THE INCREASE OF BLOOD SUGAR IN PAIN AND GREAT EMOTION
Sugar is the form in which carbohydrate material is transported in
organisms; starch is the storage form. In the bodies of animals
that have been well fed the liver contains an abundance of glycogen
or “animal starch,” which may be called upon in times of need.
At such times the glycogen is changed, and set free in the blood
as sugar. Ordinarily there is a small percentage of sugar in the
blood--from 0.06 to 0.1 per cent. When only this small amount is
present the kidneys are capable of preventing its escape in any
noteworthy amount. If the percentage rises to the neighborhood of
0.2-0.3 per cent, however, the sugar passes the obstacle set up by
the kidneys, and is readily demonstrable in the urine by ordinary
tests. The condition of “glycosuria,” therefore, may properly be
considered, in certain circumstances, as evidence of increased sugar
in the blood. The injection of adrenin can liberate sugar from the
liver to such an extent that glycosuria results. Does the adrenal
secretion discharged in pain and strong emotional excitement play
a rôle in producing glycosuria under such conditions?
In clinical literature scattered suggestions are to be found that
conditions giving rise to emotional states may be the occasion also
of more or less permanent glycosuria. Great grief and prolonged
anxiety during a momentous crisis have been regarded as causes of
individual instances of diabetes, and anger or fright has been
followed by an increase in the sugar excreted by persons who already
have the disease. Kleen[47] cites the instance of a German officer
whose diabetes and whose Iron Cross for valor both came from a
stressful experience in the Franco-Prussian War. The onset of the
disease in a man directly after his wife was discovered in adultery
is described by Naunyn;[48] and this author also mentions two cases
in his own practice--one started during the bombardment of Strassburg
(1870), the other started a few days after a companion had shot
himself. In cases of mental disease, also, states of depression have
been described accompanied by sugar in the urine. Schultze[49] has
reported that in these cases the amount of glycosuria is dependent
on the degree of depression, and that the greatest excretion of
sugar occurs in the fear-psychoses. Raimann[50] has reported that in
both melancholia and mania the assimilation limit of sugar may be
lowered. Similar results in the insane have recently been presented
by Mita,[51] and by Folin and Denis.[52] The latter investigators
found glycosuria in 12 per cent of 192 insane patients, most of
whom suffered from depression, apprehension, or excitement. And
Arndt[53] has observed glycosuria appearing and disappearing as
alcoholic delirium appeared and disappeared in his patients.
Although clinical evidence thus indicates an emotional origin of
some cases of diabetes and glycosuria, the intricacies of existence
and the complications of disease in human beings throw some doubt
on the value of that evidence. Both Naunyn[54] and Hirschfeld,
although mentioning instances of diabetes apparently due to an
emotional experience, urge a skeptical attitude toward such
statements. It is desirable, therefore, that the question of an
emotional glycosuria be tested under simpler and more controllable
conditions. “Emotional glycosuria” in experimental animals has
indeed been referred to by Waterman and Smit[55] and more recently
by Henderson and Underhill.[56] Both these references, however, are
based on the work of Böhm and Hoffmann,[57] reported in 1878.
Glycosuria From Pain
Böhm and Hoffmann found that cats, when bound to an operating
board, a tube inserted into the trachea (without anesthesia), and
in some instances a catheter inserted into the urethra through an
opening above the pubis, had in about half an hour an abundance
of sugar in the urine. In three determinations sugar in the blood
proved slightly above “normal” so long as sugar was appearing in
the urine, but returned to “normal” as the glycosuria disappeared.
Since they were able to produce the phenomenon by simply binding
animals to the holder, they called it “Fesselungsdiabetes.”
As possible causes of this glycosuria in bound animals, they
considered opening the trachea, cooling, and pain. The first two
they readily eliminated, and still they found sugar excreted. Pain
they could not obviate, and since, without binding the animals,
they caused glycosuria by merely stimulating the sciatic nerves,
they concluded that painful confinement was itself a sufficient
cause. Other factors, however, such as cooling and circulatory
disturbances, probably coöperated with pain, they believed, to
produce the result. Their observations on cats have been proved
true also of rabbits;[58] and recently it has been shown that an
operation involving some pain increases blood sugar in dogs.[59]
Temporary glycosuria has likewise been noted in association with
intense pain in human beings.
Inasmuch as Böhm and Hoffmann did not mention the emotional element
in discussing their results, and inasmuch as they admitted that
they could not obviate from their experimental procedure pain,
which they themselves proved was effective in causing glycosuria,
designating what they called “Fesselungsdiabetes” as “emotional
glycosuria” is not justified.
