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*
Nutrition and Toxicology Research Institute NUTRIM, Department of Human Biology, Maastricht University, 6200 MD Maastricht, the Netherlands and
TNO Nutrition and Food Research Institute, Food and Non-Food Analysis Department, Zeist, the Netherlands
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • insulin secretion • amino acids • postexercise recovery • leucine • phenylalanine • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Yarasheski et al. 1999
) and muscle protein degradation (Biolo et al. 1995b
) in the postexercise phase in humans. Biolo et al. (1997)
demonstrated that hyperaminoacidemia, resulting from the
intravenous infusion of amino acids, increases postexercise muscle
protein synthesis rates and prevents the exercise-induced increase
in protein degradation. Recent studies have demonstrated that amino
acid ingestion, with (Rasmussen et al. 2000
) and without
(Tipton et al. 1999
) carbohydrates, can also increase
postexercise muscle protein synthesis and net protein balance (protein
synthesis minus protein degradation). As such, postexercise
amino acid ingestion may be an effective method to maximize the
anabolic effect of exercise. The mechanisms responsible for this amino
acid–induced, anabolic response have not yet been established.
Potential regulating factors include changes in levels of various
hormones, paracrine substances and vasodilators. Insulin has been
proposed as an important factor in protein metabolism, because acute
physiologic elevations of plasma insulin levels, especially during
conditions of hyperaminoacidemia, result in an additional increase in
net muscle protein anabolism in vivo in humans (Fryburg et al. 1995
, Gelfand and Barrett, 1987
,
Hillier et al. 1998
). However, insulin should not be
regarded as a primary regulator because in the absence of elevated
amino acid concentrations, insulin levels exert only a modest effect on
muscle protein synthesis (Biolo et al. 1995a
). In
accordance, Anthony et al. (1999
and 2000)
reported a
stimulating effect of leucine ingestion on postexercise muscle protein
synthesis in rats, independent of an increase in plasma insulin
levels.
Insulin also stimulates muscle glucose utilization through the
activation of glucose transport (Ivy 1997
and 1998
,
Ivy and Kuo 1998
) and glycogen synthase (Bak et al. 1991
, Kruszynska et al. 1986
), which is
generally considered to be the major factor to determine the rate of
glycogen synthesis when substrate supply is adequate (Conlee et al. 1978
). Therefore, an increase in postexercise insulin
response, after the ingestion of protein (and amino acids) in
combination with carbohydrates, has been suggested to accelerate muscle
glycogen synthesis (van Hall et al. 2000
, van Loon et al. 2000b
, Zawadzki et al. 1992
).
Because of the proposed role of insulin and amino acids in promoting
postexercise muscle protein anabolism and/or muscle glycogen synthesis,
there is increasing interest in nutritional strategies to maximize
postexercise insulin levels and to increase plasma amino acid
availability.
In the 1960s, the synergistically stimulating effect of the combined
intake of carbohydrate and protein on plasma insulin levels was first
reported (Pallotta and Kennedy 1968
, Rabinowitz et al. 1966
) and was later confirmed by Nuttall et al. (1984
and 1985)
. In addition, the infusion of free amino acids
increases plasma insulin levels in humans (Fajans et al. 1962
, Floyd et al. 1963
, 1966
, 1968
, 1970a
, 1970b
). We recently studied the effects of the combined oral
intake of carbohydrate (0.8 g · kg-1 ·
h-1) with different amino acids and/or protein
(hydrolysates) (0.4 g · kg-1 ·
h-1) on plasma insulin levels in the
postabsorptive resting state and observed a twofold increase in insulin
response after the ingestion of carbohydrate with a mixture of wheat
protein hydrolysate, free leucine and phenylalanine compared with the
intake of only carbohydrate (van Loon et al. 2000a
). A
synergistic increase in insulin response was also observed after the
ingestion of this mixture (0.4 · kg-1 ·
h-1) with carbohydrate (0.8 g ·
kg-1 · h-1) after
exercise in trained athletes (van Loon et al. 2000b
). In
the same study, we observed that the ingestion of this mixture
accelerated postexercise muscle glycogen synthesis compared with the
ingestion of only carbohydrate (0.8 g · kg-1
· h-1) but not compared with the
ingestion of a higher amount of carbohydrate (1.2 g ·
kg-1 · h-1).
