Increased plasma

an oral glutamine
Tomas

bicarbonate
load13

and growth

tamine,

An oral
subjects

Two

and

grams

ingested
Forearm

and

at 30-mm

circulating

glutamine

over a 20-mm
venous
blood

intervals

and

mm.

60

Ninety

mm

period
samples

minutes

and

capable
hormone.

that

the

concen-

increase

plasma

growth

Subjects

and

methods

with

time

responded
glutamine
value

load

plasma
findings

glutamine

load

as plasma

is

growth

WORDS
growth
hormone

Glutamine

load, plasma

healthy

lected

plasma

secretion

rates

performed

on

same

time,

3.8,

Glutamine
ance between
blood stream
with

dietary

that

glutamine

However,

homeostasis
reflects
the minute-to-minute
balglutamine
removal
from and addition
to the
(1). Normally,
endogenous
production
combined
intake

suffice

physiological

an acid

load,

may

for

the

daily

challenges,

small

Beside
(1),

role

its unique
glutamine

intestine

(3).

organ

function

dependent

processes

matory
fact,

it is not

response

such
(6)

over-training

plasma

glutamine

siveness

as judged

perspective

an oral

cial in anticipation
could be generated.

1058

plasma
both

glutamine

under

on glutamine.
with

immune

system

to infection

(7).

supplement

might

prove

and
capable

glutamate
of

growth
Am

as well

as

the

third

decade

1) were segrowth
hor-

(10,11).

Saturdays

Studies

at exactly

the

a light breakfast
(toast,
to ensure
a low basal
growth
an initial forearm
venous
blood
(490 mL carbonated
soft drink,

20 g glucose)
or vehicle
Louis)
was
ingested
over

St

60,

present

samples

and

90

protocol

Medical

was

(2

mm.

mL)

The

approved

College

Human
Research.
Blood samples

plus
2 g
a 20-mm

drawn

at

amount

30-mm

of glutamine

were

placed

Review

Juan

Capistrano,

was

bicarbonate

drawn
(Nichols

by

State

Board

on ice and centrifuged

10 mm at 4 #{176}C),
and plasma
hormone
by radioimmunoassay
CA),

by the Louisiana

Institutional

g for
growth

for

(10 000 x

for analysis
Institute,

of
San

microgasometry,

and

glutamine
by HPLC as described
previously
(13). All analyses
were
performed
the same
day. Precision
for determining
plasma glutamine
was 3%, for total carbon
dioxide
1.5%

(95%

representing

bicarbonate),

Intrassay

5%.

growth

determined
growth

and

hormone

for

growth

variability

to be 7.8

2.8%.

hormone

is 0.06

The

hormone

for five

sensitivity

g/L,

this

From

the Department

of Physiology,

subjects

in detecting

allowing

Louisiana

lege of Medicine,
Shreveport,
LA.
2 Supported
by funding
from Research
Louisiana

benefi-

3 Address

Louisiana
LA

amino
hormone

J C/in Nutr

to

for

measure-

In

responFrom

The

University

depressed

concentrations,
eliciting

(12).

plasma

antiinflam-

reserves

y (Table
in human

32-64

consecutive

blood

30,

was

consumed
ranged from 0.016 to 0.036 g/kg (Table 1). Note that
subject A consumed
20 times this amount (0.56 g/kg) during an
identical
protocol
in an earlier study without
untoward
effects

was

multiorgan-

and

(5)

in part,

and

also

of such challenges,
providing
bicarbonate
Furthermore,
glutamine
might
also in-

arginine
potentially

find

associated

by susceptibility

generating

availability

to

immune
is

concentration

those

turnover
in muscle (4),
stores. Thus, given the
in supporting
cellular

surprising

athletes

(2).

role in supporting
renal
is the major
metabolic

to be dependent,
in

so

acid

on glutamine

Glutamine

as the

demands

amino

especially

an essential

appears
to determine
the rate of protein
the major repository
of mobile nitrogen
fundamental
roles played
by glutamine
and

growth

as a nonessential

confer

these conditions
(3).
bicarbonate
production
fuel

to meet

is classified

serial

study

might increase
this would be

100 and 45 mm after

containing
(Sigma,

with

intervals:

alkaline

decrease

after
two

0800-1

L-glutamine

of this

concentration.

aged

and juice)
designed
release
(11). After
(t = 0), either vehicle

period

Introduction

fluid

of the known

mone

coffee,
hormone

purpose

hormone

volunteers

because

sample

bicarbonate,

the body

were

pH
KEY

to increase

Nine

at 90

the

a small oral glutamine

load
glutamine
and, if so, whether

sufficient

administration

oral

Accordingly,

whether
plasma

drink

and circulating
elevated.
These

small

(8,9).

