Download Calories and gastric emptying: a regulatory capacity with

Calories and gastric emptying:
a regulatory capacity with implications
PAUL R. MCHUGH
AND TIMOTHY
H. MORAN
Department
of Psychiatry and Behavioral Sciences,
School of Medicine, Baltimore, Maryland
21205
behavior;
regulation;
Macaca
“preabsorptive”
satiety
mulatta; hunger;
stomach;
CONCEPT
THAT
BEHAVIOR
serves to support the
physiological integrity of the organism first emerged from
the studies of Curt Richter. His “cafeteria” experiments
demonstrated that feeding animals will seek and choose
those nutrient constituents they need to maintain health,
growth, and reproduction. Richter (20) said, “In the
normal intact animal the maintenance of a constant
internal environment depends not only on the physiological or chemical regulators but also on behavior. . . [and]
the effort to maintain a constant internal environment
br’homeostasis constitutes one of the most universal and
powerful of all behavior urges or drives.” The discovery
of physiological mechanisms linking the organism’s requirements and the homeostatic behaviors was the natural outcome of the Richterian concept. From it we
appreciate such linkages as a role for angiotensin in thirst
(13) and adrenocortical hormones in sodium appetite (18,
THE
19).
Behavior regulates quantity as well as quality in nutrition. The exact mechanisms linking the alternations of
hunger and satiety to the energy requirements of the
The Johns
Hopkins
University
organism are not identified despite the recognition of
hypothalamic and visceral sites of influence. However,
the regulation is not difficult to demonstrate. We (15, 16)
have shown that in rhesus monkeys the quantity of food
eaten each day is controlled, increasing or decreasing in
response to deprivation or surfeit so that the mean daily
caloric intake remains stable.
Precision in this regulation is demonstrable by infusing
liquid nutrients into the stomach prior to feeding periods.
In response the monkey will reduce the food it eats by an
amount comparable to the caloric content of the infused
“preload” maintaining total caloric intake constant. It
does so with accuracy across a range of calories in the
infusion (O-300 kcal) and equally well for infusions of
carbohydrate, fat, and protein.
An intriguing aspect of this precise regulatory response
can be discerned when an infusion given just prior to a
feeding period is followed by x ray (15, 16). Infusions of
150 kcal are not completely emptied from the monkey’s
stomach at the end of a 4-h feeding period. Despite this
the reduction in feeding is 150 kcal. A gastrointestinal
role in the caloric regulation of feeding and in the onset
of satiation would appear necessary to provide the animal
a means of estimating and responding with precision to
the energy in the unabsorbed intestinal contents.
Some visceral mechanisms in satiety have been suggested. Cannon and Washburn (Z), demonstrating that
gastric distension can interrupt feeding, proposed that
the stretching of the stomach induced by food within it
is an important signal to satiety. Gibbs et al. (5, 6),
demonstrating that cholecystokinin, a gut hormone released by nutrients entering the small bowel interrupted
feeding in rats and monkeys, proposed that this hormone
acts as a satiety signal.
Each of these visceral mechanisms could produce a
satiation effect in feeding before all ingested nutrients
were absorbed from the gut. However with none of these
proposals with the potential for “preabsorptive” satiety
has any connection to the energy in food been demonstrated. If animals can regulate their caloric intake with
accuracy before absorbing all the calories they have
ingested then some quantitative linkages between intraintestinal calories and the mechanisms inducing satiety must exist.
Important preliminary evidence of such a relationship
was reported by Hunt and Stubbs (10). These investigators by means of a retrospective study of previously
0363~6119/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
Society
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MCHUGH, PAUL R., AND TIMOTHY H. MORAN. Calories and
gastric emptying: a regulatory
capacity with implications
fur
feeding. Am. J. Physiol. 236(5): R254-R260,
1979 or Am. J.
