover, high-intensity premeal exercise may precipitate delayed hypoglycemia in some people. Glycemia benefits can be enhanced by eating a light, balanced breakfast after premeal exercise.
... It has been found that light walking commenced immediately following a meal lowered postprandial glycaemia [26], as did activity commenced 30 min after the start of a meal [27]. In contrast, delaying the commencement of activity for one hour following the start of eating resulted in no glycaemic benefit compared with a sedentary condition [28]. However, within each of these studies there was no comparison of glycaemic effectiveness between activity started at different times after eating. ...
... Nor was there consistency in the duration or intensity of the activity. In the studies by Lunde et al. [26], Nelson et al. [27], and Borer et al. [28], the activities were slow walking for 20 min, cycle ergometer for 45 min at 55% VO 2 max, and treadmill walking for two hours at 43% VO 2 max respectively. ...
... Previous studies of physical activity and blood glucose control in normal glucose tolerant adults [16,[18][19][20][21][22]29,30,[35][36][37][38][39][40][41] did not use the timing of activity as a variable. In studies that have considered timing, there has been no within-study comparison between different timings within the postprandial period [26][27][28]. Furthermore, in studies where change in postprandial blood glucose response was not observed, even with activity of higher intensities the timing of activity may have been an unacknowledged determinant [29,36,39,42]. ...
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There is scant information on how a time lag between the cessation of eating and commencement of physical activity affects postprandial glycaemia. Starting at baseline (t = 0), participants ingested white bread containing 50 g of available carbohydrates within 10 min. Using two crossover conditions, we tested the effect over 2 h on postprandial glycaemia of participants undertaking light activity at 15 or 45 min following baseline and compared it with a sedentary control condition. The activity involved cycling on a stationary ergometer for 10 min at 40 revolutions per min with zero resistance. Seventy-eight healthy adults were randomized to the 15 or 45 min activity arm and then randomised to the order in which they undertook the active and sedentary conditions. Cycling 45 min after baseline changed the course of the blood glucose response (likelihood ratio chi square = 31.47, p < 0.01) and reduced mean blood glucose by 0.44 mmol/L (95% confidence interval 0.14 to 0.74) at 60 min when compared with the sedentary control. No differences in postprandial blood glucose response were observed when cycling started 15 min after baseline compared with the sedentary control. Undertaking activity after waiting for 30 min following eating might be optimal in modifying the glycaemic response.
... after a meal, both in diabetic and healthy individuals, and the magnitude of this effect depends on exercise characteristics and timing [8,[10][11][12]. On the other hand, also preprandial exercise has been reported to lower postprandial glycaemia [13][14][15][16][17] and it has been proposed before each meal of the day to prime glucose uptake in preparation for the postprandial glucose spike [16]. In addition, recent data suggests that exercise training before the meal might be better for reducing postprandial insulinaemia and improving lipid utilization [19]. ...
... Although the postprandial responses to a single bout of exercise, performed either before or after a meal, have been compared with conflicting results [15,18,[20][21][22][23], the potential synergistic effects of exercise bouts performed both before and after the same meal remain largely unexplored despite some evidence in patients with diabetes have been produced [24,25]. Therefore, in the present study, we investigated the postprandial endocrine and metabolic responses to a standard meal when a session of aerobic exercise is performed soon after the meal or split between the early preand the postprandial period. ...
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PurposeExercise plays an important role in preventing and treating postprandial dysmetabolism. We investigated the postprandial metabolic responses to a standard lunch when a session of aerobic exercise is performed in the early postprandial phase or divided between the pre- and postprandial period.Methods Nine healthy volunteers consumed a standardised mixed lunch and rested for the following 3 h (Con) or performed 40 min of cycling at 65% V̇O2max after lunch (CPPEx), or two 20-min sessions, one before (SplitEx1) and the other after lunch (SplitEx2), at the same intensity.ResultsAt 1-h post-lunch, a significant reduction (P < 0.001) in glycaemia was observed for CPPEx (− 25 ± 10%) and SplitEx (− 34 ± 7%) compared to Con. Yet, a post-exercise rebound lessened the exercise effect on the glycaemic area under the curve (AUC) at 2 and 3 h. At 1 h, a significant reduction (P < 0.009) in plasma insulin (SplitEx − 53 ± 31%; CCPEx − 48 ± 20%) and C-peptide (SplitEx − 57 ± 20%; CCPEx − 47 ± 24%) was observed compared to Con. Glucose-dependent insulinotropic polypeptide (GIP) increased after the meal, without differences between conditions. Compared with SplitEx1, cortisol response was attenuated during SplitEx2 and CPPEx. At 3 hours, triglyceride AUC was significantly higher (P = 0.039) in SplitEx compared to Con (+ 19 ± 8%).Conclusion Forty minutes of postprandial exercise or 20 min of pre- and postprandial exercise are both effective at attenuating the glycaemic and insulinaemic response to a mixed lunch, while a higher lipaemia was found in the pre- and postprandrial exercise condition.