a light breakat zero time

control

alkaline
reserves
as well
J Clin Nutr 1995;61:1058-61.

secretion

determine
circulating

glu-

in a cola

compared

glutamine

a surprisingly

of elevating
A,n

hormone

to the

to

plasma

Eight of nine subjects

an increase
in plasma

both plasma
bicarbonate
concentration
growth
hormone
concentration
were
demonstrate

on

45 mm after
were obtained

returning

after

administered

dissolved

for 90 mm

before

was
effect

growth

were

controls
obtained
I wk earlier.
to the oral glutamine
load with
at 30

load
the

1995;61:1058-61.

Education

Quality

reprint

requests

State

University

Support

State

Corporation

Fund
College,

October

31,

Technology

Coland the

RD-A-IS.

to TC Welbourne,
Medical

University

Department
P0

Box

of Physiology,

33932,

Shreveport,

71130.
Received

June

Accepted

for

Printed

24,

1994.

publication
in USA.

1995

American

1994.
Society

for Clinical

Nutrition

Downloaded from ajcn.nutrition.org by guest on October 11, 2015

and
fast.

glutamine

to determine

bicarbonate,

trations.

acids

after

C Welbourne

ABSTRACT
nine healthy

crease

hormone

GLUTAMINE,
TABLE

AND

Summary

GROWTH

as shown
of subject

Subject

characteristics

code

and glutamine

Age

Sex

dose

BMI

Glutamine

kg/rn2

BICARBONATE,

dose

zg/kg both

HORMONE

1. The increase

in Figure

with

the time

mm,

with

control

a gradual

initial

glutamine

50

23.5

28

vs 744 36 moVL,

64

26.4

21

60 mm after

35

21.5

29

44

35.0

18

40

23.2

25

42

26.6

27

load

36

26.25

32

38.55

16

did

37

22.32

36

show

, ii

43.5

8: subject

25.6

3.4

H not included

30

produced

1.5

in population

not
The

27 2

effect

hormone

means.

of 2.7

the
of

the

of concentrations

Kit,

acids

were

(hexokinase
Boehringer
Statistical

90

(ANOVA;

p.g/L

Glucose
using

(catalog

and

#40-2205;

nonesterified

determined

by

enzymatic
Mannheim,

assay,
Sigma,
and colorimetric
Mannheim,
Germany).

commercially

fatty

available

oral

kits
assay,

repeated

differences

test.

Where

one-tailed

measurements).
were

growth

by using

changes

was

used,

hormone;

were

otherwise

a priori,
carbon

a two-tailed

plasma

growth

control,

growth

0.029

0.015

plasma

was

hormone

subjects

showed

concentration
value
P

(0.084

0.09

by paired

a discernible

and

respectively,

peak

0.020

with

discern-

in only three of
treatment
the

4.3-fold

higher

0.04

compared
t test);
seven

at this

time.

than
with
of the
In fact,

Students

predicted
total

on

0 and 90 mm,

the time control

90-mm
0.019
0.002
nmol/L;

not

3. For the time

were

load

did

time

a paired

ie, glutamine,

glutamine

also

concentration.

apparent
glutamine

growth

433
30 or

at 0, 30,
variance

Between-treatment

analyzed

directional
t test

time,
of

increase,

bicarbonate

ible peaks (> 25% of preceding

nadir)
the subjects.
In contrast,
90 mm after

eight

in plasma
glutamine
and glucose
with
mm,
were
analyzed
by analysis

point

and

as 0.1

Institute).

a,ialysi.s

Changes
and

60,

as low

Nichols

subjects,
at either

t test

dioxide,
was

Time Control

used.

GIN

30
Results
Eight
responded

of the nine subjects

with an elevation

receiving
in systemic

the

oral
plasma

glutamine
load
concentration

28

. L-G(utamine

26

-J

0 Vehicle

-I

0.9

E
w

24

DS

0.8

E
0

(D
0

I
06

#{149}

0.5

Q_

0.4

30

60

90

Minutes

FIGURE
ingestion
control.
sampling
vehicle
test).
both

1. Peripheral

plasma

(2 g).