Physiol.: Regulatory
Integrative
Comp. Physiol. 5(3): R254R2k10, 1979.~Gastric
emptying
in four unanesthetized
male
IMacaca mulatta was studied with the serial test meal method
of Hunt and Spurrell.
Liquid meals were infused into the
stomach through a chronic indwelling
Silastic cannula. Saline
meals empty rapidly and exponentially.
Doubling
the volume
of saline from 150 to 300 ml increased the emptying rate so that
the half-life remained unchanged (15 min). The 150-ml glucose
meals (0.05, 0.125, and 0.25 g/ml) emptied more slowly than
saline, progressively more slowly with increasing concentrations
(0.05-1.8, 0.125-0.78,
and 0.25-O-37 ml/min)
and linearly
through most of their course. Doubling the volume of 0.125 g/
ml-glucose meal did not change the rate of emptying. Converting grams of glucose to their caloric content, the emptying rate
in kcal/min
becomes constant (approx 0.4 kcal/min)
in this
range of concentrations.
Isocaloric casein hydrolysate and medium-chain
triglyceride
oil meals at 0.5 kcaffml empty at the
same rate as glucose. The precision of this regulation
is sufficient to give it a role in preabsorptive
satiety and the control of
caloric intake.
for feeding
CALORIC
KEGULATION
IN
GASTKIC
R255
EMPTYING
METHODS
The experimental animals were four male Macaca
mulatta weighing between 6 and 8 kg. They were housed
in individual cages and had access to food in the form of
monkey chow 4 h/day. Water was available ad libitum
except during the experimental periods. They were each
equipped with a chronic indwelling gastric cannula that
permits the infusion into and withdrawal of liquids from
the stomach. This cannulation method and its maintenance by investing the monkey in a leather jacket are
described in detail elsewhere (15). It permits us to maintain an essentially freely moving monkey and gives us
easy and chronic access to gastric contents.
To study gastric emptying, we employed the serial test
meal method of Hunt and Spurrell (9). The monkeys
were fasted overnight (18-20 h). A wash of the stomach
with 50 ml of distilled water preceded the introduction of
the test meal through the cannula. The test meals were
infused by hand from syringes at approximately 100 ml/
min. Phenolsulfonphthalein was mixed with the test meal
to serve as an indicator. Test meals were all given at
38°C. After an interval, the gastric contents were withdrawn, their volume was measured, and the dilution of
phenolsulfonphthalein as determined by calorimeter employed to calculate the volume of the test meal remaining
in the recovered gastric contents. For each monkey on
successive days, in accordance with the serial test meal
method, different intervals between infusion and withdrawal were employed so that a display of the emptying
of a given liquid meal over time could be obtained.
Occasionally there might be some obstruction to the
cannula and in such situations the monkey was tranquil-
ized with ketamine hydrochloride and gavaged to get a
complete withdrawal. Results obtained in this way did
not differ from the others.
Test meals used were one of the following: physiologic
saline, glucose hydrous solutions of various concentations
(0.05-0.5 g/ml), 0.125 g/ml casein hydrolysate solution,
or a suspension of 19.5 ml of medium-chain triglyceride
oil (MCT) in water. All nutrient meals were given in a
volume of 150 ml; the saline and the 0.125-g/ml glucose
meal were also given in a 300-ml volume. The standard
estimates of 4 kcal/g were employed for the caloric
densities of glucose and casein and 9 kcal/g for MCT.
Osmolarity of appropriate meals was measured with the
vapor pressure osmometer.
Results were analyzed using the least-squares linear
regression method.
RESULTS
All results are summarized in Table 1 where the rates
of emptying of the test meals can be compared.
Physiologic saline (287 mosmol/& As shown in Fig. 1,
test meals of physiologic saline (NaCl 0.9%) empty rapidly and exponentially from the monkey’s stomach. Increasing the volume of the test meal from 150 to 300 ml
increases the rate of emptying. The logarithmic display
(Fig. 2) reveals parallel log regression lines with essentially identical half-lives. These saline emptying curves
conform to an exponential (first-order kinetic) equation
with a significance level of P < 0.001.