The present study was designed to investigate the effects of the ingestion of different amounts of protein hydrolysate, with and without the addition of free leucine and phenylalanine, in combination with a large amount (1.2 g · kg-1 · h-1) of carbohydrate, on the postexercise insulin response and plasma amino acid concentration in trained athletes. Our aim was to define the mixture with the strongest insulinotropic properties in combination with increased amino acid availability when ingested in the postexercise phase. Theoretically, this mixture would be the best candidate to explore whether such an insulinotropic mixture can maximize postexercise net muscle protein anabolism and glycogen synthesis rates.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eight highly trained male cyclists [age 24.0 ± 0.6 y, body mass 70.0 ± 1.0 kg, body mass index 21.4 ± 0.6 kg/m2, maximum workload (Wmax)3 390 ± 8 W, maximum heart rate 191 ± 3 bpm) participated in this study. Subjects trained at least three times a week for 2 h and had a training history of >5 y. All subjects were informed about the nature and risks of the experimental procedures before their informed consent was obtained. This study was approved by the local ethics committee.
Pretesting.
Maximum oxygen uptake capacity (
O2
max) and Wmax were measured on an
electronically braked cycle ergometer (Lode Excalibur, Groningen, the
Netherlands) during an incremental exhaustive exercise test 1 wk before
the first experimental trial (Kuipers et al. 1985
).
These findings were used to determine the power output settings in the
glycogen-depletion protocol.
Experimental trials.
Each subject participated in five trials, separated by 
3 d, in which
five different beverages were tested. During those trials, subjects
first performed a glycogen-depletion protocol (Kuipers et al. 1987
). Thereafter, subjects were studied for 3 h while
ingesting 1.2 g of carbohydrate · kg-1 ·
h-1 (60:40% maltodextrin/glucose). Blood samples were
taken at 30-min intervals. During those 3 h, subjects remained
physically inactive. Beverages were provided in a random order. Both
subjects and researchers who were present were unaware of the specific
drink being tested. All drinks were vanilla flavored to make the taste
similar among the trials. Subjects were instructed to refrain from
heavy physical labor and to keep their diet constant the day before the
trials. Subjects fasted for 12 h before reporting to the
laboratory but were allowed to drink water ad libitum.
Protocol.
Subjects reported to the laboratory at 0830 h. Muscle glycogen
depletion was established by performing an intense cycle ergometer test
(Kuipers et al. 1987
). This muscle
glycogen-depletion protocol started off with a 10-min warm-up
period at a workload of 50% Wmax. Thereafter subjects were
instructed to cycle for 2-min block periods at alternating workloads of
90 and 50% Wmax. This was continued until subjects were no
longer able to complete the 2 min at 90% Wmax. That moment
was defined as the inability to maintain cycling speed at 60 rpm. At
that moment, the high intensity blocks were reduced to an intensity
equal to 80% Wmax. Again, subjects had to cycle until they
were unable to complete a 2-min block at 80% Wmax, after
which the high intensity block was reduced to 70% Wmax.
Subjects were allowed to stop exercising when they were not able to
maintain pedaling speed at >60 rpm at this 70% Wmax.
Subjects were allowed to drink up to 1.0 L of water during the
depletion test. After cessation of the exercise, subjects were allowed
to take a 5-min shower, after which a Teflon catheter (Baxter BV,
Utrecht, the Netherlands) was inserted into an antecubital vein and a
resting blood sample was drawn (t = 0 min). Immediately
thereafter, subjects drank an initial bolus (3.5 mL ·
kg-1) of a given test drink. Subjects were seated for the
next 3 h, during which they received a beverage volume of 3.5 mL
· kg-1 every 30 min until t = 150. Blood
samples (4 mL) were taken every 30 min for the measurement of plasma
glucose, insulin and amino acids until t = 180.
Beverages.
All beverages contained 68.5 g · L-1 glucose,
102.8 g · L-1 maltodextrin, 0.20 g ·
L-1 sodium saccharinate, 1.80 g · L-1
citric acid and 5.00 g · L-1 vanilla cream flavor.