Emotional Glycosuria
The discovery that during strong emotion adrenal secretion is
increased, and the fact that injection of adrenin gives rise to
glycosuria, suggested that glycosuria might be called forth by
emotional excitement, and then that even without the painful element
of Böhm and Hoffmann’s experiments, sugar might be found in the
urine. The testing of this possibility was undertaken by A. T.
Shohl, W. S. Wright and myself in 1911.
Our first procedure was a repetition of Böhm and Hoffmann’s
experiments, freed from the factor of pain. The animals (cats) were
bound to a comfortable holder, which left the head unfastened. This
holder I had used hundreds of times in X-ray studies of digestion,
with many different animals, without causing any signs of even so
much as uneasiness. Just as in observations on the movements of the
alimentary canal, however, so here, the animals reacted differently
to the experience of being confined. Young males usually became quite
frantic, and with eyes wide, pupils dilated, pulse accelerated,
hairs of the tail more or less erect, they struggled, snarling and
growling, to free themselves. Females, on the contrary, especially
if elderly, were as a rule much more calm, and resignedly accepted
the novel situation.
According to differences in reaction the animals were left in the
holder for periods varying in length from thirty minutes to five
hours. In order to insure prompt urination, considerable quantities
of water were given by stomach tube at the beginning of the
experiment and in some cases again later. Arrangements were made for
draining the urine promptly, when the animal was on the holder or
when afterwards in a metal metabolism cage, into a glass receiver
containing a few drops of chloroform to prevent fermentation. The
diet in all cases consisted of customary raw meat and milk. In every
instance the urine was proved free from sugar before the animal
was excited.
In our series of observations twelve cats were used, and in every
one a well-marked glycosuria was developed. The shortest periods
of confinement to the holder which were effective were thirty and
forty minutes; the longest we employed, five hours. The average
time required to bring about a glycosuria was less than an hour
and a half; the average in seven of the twelve cases was less than
forty minutes. In all cases no sugar was found in the urine passed
on the day after the excitement.
The promptness with which the glycosuria developed was directly
related to the emotional state of the animal. Sugar was found early
in animals which early showed signs of being frightened or in a
rage, and much later in animals which took the experience more
calmly.
As cooling may result in increased sugar in the blood, and consequent
glycosuria, the rectal temperature was observed from time to time,
and it was found to vary so slightly that in these experiments it
was a wholly negligible factor. In one cat the rectal temperature
fell to 36° C. while the animal was bound and placed in a cold
room (about 2° C.) for fifty minutes, but no sugar appeared in the
urine.
Further evidence that the appearance of sugar in the urine may arise
purely from emotional excitement was obtained from three cats which
gave negative results when bound in the holder for varying periods
up to four hours. It was noteworthy that these animals remained calm
and passive in their confinement. When, however, they were placed,
separately, in a small wire cage, and were barked at by an energetic
little dog, that jumped at them and made signs of attack, the cats
became much excited, they showed their teeth, humped their backs,
and growled defiance. This sham fight was permitted to continue for
a half hour in each of the three cases. In each case the animal,
which after four hours of bondage had exhibited no glycosuria, now
had sugar in the urine. Pain, cooling, and bondage were not factors
in these experiments. The animal was either frightened or enraged
by the barking dog, and that excitement was attended by glycosuria.
The sugar excreted in the twenty-four hours which included the
period of excitement was determined by the Bertrand method.[60] It
ranged from 0.024 gram to 1.93 grams, or from 0.008 gram to 0.62
gram per kilo body weight, for the twenty-four hours’ quantity.
The presence of sugar in the urine may be used as an indication of
increased sugar in the blood, for unless injury has been done to
the cells of the kidneys, they do not permit sugar to escape until
the percentage in the blood has risen to a considerable degree.
Thus, though testing the urine reveals the instances of a high
content of blood sugar, it does not show the fine variations that
appear when the blood itself is examined. Recently Scott[61] has
concluded a thorough investigation of the variations of blood sugar
in cats, and has found that merely incidental conditions, producing
even mild excitement, as indicated by crying or otherwise, result
in a noticeable rise in the amount. Indeed, so sensitive is the
sugar-liberating mechanism that all the early determinations of the
“normal” content of sugar in blood which has been drawn from an
artery or vein in the absence of anesthesia, are of very doubtful
value. Certainly when care is taken to obtain blood suddenly from a
tranquil animal, the percentage (0.069, Scott; 0.088, Pavy) is much
less than when the blood is drawn without anesthesia (0.15, Böhm and
Hoffmann), or after light narcosis (0.282, Rona and Takahashi[62]).
Our observations on cats have since been found valid for rabbits.