GZucose. Test meals of glucose empty from the stomach in a fashion different from saline. Even for the
concentration osmotically comparable to physiologic saline the emptying of glucose is slower (saline 4.25 and
glucose la81 ml/min) and more linear. This latter feature
is displayed in Fig. 3 where the emptying curves of 150
1. Rates of gastric emptying
of experimental meals
TABLE
Meal
n
--
Calorir
Conrn,
kral/ml
Vol, ml
OsmolalEmptying
ity. mosKatch. ml/
mol/ kg
min
---._-- -_-
25
Saline
150
286
20
Saline
300
286
24
Glucose
0.2
150
272
32
Glucose
0.5
150
682
26
Glucose
1.0
150
1,364
18
Glucose
1.33
150
1,819
23
Glucose
2.0
150
2,728
36
Glucose
0.5
300
682
16
Casein
hydrolysate
MCT
0.5
150
839
0.5
150
16
4.25
kO.571
6.82
&0.92-jI.814
~0.121
0.783
to.039
0.373
kO.025
0.348
kO.023
0.321
kO.029
0.847
kO.028
0.771
20.069
0.758
kO.053
n, Number
of test meals. P values refer to comparisons
rate with change in meal volume for * glucose 0.5 kcal/ml
ological saline.
* P > 0.2.
t P < 0.02.
Ihq)t.ving
Kate, kd/
min
0.363
*o-o24
0.39 I
*0.020*
0.373
kO.025
0.452
kO.29
0.640
t0.058
0.423
*0.014*
0.385
to.034
0.377
-to.028
of emptying
and t physi-
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.6 on June 16, 2017
published experiments
in man recognized a slowing of
gastric emptying with increasing caloric density of meals.
The linkage between gastric emptying and calories did
not seem to provide a regulatory
capacity since the
slowing of gastric emptying as caloric concentration
increased was not sufficient to make the flow of calories
from the stomach constant. But their report suggested
t.hat gastric emptying is in some fashion tied to the
energy content of nutrients.
This relationship
must be
further explored because any demonstration
of quantitative accuracy in the function of this organ to the caloric
content of ingested foods might form a mechanism for
precision of preabsorptive
satiety and the regulation of
caloric ingestion.
Consequently
we have directly examined gastric empt.ying in the rhesus monkey by employing gastric infusions of liquid meals of varying concentration
of calories
and varying nutrient constituents.
In this series of experiments we sought information
on four points: 1) is there
caloric regulation of gastric emptying in rhesus monkeys;
2) over what range of energy densities, if any, is there a
stabilization of energy delivery to the duodenum; 3) can
isocaloric concentrations
of carbohydrate,
protein, and
fat produce equal gastric slowing in the monkey; and 4)
is the precision of any demonstrated
control sufficient to
give it a possible role in feeding where behavior regulates
energy intake? Preliminary reports of these findings have
been presented (14, 17),
P. R, MCHUGH
W-
1. Gastric
time. Points
emptying
are means
FIG.
over
(min)
of 150- and
k SE.
300~ml
physiological
saline
I
*F 100-j
I
1
--------~------
.- C
0
j
3
-“E
P
~~~
50
1
I
L
1
5
1
1
20
10
Time
FIG. 2. Semilogarithmic
ml physiological
saline.
display
Tb, half-life.
3b
(min)
of gastric
emptying
of 150- and 300-
ml of glucose in’concentrations
of 0.05 g/ml (272 mosmol/
l), 0.125 g/ml (682 mosmol/l),
0.25 g/ml (1,364 mosmol/
1) are shown. From 20 min after their infusion these
glucose meals empty in a manner conforming to a straight
line (zero-order kinetic) equation with a significance level
of P < 0.001. Increasing the glucose concentration
of test
meals results in a progressively
slower rate of gastric
emptying.