SEM;

Glutamine

was

at 30-mm

consumed

intervals.

at 30 and 60 mm,
Changes
vehicle

glutamine

in glutamine
and L-glutamine

concentrations

n = 8 subjects
over

Significant

0.01

<

20 mm,

and P
0.01,

with

difference

concentration

(P

compared

0-20
between

0.02,
with

ANOVA).

time

after

glutamine

their

own

mm

90

90

Mm

Mm

and

(paired

significant

serial

glutamine

respectively
were

with

time

a
for

FIGURE
either

vehicle

Time

averages

2.

Plasma

(time
from

bicarbonate

control)
eight

concentration

or L-glutamine
subjects

(0)

(GLN)
(subject

before

and 9() mm

after

(2 g for n = 9 subjects).
H not

included).

Downloaded from ajcn.nutrition.org by guest on October 11, 2015

HGH

an increase

glutamine

plasma

in Figure

hormone
concentrations
0.002
nmol/L
at t =
ment

H had a lower

eight

0.7 mmolfL
compared
with -0.7
control,
P < 0.02. Subject
H, who

plasma

in his

is shown

subject

at 60

different

load.

for the time

exhibit

12%

significantly

load increased
the plasma
bicarbonate
in Figure
2. After 90 mm, the glutamine

a gain

an increase

it was

the other

and did not show

glutamine
as seen

0.6 mmol/L

not

at 90 mm. In contrast,
than

19% compared

sustained,

to a value

the glutamine

The oral
concentration

:!: SEM

return

was prompt,

and

concentration

at 30 mm,

from the time control

ttt

1059

1060

WELBOURNE
8.0

.30

Time Control

. L-Glutamine

7.5

0 Vehicle

-J
-

.20

6.5

E
jo.0
.10
8

5.5

(D

5.0

-J
4.5

4.0

C
-.9

0.05

0)

30

90

60

Minutes

FIGURE

0
0.04

ingestion

.C

both

0.03

example,
mm

0.02

____________
0
90
Mm
Plasma

vehicle
Average

growth

(time
for

hormone

control)

concentration

or L-glutamine

all the subjects

this

____________
0
90
Mm

subjects).

before
(GLN)

and 90 mm

(2 g for

(#{149})(subject H not

n =

included).

and

respond

60

mm,

respectively.

In

to the glutamine

concentration
mm (0% and

load

The

forearm

seen

in

glucose

venous

in Figure

mrnol/L,

forearm

subject

plasma

H did

growth

ingestion
occurs
at 30 mm as shown

occurred

blood

was

5. A greater

was observed
the time control
P

the

however,

increased
19%

this

plasma

observed

at 30

load

provoked

obese

not

glutamine

individual.

clearance

an

with

activation

of

consistent

Nevertheless,

the

present

study

clearly

ability

to

increase

plasma

bicarbonate

concentration

and

thus the buffering

capacity
of body fluid. Indeed, with the load
used, plasma bicarbonate
increased
in a manner consistent
with
the elevation
in circulating
glutamine
and glutamines
role as a

hormone

in

both

time

despite
a
in Figure
control

and

groups, reflecting
the glucose content of the vehicle.
with glucose,
the free fatty acid concentration
in

concentration
pared
with

study;

higher

with

at, or below,
the time control
value
at 30 and 60
-28%,
respectively).
Note that the rise in plasma

rise

glutamine
In contrast

contrast,

with

growth
hormone
after glutamine
small increase
in plasma glucose
4.

20 times

for

(ANOVA).

shows
that an oral glutamine
load approximating
the dose
range shown here appears to attain a window
of effectiveness
in achieving
the desired objectives
without
calling into play the
formidable,
and even counterproductive,
hepatic
mechanism
for responding
to a large increase
in plasma
glutamine
(1).
The effectiveness
of an oral glutamine
load would depend on
its

both subjects
C and F exhibited
early peak responses
that
averaged
increases
of 67% and 78% above their time control at
30

present

load

compared

0.01

<

and glutamine

was significant

hepatic glutamine
removal
(16). On the other hand, smaller oral
loads,
1 g, run the risk of being
unable
to significantly
elevate
circulating
plasma
glutamine.
The failure
to elicit a
response
in subject
H might well reflect
the limiting
dose in

3.

in the

(12)

glutamine,

vehicle

glucose

Gi
B
H

either

214%

plus

after

in plasma

accelerated

FIGURE

a glutamine

concentration

Elevation

0.01

and vehicle

glutamine

after

vehicle

glucose

subjects.