... If muscle conditioning, body composition or performance improvement is the goal, training under pre-meal conditions is the way to go. Although a short bout of pre-meal exercise results in post-exertion glucose elevation [23,[28][29][30] long duration premeal exercises do offer glycemia benefits [31][32][33] likely because of significant glycogen depletion. The patient noticed that short duration premeal exercises may be most beneficial provided a post-meal walk is also done to use up the extra glucose coming to the blood stream forming the post-exertion glucose elevation (FIGURE 1D AND FIGURE 2D) light solid line. ...
... The immediate and short term glycemia benefit makes it superior to the post-meal options, for overall glycemia benefit. Long duration premeal walk has been known to improve fasting glucose [31]. These pre-meal options may work for retired individuals every day and also for working people on weekends. ...
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A physician with type 2 diabetes for 19 years and impaired awareness of hypoglycemia sought to lower the hypoglycemia risk with the help of continuous glucose monitoring. The idea was to optimize the medications-meals-exercise triad. When the patient adopted a personalized low carb, balanced meal plan, glargine insulin dose came down from 36 units to 18. The meal plan called for eating every 2-4 hours. Also, more carbohydrate ingestion during early part of the day lowered glycemic variability. Insulin dose came down further to 7 units when a third medication, dulaglutide, was added to metformin and insulin. In the course of this lifestyle modification the patient made a remarkable observation: although four glycogen depleting exercises, followed by a brief walk offered comparable immediate glycemia benefits, the effect extending significantly to the next day was seen only with the split exercise (pre-breakfast+post-breakfast walk). Several exercise combinations were identified for lowering glycemic variability. Weight, HbA1c and lipids have been moving in the right direction with the new lifestyle.
... 8 A 30-to 60-minute morning walk every other day offers many benefits: no hypoglycemia during the activity, glucose tolerance improves for 24 hours and beyond, and fasting glucose normalizes. 9,10 A 20-to 25-minute brisk walk or yard work 30 minutes after the start of lunch will blunt the glucose surge in real time. 9 Post-meal walks can be alternated with pre-meal walks. ...
... In this example, exercise should be performed before feeding time, as it results in a significantly higher improvement in blood glucose control [206] and lipid metabolism [207] in contrast to post-meal exercise. However, for other diseases or exercise types, the individual condition of the person must be taken into account. ...
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The circadian rhythmicity of endogenous metabolic and hormonal processes is controlled by a complex system of central and peripheral pacemakers, influenced by exogenous factors like light/dark-cycles, nutrition and exercise timing. There is evidence that alterations in this system may be involved in the pathogenesis of metabolic diseases. It has been shown that disruptions to normal diurnal rhythms lead to drastic changes in circadian processes, as often seen in modern society due to excessive exposure to unnatural light sources. Out of that, research has focused on time-restricted feeding and exercise, as both seem to be able to reset disruptions in circadian pacemakers. Based on these results and personal physical goals, optimal time periods for food intake and exercise have been identified. This review shows that appropriate nutrition and exercise timing are powerful tools to support, rather than not disturb, the circadian rhythm and potentially contribute to the prevention of metabolic diseases. Nevertheless, both lifestyle interventions are unable to address the real issue: the misalignment of our biological with our social time.
... This is because exercise, by lowering blood glucose levels prevents the release of insulin from the pancrease [15]. Studies have also shown that total blood cholesterol levels are lowered with high-intensity aerobic exercise compared to low aerobic physical activity [16] [17]. Also endurance exercise has been found to lower triglyceride concentration especially among individuals who have raised initial pre-exercise levels [16]. ...