A regulatory implication of this progressive slowing of
emptying with increasing concentrations
of glucose in
the meals is revealed when attention is directed to meal
calories emptied over time rather than meal volume
emptied over time. The y-axis of Fig. 3 can be changed
from meal volume remaining in the stomach to meal
calories remaining. Figure 4 is the resu It . With each
increase in concentration
of glucose there iS an increase
in the total calories in the stomach and thus a progressive
elevation in the initial value. However, the rate of emp-
T. H. MORAN
tying of these calories shown by the slope of these emptying curves is the same. The three curves are parallel.
Thus Figs. 3 and 4 reveal that within
a range of
concentrations
of glucose from 0.2 to 1.0 kcal/ml the rate
of emptying of 150 ml of glucose changes sufficiently with
changing concentration
to stabilize the delivery of calories to the small intestine. That is, the rate of emptying
of glucose is such that the product of energy density
(k&/ml)
and emptying rate (ml/min)
gives a constant
rate of emptying of energy (kcal/min)
from the stomach
(Table 1).
A similar regulatory
implication
appears in another
difference between the gastric emptying of saline and
glucose. Doubling the volume of saline from 150 to 300
ml increases its emptying rate and keeps “half-life”
constant: an exponential
characteristic
(Figs. 1 and 2). In
contrast doubling the volume of a glucose meal (0.5 kcal/
ml) from 150 to 300 ml does not significantly
(P > 0.2)
change its emptying rate (Table 1). Figure 5 draws out
the regulatory implication to be derived from the loss of
this exponential characteristic
to the doubling of volume
by depicting it together with the slowing of gastric emptying produced by doubling the concentration
of glucose
in a meal. The slopes of the emptying curves of 0.5-k&
ml meals are comparable at 150 and 300 ml so that these
curves appear as parallel lines. The emptying curve of
the 150~ml LO-k&ml
meal is superimposed
in Fig. 5.
This meal empties more slowly than the 0.5-kcal/ml
meals but just slow enough so that it is completely
emptied from the stomach in the same time as the 300ml O.&kcal/mI
meal. Thus it appears that 150 kcal of
glucose empty completely from the stomach in the same
period of time whether these calories are given in meals
of higher concentration
and lower volume (150 ml at 1.0
kcaI/mI)
or lower concentration
and greater volume (300
ml at 0.5 kcal/ml).
As shown in Fig. 6 and Table 1 when glucose concentration exceeds 1.0 k&/ml,
gastric emptying does not
slow further. As a result with each increment in concentration above 1.0 k&ml,
there is more rapid delivery of
calories to the small bowel, i.e., a loss of regulation to
caloric concentration.
Protein and Z&id. To exclude the possibility
that the
feature controlling glucose emptying was coincidental to
the nutrient content, we have examined the gastric emptying of nutrients
of different chemical character
but
identical in caloric value, Isocaloric meals (150 ml at 0.5
k&/ml)
of casein hydrolysate
and of a suspension of
medium-chain
triglyceride
oil are compared in their gastric emptying with an isocaloric (150 ml at 0.5 kcal/ml)
glucose meal in Fig. 7. The three regression
lines of
gastric emptying are superimposable.
Isocaloric loads of
three nutrient types (carbohydrate,
protein, fat) empty
from the stomach at the same rate (Table I).
The results are summarized in Table 1. Saline empties
exponentially
and increasing
its volume increases the
rate of emptying. Glucose empties so as to maintain a
constant rate of delivery of calories to the small intestine
over a range of energy densities of 0.2-1.0 k&ml.
Doubling the volume of a glucose meal does not significantly
alter the rate of emptying. Isocaloric loads of carbohy-
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Time
AND
CALORIC
REGULATION
IN
GASTRIC
R257
EMPTYING
.05gm/mtw
.12Sgnl/d e--o
.25 p/ml 4
FIG. 3. Gastric
emptying
of 150-ml glucose meals
of varying
concentrations.