In addition, beverages 2 and 3 contained 28.6 and 57.1 g ·
L-1 wheat protein hydrolysate, respectively, whereas
beverage 4 contained 14.3 g · L-1 wheat protein
hydrolysate and 7.1 g · L-1 of both free leucine
and phenylalanine. Beverage 5 contained twice the level of wheat
protein hydrolysate and free leucine and phenylalanine compared with
beverage 4. At t = 0, 30, 60 90, 120 and 150 min, subjects
received a beverage volume of 3.5 mL · kg-1 to ensure a
given dosage of 1.2 g · kg-1 · h-1
carbohydrate (40:60% maltodextrin/glucose) and 0, 0.2 or 0.4 g
· kg-1 · h-1 of a mixture containing
wheat hydrolysate or wheat hydrolysate with the addition of free
leucine and phenylalanine. Glucose and maltodextrin were obtained from
AVEBE (Veendam, the Netherlands), crystalline amino acids were obtained
from BUFA (Uitgeest, the Netherlands) and the protein hydrolysate
(Hyprol) was prepared by Quest International (Naarden, the
Netherlands). The protein hydrolysate is prepared from wheat protein
via enzymatic digestion and has a medium chain length of 11 amino
acids. The amino acid profile of the wheat hydrolysate is listed in
Table 1
. The maltodextrin used had a medium chain length of 14–16 glycosyl
units. To make the taste comparable in all trials, sodium saccharinate,
citric acid and vanilla cream flavor (Quest International) were added.
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Blood was collected in EDTA-containing tubes and was centrifuged at 1000 x g and 4°C for 5 min. Aliquots of plasma were frozen immediately in liquid nitrogen and stored at -40°C. Glucose (Uni Kit III 07367204; Hoffman-La Roche, Basel, Switzerland) was analyzed with the COBAS FARA semiautomatic analyzer (Hoffman-La Roche). Insulin was analyzed by radioimmunoassay (Insulin RIA 100 kit; Pharmacia, Uppsala, Sweden). Plasma (200 µL) for amino acid analysis was deproteinized on ice with 500 g · L-1 5-sulfosalicylic acid and vortex mixed. The clear supernatant obtained after centrifugation was stored at -80°C until analysis for amino acids. Amino acids were analyzed on an automated dedicated amino acid analyzer (LC5001; Biotronik, München, Germany) using a cationic exchange resin (type BTC2710; Biotronik), a gradient of lithium citrate elution buffers and postcolumn derivatization with ninhydrin, all according to working recipes of the supplier. Same procedures were performed to determine the amino acid composition of the wheat protein hydrolysate except for the use of a different amino acid analyzer (Pharmacia LKB Biotechnology, Roosendaal, the Netherlands). Calibration curves of the amino acids were obtained using commercial amino acid mixtures. Norvaline was used as internal standard and added to all plasma samples before deproteinization.
Statistics.
All data are expressed as means ± SEM (n = 8). Analysis of variance for repeated measures was performed to study differences in plasma glucose and insulin concentrations over time between groups. A Scheffé post hoc test was applied in case of a significant F-ratio to locate the differences. The plasma glucose, insulin and amino acid responses were calculated as the area under the curve above baseline value (t = 0 min). Statistical analyses of these data were conducted with a two-factor analysis of variance with treatment and subject as the two factors. Differences between drinks were checked for statistical significance using the Tukey post hoc test. Simple regression analysis was performed to calculate correlations between the insulin response and the different plasma amino acid responses. Statistical significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). After expression of the glucose response as the area under the curve
(above baseline) during the entire 3-h period, no significant
differences were observed between the different test drink trials.
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). The ingestion of drink 5 resulted in significantly higher insulin
levels at t = 60, 90, 120 and 150 min compared with drinks 1, 2
and 3. After expression of the insulin response as the area under the
curve during the entire 3-h period (Fig. 3
), insulin responses after the ingestion of drinks 4 and 5 were
significantly higher than control (+52 ± 10 and +107 ± 17%, respectively; P < 0.05). The ingestion of drinks
2 and 3 did not result in significantly higher postexercise insulin
responses compared with the control drink, and responses were
significantly lower compared with the insulin responses reported after
the ingestion of the free amino acid–containing drinks (drinks 4 and
5). In addition, the ingestion of drink 5 resulted in a significantly
higher insulin response (+36 ± 6%; P < 0.05)
compared with drink 4, in which a lower dose of the same mixture was
ingested (0.4 versus 0.2 g · kg-1 ·
h-1, respectively).