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The albumin and lipid profile changes following treadmill exercise were assessed among 160 apparently healthy student volunteers made up of 80 males and 80 females within the age bracket of 18-30 years, the physically active age group within the universities. The anthropometric indices (weight, height and BMI) of the subjects were taken using reference/standard methods. The blood pressures and pulse rate, then albumin and lipid profiles were also taken before and after exercise. The participants ran on a treadmill and their physical conditions were assessed using the Bruce protocol. Immediate post-exercise blood samples were again analyzed in the laboratory. There were significant increases (P < 0.05) in the after-exercise systolic BP, pulse rate and serum albu-min, while marked decrease in diastolic BP was recorded (P < 0.05). Following exercise, total cholesterol and Low Density Lipoprotein reduced significantly (P < 0.01) in both sexes while High Density Lipoprotein increased markedly in males (P < 0.01) but not significantly increased in females (P > 0.5). There were gender variations in response to the treadmill exercise. Some of these findings indicate the expected functional alterations in the life of the students and there is a need to recommend the adoption of regular moderate exercise pattern to the students. These can bring about positive changes in their serum lipid and albumin profiles for better health in the face of stressful academic life.
... 3%/year for type-1-diabetes (Federation 2017)) and is associated with signs of microvascular and macrovascular complications, hypertension, dyslipidemia (Dean 2007;Pulgaron et al. 2014), and cardiovascular disease risk factors which can present as early as pre-adolescence in people with diabetes (Babar et al. 2011). In adults with type-2-diabetes, research indicates benefits from both pre-and post-meal exercise (Borer et al. 2009). Adult subjects with and without diabetes demonstrated that light (60-min) or moderate intensity (20-45-min) aerobic exercise starting 30min post-meal can efficiently blunt hyperglycemia, with minimal risk of hypoglycemia (Chacko 2016). ...
Article
Currently, exercise prescription relies heavily on parameters included in the FITT principle: frequency, intensity, time (duration), and type of exercise. In this paper, the benefits of including timing (FITT+T), referring to when exercise is performed in relation to meal-time, is discussed. Current research indicates that timing is outcome-specific. Total energy and lipid intakes, and postprandial hypertriglyceridemia can be reduced when exercise is performed pre-meal, while glycemic control is improved with post-meal exercise. Although findings indicate that timing can aid in obesity management and cardiometabolic-risk reduction, most research involves adult subjects and acute investigations. Some research with children, concerning the effect of timing on appetite, indicates that pre-meal exercise helps regulate energy balance, but also identifies key differences in response compared with adults. Overall, current findings support the benefits of timing, but research is required to establish guidelines that are specific to the pediatric population and their health-related goals, while incorporating other FITT components.
Article
Spectral analysis of spontaneous heart rate fluctuations were assessed by use of autonomic blocking agents and changes in posture. Low-frequency fluctuations (below 0.12 Hz) in the supine position are mediated entirely by the parasympathetic nervous system. On standing, the low-frequency fluctuations increase and are jointly mediated by the sympathetic and parasympathetic nervous systems. High-frequency fluctuations, at the respiratory frequency, are decreased by standing and are mediated solely by the parasympathetic system. Heart rate spectral analysis is a powerful noninvasive tool for quantifying autonomic nervous system activity.
Chapter
It is known that during heavy exercise the glucose production from the liver is increased (3, 4, 8, 9). The glucose production appears to increase successively during continued exercise, which also means that the glucose production from the liver increases concomitantly with decreasing glycogen stores in working skeletal muscle. Glucose production can increase from rest values of 100–150 mg/mm to 900–1,100 mg/mm at the end of heavy exercise (4) (Fig. 1). This increased output can be due to glycogenolysis of the glycogen store in liver or to an increased rate of gluconeogenesis. Gluconeogenic substrates are increased during exercise, both lactate and glycerol levels in blood being elevated. On the other hand, the splanchnic uptake of lactate is not increasing during the exercise period (4, 8). It was also shown many years ago that no increase in urea production occurred during exercise (6, 10). These facts are not consistent with a pronounced increase in gluconeogenesis during the exercise period.