Lines obtained
by leastsquares linear regression
method.
sb
8b
120
I60
\
12
200
.
240
TIME hn)
.05gmlml
.t25
p/ml
.25gm/ml
--- - --
0.2 kcatht
0.5 kcatht
1.0 kca I/m t
FIG. 4. Caloric
emptying
of 150-ml
glucose meals at varying
concentrations.
.40
80
PO
Time
160
200
240
280
in minutes
drate, protein, and fat produce equal slowing of gastric
emptying.
DISCUSSION
The method we have chosen to study gastric emptying
is the traditional one-the serial test meal of Hunt and
Spurrell(9). This method provides information about the
emptying of the meal instilled and should be distinguished from the indicator-dilution method of George (4)
that gives information about the total volume of gastric
contents (meal plus secretion), without allowing any conclusions about the emptying rates of either meal or
secretion specifically. It is the emptying of meals rather
than total gastric contents that is our prime interest.
From these data, it would appear that the rate of
gastric emptying of liquid meals in rhesus monkeys is
under the control of a regulatory system sensitive to
some physical properties of nutrients associated with
energy content. Nonnutrient physiologic saline empties
in a different fashion, rapidly and exponentially, with the
particular feature that the volume of infused saline affects the emptying rate while maintaining a constant
half-life as first shown by Marbaix (12). With nutrient,
the emptying is slower, the exponential character of
saline emptying is replaced by a more linear one and the
prominent effect of volume is lost. For meals within the
range of 0.2-l k&/ml
(the caloric density of most nutrients consumed by this primate in the wild) (13) the
emptying is so controlled that the rates of delivery of
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-
R258
P. R. MCHUGH
energy to the duodenum are equal (approx 0.4 kcal/min).
This finding differs from that of Hunt and Stubbs (10)
who recognized slowing but not regulation in the emptying of calories. A distinction in method probably explains our differences. The linear emptying and caloric
regulation is found only after filling the stomach. As the
stomach is filled a sample of the infused meal regardless
of concentration enters the duodenum and small intestine
as a bolus of 20-30 ml (16, 22). The slowing of emptying
follows this intestinal sampling of the gastric load. We
AND
T. H. MORAN
can recognize this initial bolus both on x ray (16) and
from the fact that the linear regressions do not extrapolate back to intersect the y-axis at 150 ml, the infused
volume, but fall below that point by 20-30 ml. If as with
Hunt and Stubbs the time for a meal to be half emptied
is employed as a measure of gastric emptying, the precision of regulation will be obscured by the unregulated
calories in the initial bolus. Information on the dynamics
of gastric emptying during the initial filling of the stomach is needed, but would not alter our point: within the
..
-m --. .
I
80
I
120
m
160
I
200
m
240
Time (min)
FIG. 6. Rates of gastric emptying
of 150-ml
meals differing
in caloric concentrations.
glucose
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FIG. 5. Emptying
of 150 kcal of glucose in same
time whether
given in greater
volume
or in greater
concentration.
Meals of 0.5 kcal/ml
( w----#;
1 .O-kcal/
ml meals (W - -I). a: lower Line totals 150 ml and 75
kcals, upper Line totals 300 ml and 150 kcal. H: Line
depicts meals totaling
150 ml and 150 kcal.
CALORIC
REGULATION
IN
GASTRIC
R259
EMPTYING
Glucose
MCT
Casein
e-m
m-4
*--0
FIG.
case,
7. G bastric emptying
of 15O-ml isocaloric
case m hydrolysate,
and MCT meals.
glu-
range 0.2-1.0 kcal/ml the change in the rate of gastric
emptying produced by changing the caloric concentration
of liquid meals makes the rate of entry of calories into
the small bowel equal for all these meals over a substantial portion of their emptying periods.
The mechanisms
that lead to the changes in gastric
emptying with nutrients
are not presently
elucidated.