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). Only the findings most relevant for the aim of this study are
reported here. After the postexercise ingestion of the control drink, a
decrease was seen in the concentration of all amino acids. The
ingestion of drinks 2 and 3 (wheat) resulted in a significantly higher
plasma concentration for most amino acids measured compared with the
control. The ingestion of drinks 4 and 5 resulted in a substantial
increase in plasma leucine, phenylalanine and tyrosine responses
compared with the other drinks (Table 2)
. Regression analysis revealed
a strong positive correlation between the size of the insulin response
and the change in plasma leucine (P < 0.0001,
r = 0.66), phenylalanine (P < 0.0001,
r = 0.62) and tyrosine (P < 0.0001,
r = 0.57) concentrations. Plasma threonine, asparagine,
glycine, alanine, valine, methionine, isoleucine and histidine
responses showed a negative correlation with the insulin response
(P < 0.05, r = -0.33 to -0.48)
within this postexercise setting.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In addition, the use of an intact protein when ingested
as a beverage has another practical disadvantage because most intact
proteins are poorly soluble in water. In an attempt to combine
gastrointestinal tolerance and palatability with a maximal insulin
response, a mixture of wheat hydrolysate with free leucine and
phenylalanine was defined (van Loon et al. 2000a
). The
insulinotropic properties after the ingestion of this mixture in the
postabsorptive resting state exceeded those of most other combinations
and did not cause any gastrointestinal or other complaints.
The aim of the present study was to maximize postexercise insulin
levels and to increase plasma amino acid availability in trained
athletes. Our data did not show an increase in postexercise insulin
response after the ingestion of a wheat protein hydrolysate only (at an
intake of 0.2 or 0.4 g · kg-1 ·
h-1) in combination with carbohydrate (1.2 g ·
kg-1 · h-1) compared
with the ingestion of only carbohydrate. This is in contrast to earlier
findings in the postabsorptive resting state (van Loon et al. 2000a
), during which considerable, but nonsignificant,
increases in insulin response were observed after the ingestion of
carbohydrate (0.8 g · kg-1 ·
h-1) combined with pea, whey or wheat protein
hydrolysate in comparison with the ingestion of only carbohydrate. This
could be related to the preceding exercise in the present study,
because muscle contraction stimulates glucose transport via GLUT4
translocation (Ivy 1997
), which is likely to result in a
reduction in postexercise insulin response. In addition, endurance
trained athletes exhibit a markedly reduced secretory insulin response
after glucose administration (Lohmann et al. 1978
,
Rodnick et al. 1987
). However, a significant, additional
increase in plasma insulin level occurs after the ingestion of
carbohydrate (0.8 g · kg-1 ·
h-1) with a whey or wheat protein hydrolysate
(0.4 g · kg-1 · h-1)
in endurance trained athletes after exercise (van Hall et al. 2000
). Therefore, the apparent contradictory findings should be
explained by the higher carbohydrate ingestion rate (1.2 versus
0.8 g · kg-1 ·
h-1) that was applied in the present study.
We observed a substantial additional increase in insulin response after
the ingestion of the mixtures containing wheat protein hydrolysate in
combination with free leucine and phenylalanine. The addition of these
free amino acids clearly led to a significant increase in the insulin
response (the area under the curve) compared with the control and wheat
protein–only trials (Fig. 3)
. A dose-effect relationship existed
in that doubling the ingestion rate of the hydrolysate–amino acid
mixture up to 0.4 g · kg-1 ·
h-1 resulted in a substantial increase in
insulin response (the area under the curve) compared with the ingestion
of only 0.2 g · kg-1 ·
h-1 of the same mixture.