Article
Antecedent hypoglycemia can blunt counterregulatory responses to subsequent hypoglycemia. It is uncertain, however, if prior hypoglycemia can blunt counterregulatory responses to other physiologic stresses. The aim of this study, therefore, was to determine whether antecedent hypoglycemia attenuates subsequent neuroendocrine and metabolic responses to exercise. Sixteen lean, healthy adults (eight men and eight women, ages 28+/-2 years, BMI 22+/-1 kg/m2, VO2max 43+/-3 ml x kg(-1) x min(-1)) were studied during 2-day protocols on two randomized occasions separated by 2 months. On day 1, subjects underwent morning and afternoon 2-h hyperinsulinemic (528+/-30 pmol/l) glucose clamp studies of 5.3+/-0.1 mmol/l (euglycemic control) or 2.9+/-0.1 mmol/l (hypoglycemic study). On day 2, subjects underwent 90 min of exercise on a static cycle ergometer at 80% of their anaerobic threshold (approximately 50% VO2max). Glycemia was equated during day 2 exercise studies via an exogenous glucose infusion. Day 1 hypoglycemia had significant effects on neuroendocrine and metabolic responses during day 2 exercise. The usual exercise-induced reduction in insulin, together with elevations of plasma epinephrine, norepinephrine, glucagon, growth hormone, pancreatic polypeptide, and cortisol levels, was significantly blunted after day 1 hypoglycemia (P<0.01). Commensurate with reduced neuroendocrine responses, key metabolic counterregulatory mechanisms of endogenous glucose production (EGP), lipolytic responses, and ketogenesis were also significantly attenuated (P<0.01) after day 1 hypoglycemia. Significantly greater rates of glucose infusion were required to maintain euglycemia during exercise after day 1 hypoglycemia compared with day 1 euglycemia (8.8+/-2.2 vs. 0.6+/-0.6 micromol x kg(-1) x min(-1); P<0.01). During the first 30 min of exercise, day 1 hypoglycemia had little effect on EGP, but during the latter 60 min of exercise, day 1 hypoglycemia was associated with a progressively smaller increase in EGP compared with day 1 euglycemia. Thus, by 90 min, the entire exercise-induced increment in EGP (8.8+/-1.1 micromol x kg(-1) x min(-1)) was abolished by day 1 hypoglycemia. We conclude that 1) antecedent hypoglycemia results in significant blunting of essential neuroendocrine (glucagon, insulin, catecholamines) and metabolic (endogenous glucose production, lipolysis, ketogenesis) responses to exercise; 2) antecedent hypoglycemia may play a role in the pathogenesis of exercise-related hypoglycemia in type 1 diabetic patients; and 3) antecedent hypoglycemia can blunt counterregulatory responses to other physiologic stresses in addition to hypoglycemia.
Article
Respiratory sinus arrhythmia (RSA) was examined in aerobically trained (AT) and untrained (NT) college-aged males during 12 periods consisting of a 3-min sitting baseline, six common 3-min absolute exercise stages, and five 3-min recovery stages that followed voluntary exhaustion to determine the relationship of work and training status to parasympathetic influence upon the heart. RSA systematically decreased during absolute exercise, was observed at heart rates (HR) above 100 beats x min(-1), and progressively increased during recovery. Additionally, independent of work stages, comparative regression analyses were conducted for both the exercise and recovery phases, separately, in which HR was regressed on RSA, as well as RSA on % VO2max, to contrast the obtained relationships for the AT and NT. No differences were revealed as a function of endurance training status as the slopes and intercepts obtained for the two groups from each of these analyses were similar. The within-subject correlations between RSA and % VO2max, calculated for each of the individuals across all 12 periods, were consistently negative. Between-subjects correlations of RSA with RR and tidal volume were predominantly nonsignificant, indicating that RSA, as measured here, is independent of individual differences in ventilatory activity and, as such, can be compared between groups during exercise. The findings demonstrate that RSA is detectable during both exercise and recovery, even at HR beyond 100 beats x min(-1), and reveals a similar relationship to HR and metabolic state in both aerobically trained and untrained populations.