They can be the results of changes in activity of stomach,
pylorus, and duodenum, or combinations
of the three.
Some receptor function presumably
in small intestine is
likely. Hunt and others (1, 7, 8) have proposed that
duodenal receptors monitor the osmolarity of gastric
efflux and by a feedback-loop influence the rate of gastric
emptying. Identification of either the receptors or the
pathways, neural or humoral, by which they might exert
their control is lacking. The data presented here for
glucose might depend on osmoreception, as the relationship between osmolarity and energy density is constant.
However, such a mechanism can not be easily called
upon to explain the differences in gastric emptying between saline and a glucose solution of comparable osmolarity. Also the emptying of fat cannot depend on
osmolarity.
Whatever the mechanisms, this phenomenon has several critical implications. As far as we know this is the
first demonstration of precise functional regulation to
calories found in the activity of a physiological system
tied directly to feeding behavior-the
stomach and small
bowel. This fact in itself suggeststhat some aspect of the
controlled emptying of the stomach may play a role in
feeding and particularly in the precision of satiety. Other
possibilities exist however.
This regulatory function may not be an element in the
links between food consumption and satiety but may be
either an independent or a parallel regulatory event.
Thus the controlled slowing of gastric emptying by food
might be an independent gastrointestinal function with
the effect of avoiding either osmotic overloading of the
intestine or the wastage of nutrients, as might occur if
renal thresholds were exceeded by an excessively rapid
intestinal absorption of nutrients such as glucose. It is
also possible that satiety for food and the caloric regulation in gastric emptying are parallel functions provoked
by similar signals but in no direct fashion depending on
one another. The present data cannot refute these possibilities and only a complete comprehension of the
mechanisms, receptors, transmitters, and sites of action
that produce satiety and influence gastric emptying will
resolve them.
However, there are some aspects of our observations
to suggest that this regulation of caloric delivery by the
stomach could have a direct role in the control of food
intake. Thus although this mechanism does avoid osmotic overloading and renal wastage of glucose, it also
regulates the emptying of lipid calories exactly as glucose
even though this nutrient is without osmotic effects and
lacks a renal threshold. Also it seems unlikely that the
phenomena demonstrated here, i.e., the rapid elimination
of nonnutrient saline but retention and gradual regulated
release of nutrients from the stomach, would have no
satiety influence. Distension of the stomach has long
been demonstrated to interrupt feeding (2, 1I, 21). The
precise control of gastric emptying may in fact provide a
quantitative basis for relating Cannon’s observations on
the effects of gastric distension to a dynamic physiology
with behavior.
Thus that the stomach empties at a rate determined,
within limits, by the caloric concentration and not by
weight, bulk, volume, or character of its nutrient contents
makes its emptying a potential visceral sensory event
that could lead to accuracy in estimating the calories
that have been ingested. Such a sensory event may
function in conditional or unconditional reflexes. Its effects may be modified by other influences such as the
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.6 on June 16, 2017
TIME
(min)
R260
presence of solids in the stomach, the state of circulating
or stored nutrients
(blood sugar, fat, glycogen) or by
activity in the ventromedial
or lateral hypothalamus.
But
with the demonstrated
precision it is exactly the kind of
phenomenon needed for preabsorptive
satiety, a crucial
feature in the behavior of feeding. For feeding is an
activity that occurs intermittently,
ceases before ingested
nutrients
are metabolized, but maintains a remarkable
balance between intake and need. The stomach and small
P, R. MCHUGH
AND
T. H. MORAN
bowel, by showing similar regulation in the management
of nutrients within them, are sites capable of generating
from their responses to these contents a quantitative
influence on the behavior.
We thank
Professor
J. N. Hunt for his gracious
generous
advice in the development
of this work.
This work was supported
by National
Institutes
suggestions
of Health
and
Grant
ROf-AM-19302.
Received
29 June
1978; accepted
in fmaI form
31 October
1978.
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