Recently, we studied the effects of ingestion of carbohydrate with this
mixture of wheat protein hydrolysate, free leucine and phenylalanine on
postexercise insulin levels and muscle glycogen synthesis rates in
trained athletes (van Loon et al. 2000b
). We
demonstrated a substantial, additional increase in insulin response
after the ingestion of this mixture (0.4 g ·
kg-1 · h-1) in addition
to normal postexercise carbohydrate consumption rates (0.8 g ·
kg-1 · h-1). In
accordance with Zawadzki et al. (1992)
, we reported a
significant acceleration of muscle glycogen synthesis rates compared
with the ingestion of only carbohydrate (0.8 g ·
kg-1 · h-1). However,
these increased muscle glycogen synthesis rates were not significantly
higher than synthesis rates observed after the ingestion of larger
amounts of carbohydrate (1.2 g · kg-1 ·
h-1). Future research will be necessary to
investigate whether muscle glycogen synthesis can be further
accelerated by ingesting an insulinotropic protein hydrolysate (and
amino acid) mixture in combination with a carbohydrate intake of 1.2
g · kg-1 · h-1.
Consistent with recent findings in the postabsorptive resting state
(van Loon et al. 2000a
), the magnitude of the in vivo
insulin response correlated with the increase in plasma leucine,
phenylalanine and tyrosine concentrations. Regression analysis showed a
strong positive correlation between plasma leucine, phenylalanine and
tyrosine concentrations and the insulin response. This suggested
relationship is in accordance with the effects of leucine and
phenylalanine in vitro in studies with incubated ß cells of the
pancreas (Blachier et al. 1989a
and 1989b
, Hutton et al. 1980
, Malaisse et al. 1991
,
Malaisse Lagae et al. 1971
, Sener et al. 1989
and 1981
, Sener and Malaisse, 1980
and 1981
,
Varnier et al. 1995
) and with the in vivo studies by
Floyd and coworkers (Fajans et al. 1962
, Floyd et al. 1963
, 1966
, 1968
, 1970a
and 1970b
) in which several
(combinations of) amino acids with and without glucose were infused.
The positive correlation observed with plasma tyrosine concentrations
may be explained by the fact that tyrosine, the hydroxylation product
of phenylalanine in the liver, is formed when large amounts of
phenylalanine are ingested (Pogson et al. 1985
).
Furthermore, we observed a less substantial but significant negative
correlation between the insulin response and plasma threonine,
asparagine, glycine, alanine, valine, methionine, isoleucine and
histidine concentrations. These negative correlations could be
explained by an increased amino acid uptake after an increase in
insulin level. Interestingly, the amino acids that revealed significant
negative correlations included all of the essential amino acids (of
course, with the exclusion of the supplemented amino acids leucine,
phenylalanine and its product tyrosine). Plasma amino acid
concentrations were generally lower after the ingestion of drinks 4 and
5 compared with the control trial, although in the latter, considerable
amounts of protein and amino acids were ingested, which would normally
increase the plasma amino acid response as shown in trials 2 and 3.
This seems to suggest that tissue amino acid uptake and possibly also
postexercise net muscle protein balance were increased after the
ingestion of this insulinotropic mixture. This would be in line with
several studies demonstrating that an increase in plasma insulin
concentration, during conditions of hyperaminoacidemia, further
increases net muscle protein balance in vivo in humans (Fryburg et al. 1995
, Gelfand and Barrett, 1987
,
Hillier et al. 1998
). Such a stimulating effect on net
protein balance may in part also be a consequence of a stimulating
effect of leucine on skeletal muscle protein synthesis, independent of
an increase in insulin levels (Anthony et al. 1999
and 2000
). However, the potential of insulinotropic protein
hydrolysate and amino acid mixtures to stimulate postexercise net
muscle protein anabolism, and the mechanisms involved, remains to be
investigated.
The present study shows that the ingestion of a mixture of wheat protein hydrolysate, free leucine and phenylalanine, in combination with carbohydrate, results in a substantial, additional increase in the postexercise insulin response compared with the ingestion of only carbohydrate. Furthermore, it is demonstrated that the magnitude of this increase in insulin response is dose dependent. Consequently, this mixture provides a practical tool to strongly elevate postexercise insulin levels via dietary manipulation only. This mixture has previously been shown to stimulate glycogen synthesis after exercise when added to a carbohydrate-containing solution (0.8 g · kg-1 · h-1) and may also serve to increase net protein balance in the postexercise phase and be applied as a tool in metabolic research investigating the effects of high plasma insulin concentrations.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviation used: Wmax, maximal workload.
Manuscript received May 11, 2000. Initial review completed June 12, 2000. Revision accepted June 26, 2000.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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