Article
Unlabelled: The importance of carbohydrate availability during exercise for metabolism and plasma hormone levels was studied. Seven healthy men ran on a treadmill at 70% of individual maximal oxygen uptake having eaten a diet low (F) or high (CH) in carbohydrate through 4 days. At exhaustion the subjects were encouraged to continue to run while glucose infusion increased plasma glucose to preexercise levels. Forearm venous blood, biopsies from vastus muscle and expiratory gas were analyzed. Time to exhaustion was longer in CH- (106 +/- 5 min (S.E.)) than in F-expts. (64 +/- 6). During exercise, overall carbohydrate combustion rate, muscular glycogen depletion and glucose and lactate concentrations, carbohydrate metabolites in plasma, and estimated rate of hepatic glucose production were higher, fat metabolites lower, and the decrease in plasma glucose slower in CH- than in F-expts. Plasma norepinephrine increased and insulin decreased similarly in CH- and F-expts., whereas the increase in glucagon, epinephrine, growth hormone and cortisol was enhanced in F-expts. Glucose infusion eliminated hypoglycemic symptoms but did not substantially increase performance time. During the infusion epinephrine decreased markedly and glucagon even to preexercise levels. Infusion of insulin (to 436% of preexercise concentration) in addition to glucose in F-expts. did not change the plasma levels of the other hormones more than infusion of glucose only but reduced fat metabolites in plasma. At exhaustion muscular glycogen depletion was slow, and the glucose gradient between plasma and sarcoplasma as well as the muscular glucose 6-phosphate concentration had decreased. Conclusions: The preceding diet modifies the energy depots, the state of which (as regards size, receptors and enzymes) is of prime importance for metabolism during prolonged exercise. Plentiful carbohydrate stores favor both glucose oxidation and lactate production. During exercise norepinephrine increases and insulin decreases independent of plasma glucose changes whereas receptors sensitive to glucose privation but not to acute changes in insulin levels enhance the exercise-induced secretion of glucagon, epinephrine, growth hormone and cortisol. Abolition of cerebral hypoglycemia does not inevitably increase performance time, because elimination of the hypoglycemia may not abolish muscular energy lack.
The effects of glucose ingestion on the changes in blood glucose, FFA, insulin and glucagon levels induced by a prolonged exercise at about 50% of maximal oxygen uptake were investigated. Healthy volunteers were submitted to the following procedures: 1. a control test at rest consisting of the ingestion of 100 g glucose, 2. an exercise test without, or 3. with ingestion of 100 g of glucose. Exercise without glucose induced a progressive decrease in blood glucose and plasma insulin; plasma glucagon rose significantly from the 60th min onward (+45 pg/ml), the maximal increase being recorded during the 4th h of exercise (+135 pg/ml); plasma FFA rose significantly from the 60th min onward and reached their maximal values during the 4th h of exercise (2177 +/- 144 muEq/l, m +/- SE). Exercise with glucose ingestion blunted almost completely the normal insulin response to glucose. Under these conditions, exercise did not increase plasma glucagon before the 210th min; similarly, the exercise-induced increase in plasma FFA was markedly delayed and reduced by about 60%. It is suggested that glucose availability reduces exercise-induced glucagon secretion and, possibly consequently, FFA mobilization.
Article
Seven men ran at 60% of individual maximal oxygen uptake to exhaustion during beta-adrenergic blockade with propranolol or without drugs. After propranolol administration the increases during exercise in plasma glucagon and epinephrine concentrations as well as the decrease in plasma glucose concentrations were faster than in control experiments. When euglycemia was maintained by glucose infusion during beta-adrenergic blockade, glucagon and epinephrine responses to exercise, although not abolished, were markedly reduced. The diminution of the exercise-induced decline in glucose concentrations correlated significantly with the diminution of the glucagon as well as the epinephrine responses. Thus decreased glucose concentrations may significantly enhance the secretion of glucagon and epinephrine during prolonged exercise in man. Since the diminution of the glucagon response produced by glucose infusion was not accompanied by significant alterations in the levels of nonesterified fatty acid (NEFA) and glycerol, increased glucagon secretion does not seem to be a major determinant of lipolysis during exercise in man. During glucose infusion, glycogen utilization rates in muscle (n = 4) tended to decrease, whereas carbohydrate combustion rate and concentrations of norepinephrine, insulin, alanine, and lactate were unchanged.