0.08,

free fatty

paired

acid

affected

by

the

glutamine

fall in the plasma

over
(-0.29
t

utilization

test)

the

30-60-mm
0.10 vs

consistent
(14).

free

load

fatty

as

acid

period
corn-0.10
0.04

with

enhanced

-I

U-

LU

0
E
E

ci)

0)
C
0

-C

Discussion
A surprisingly
small oral glutarnine
load, 2 g, was able to
produce
a prompt and sustained
(0.5 h) elevation
in circulating
plasma
glutamine,
indicating
that significant
amounts
of an
orally
administered
glutamine
load did reach the periphery
(15). Larger glutamine
loads would increase
plasma glutamine
even further but carry the risk of activating
hepatic uptake.
For

0-30

FIGURE

5. Glutamine

free

fatty

acid

fied

fatty

acids.

concentration

Mm

Mm

30-60

ingestion
compared

accelerates
with

60-90

the decrease
vehicle.

NEFA,

Mm

in forearm
nonesteri-

Downloaded from ajcn.nutrition.org by guest on October 11, 2015

0
0

4. Plasma
for eight

GLUTAMINE,
precursor
in plasma

drive

for renal
bicarbonate

up muscle

ing

protein

base
and

generation
(1).
oral glutamine

cellular

glutamine

breakdown

(4),

also

associated

above
trols.

the low
Because

time

and

with

after

an increase

intake

(17),

(10)

the

peaks

are defined

more than
in growth
exceeded

represents
that

note

effective

Indeed,

in the time
fluctuates

conditions

were

increments,
How
an

the

smaller

secretion

However,

glutamine

was

not

growth

hormone

might

in shifting

in

(23),

(9).

utilization

exercise
Note

creases
pressed

that

a stimulus
release

to fatty
proposed
Growth

ering

plasma

increases
which

when

by acid

circulating

growth

alkaline

shown

I thank

(ammonium

homeostasis.

a potential

benefit

Sudhir

for technical

concentration
small

in terms

mix

oral

suplow-

renal

18.

20.

idosis.

JPEN

2. Rose WC.

metabolism

during

1990;l4:775-855.

Amino

acid

requirements

Fed Proc

1949;8:546-52.

stimulates
somatostatin

186-9.
2nd

ed.

New

York:

DE,

N. The

GA,

Bain

population:

RP.

relation

to

effect

of glutamine

in normal

subjects

adminisand patients

1972;51:1852-60.

Growth

hormone

accelerates

tubular

acid

1991;260:R1036-42.
GA,

Zierler

and adipose

Invest

G, Fleming

1981;67:1361-9.

Invest

Klassen

KL.

tissue

Effect

of

metabolism

human

growth

in the forearm

of

1965;44:51-61.

Marano

MA,

Campbell

and glutamic
M,

acids

McKellar

glutamine

uptake

RG.

Splanchnic

in humans.

Reach

D, Channon

Am

bed utilization

J Physiol

1993;264:

of

JOL,

ac-

26.

Johnson

endogenous

glu-

Goodship

Ammonium

and amino

acid

1992;263:E735-9.
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Minimizing

J, George

J Physiol

K, et al. Marked

on day-to-day

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THJ.

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false-positive

er-

1985;248:E475-81.
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of sustained

metabolism:

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I Clin

in

Endocri-

1993;77:1589-96.
BC,

of potent

Rational

design

receptor.

Windmueller

Science
HG,

Spaeth

HG,

I Physiol

Fukunaga

R, Nagata

antagonists

5, Golddel

DV,

to the human

Wells

growth

hor-

1992;256:1677-80.

by the small

Windmueller

AE.

Uptake

and

intestine.

J Biol

Chem

Spaeth

AE.

Source

metabolism

of

plasma

1974;249:5070-9.

and fate of circulating

citrulline.

1981;241:E473-80.

Costill

DL,

balance

during

I Sports

Med

Verstappen

H, Janssen

of exercise:

WJ, Vos NH,

on

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JR. Jones
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bouts

E, Fink

influence

W. Acid-base

of bicarbonate.

Int

1984;5:228-31.

balance
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F, Kuipers

repeated

SE, Kraemer

50:241-7.

CM,

Am

JA.

Sutton

in

hepatic

1987;252:E746-50.

spares

detection.
levels

patients

Metab

Am
24.

Moller

hormone

glutamine
23.

AD,

pulse

J Physiol

protein

I Physiol

Fuh G, Cunningham
mone

22.

increases

Rogol

interaction

in modulating

1994;18:243-7.

Scringeour

JD,

in hormonal

JPEN

Am

Gut-liver

glutamine

SM,

Veldhuis

TC.
ammonia

Am

S. Enteral

acidosis

in humans.

growth

Welbourne

acidosis.

oxidation

nol
21.

may

Joshi

in chronic

Jorgensen

D,

role of portal

and metabolism.

TC,

tamine

base
of man.

D,

Lubin

excretion

MI.

I Physiol

homeostasis:

low

assistance.

glutamine

of the

on isolated

K. Arginine

in the adult

M, Bank

I Clin

glutamine

intensity
S. Interorgan

Am

J Clin

acid-base
Joshi

E. A

and cells

endogenous

1988;67:1

CM,

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on muscle

25. Gordon

TC,

Newsholme

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TC,

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J, von Werder

Rogers

Weber

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favoring

neutrophils.

of n-methyl-D,L-aspartate

medical

J Clin

TC,

15. Matthews

(26),

that

patient

Biochem

by suppressing

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19.

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in elevating
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hormone-dependent

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loading

for growth

growth

performance

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(25). Interestingly,

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to acid-base

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17. Welboume

a major
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concentration

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I Nutr

skeletal

L. Effect

secretion

HM.
Press,

with

in muscle

elimination
role during

limit

hormone

hormone

a role

to be effective

reserves

contribute
suggests

with

In summary,

was

may

growth

bicarbonate

homeostasis.

load

acidogenesis

exercise
and
administration

is consistent

facilitates
important

glutamine

Endocrinology

J Clin

16. Buttrose

acids

Mi.

on phagocytosis

K. Enteral
E, McAndrew

between

Int J Sports

J, Miller

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14.

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rat skeletal

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hormone

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13.

Rennie

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inflammation.

P, Ohlsson

10. Goodman

hormone

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PW,

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A, Horton

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system.

growth

11.

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E848-54.

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glucose

recently
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King
M,

9. Alba-Roth

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role of growth

B, Watt

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growth

TC,
efflux

8. Lindstrom

tration

for

K, Weryk
by glutamine

killing

7. Parry-Billings

12.

conver(22) sup-

a conditionally

1988;257:133-6.

glutathione

that

stimulus

Smith

age and adiposity.

for directly
activating
(8). Thus,
either
one or

glutamine

from

circulating

in strenuous
by bicarbonate

be

Is glutamine

1994;18:128-33.

immune

rise
and

fluxes

Lett

6. Welboume

study.

conversion

ates renal acid secretion

(13) and thereby
of acid from the body fluids, a potentially
(24).

acid

PA,

breakdown

and bacterial

larger

present

known

In addition,

to an oral

growth
hormone
was
in acid-base
homeostasis

strenuous

the

amino

to the better-recognized
fuel

be

DW.

1990;48:299-309.

communicational

20%

may

would

play a role in stimulating

in response

In addition
(14),
role

to

study
the
subjects

secretion.
For example,
in the small
intestine

synthesis

secretion

effectors

secretion

selected

increments

secondary

tamine
to glutamate
provides
somatotrophic
growth
hormone

both

conwith

as being

than

elucidated

initiates

arginine

MacLennan

JPEN

exert
autoinhibiting
effects
(21).
load might
stimulate
basal
growth

could
affect
growth
hormone
sion of glutamine
to citrulline
renal

ligand

activation

which
could
oral glutamine

hormone

ports

criteria

Rev

5. Ogle CK, Ogle JD, Mao J-X, et al. Effect

of age-dependent
conditions,
signifi-

(19). In the present

in seven
of eight

in receptor

4.

Wilmore

NL,

the

growth

J AppI
Toews

Lynch

Physiol
Ci.

at rest and during

JM,

hormone

Knuttgen
response

HG.

Effect

to acute

of

high-

1994;76:821-9.

Growth
exercise.

hormone
Clin

secretion
Sci

Mol

in acidMed

1976;

Downloaded from ajcn.nutrition.org by guest on October 11, 2015

(20).

more

Nutr

hormone

the time
control
value
by fourfold.
Although
this
a small
increment
in circulating
growth
hormone,
it is effective
in eliciting
growth
hormones
metabolic

effects

JM,

acid?

1061

HORMONE

of protein

load

growth

observed
concentration

the

nadir
occurred

3. Lacey

acido-

glutamine

in plasma

by the threshold

a preceding
hormone

slow-

under

oral

provide
a minimal
secretion
in a population
low secreters
(1 1). Under such controlled
cant

thereby

accelerated

GROWTH

FEBS

basal
concentrations
growth
hormone

food

AND

Note that both the rise

would
be expected
to

content

a process

genic
conditions
(17,18).
The rise in plasma
glutamine
was

BICARBONATE,