Rolly and Oppermann, Jacobsen, and Hirsch and Reinbach[63] have
recently recorded that the mere handling of a rabbit preparatory
to operating on it will increase the percentage of blood sugar (in
some cases from 0.10 to 0.23 and 0.27 per cent). Dogs are said to be
much less likely to be disturbed by the nature of their surroundings
than are rabbits and cats. Nevertheless, pain and excitement are
such fundamental experiences in animals that without much doubt the
same mechanism is operative in all when these experiences occur.
Probably, just as the digestion of dogs is disturbed by strong
emotion, the blood sugar likewise is increased, for sympathetic
impulses occasion both changes.[*] Gib has given an account of a
bitch that became much agitated when shut up, and after such enforced
seclusion, but never otherwise, she excreted small quantities of
sugar in the urine.[64]
*[Footnote: Since the foregoing sentences were written Hirsch and
Reinbach have reported (Zeitschrift für physiologische Chemie,
1914, xci, p. 292) a “psychic hyperglycemia” in dogs, that resulted
from fastening the animals to a table. The blood sugar rose in
one instance from 0.11 to 0.14 per cent, and in another from 0.09
to 0.16 per cent.]
The results noted in these lower animals have been confirmed in
human beings. One of my former students, W. G. Smillie, found that
four of nine medical students, all normally without sugar in their
urine, had glycosuria after a hard examination, and only one of the
nine had glycosuria after an easier examination. The tests, which
were positive with Fehling’s solution, Nylander’s reagent, and also
with phenyl-hydrazine, were made on the first urine passed after
the examination. Furthermore, C. H. Fiske and I examined the urine
of twenty-five members of the Harvard University football squad
immediately after the final and most exciting contest of the season
of 1913, and found sugar in twelve cases. Five of these positive
cases were among substitutes not called upon to enter the game.
The only excited spectator of the Harvard victory whose urine was
examined also had a marked glycosuria, which on the following day
had disappeared.
Other tests made on students before and after important scholastic
examinations have been published by Folin, Denis and Smillie.[65]
Of thirty-four second-year medical students tested, one had sugar
before the examination as well as afterwards. Of the remaining
thirty-three, six, or 18 per cent, had small but unmistakable traces
of sugar in the urine passed directly following the ordeal. A
similar study was made on second-year students at a women’s college.
Of thirty-six students who had no sugar in the urine on the day
before, six, or 17 per cent, eliminated sugar with the urine passed
immediately after the examination.
From the foregoing results it is reasonable to conclude that just as
in the cat, dog, and rabbit, so also in man, emotional excitement
produces temporary increase of blood sugar.
The Rôle of the Adrenal Glands in Emotional Glycosuria
Since artificial stimulation of the splanchnic nerves produces
glycosuria,[66] and since major emotions, such as rage and fright,
are attended by nervous discharges along splanchnic pathways,
glycosuria as an accompaniment of emotional excitement would
naturally be expected to occur. To what extent the adrenal glands
which, as already mentioned, are stimulated to increased secretion by
excitement, might play a part in this process, has been in dispute.
Removal of these glands or cutting of the nerve fibres supplying
them, according to some observers,[67] prevents glycosuria after
puncture of the fourth ventricle of the brain (the “sugar puncture,”
which typically induces glycosuria) and also after stimulation of the
splanchnics.[68] On the other hand, Wertheimer and Battez[69] have
stated that removal of the glands does not abolish the effects of
sugar puncture in the cat. It was questionable, therefore, whether
removal of the adrenal glands would affect emotional glycosuria.
Evidence on this point I secured with Shohl and Wright in
observations on three animals in which the adrenals were removed
aseptically under ether. The animals selected had all become quickly
excited on being bound to the holder, and had manifested glycosuria
after about an hour of confinement. In the operation, to avoid
discharge of adrenin by handling, the adrenal veins were first
tied, and then the glands freed from their attachments and removed
as quickly and with as little manipulation as possible. In one cat
the entire operation was finished in twenty minutes. In two of the
cats a small catheter was introduced into the urethra through an
incision, so that the bladder could be emptied at any time.
In all three cases urine that was free from sugar was obtained
soon after the operation. Although the animals deprived of their
adrenals manifested a general lessening of muscular tone, they
still displayed much of their former rage or excitement when bound.
Indeed, one was more excited after removal of the adrenals than
before. That the animals might not be excessively cooled they were
kept warm with coverings or an electric heating pad. Although they
were now bound for periods from two to three times as long as the
periods required formerly to cause glycosuria, no trace of sugar
was found in the urine in any instance. The evidence thus secured
tends, therefore, to support the view that the adrenal glands
perform an important contributory rôle in the glycosuria resulting
from splanchnic stimulation.
Possibly the emotional element is in part accountable for the
glycosuria observed after painful stimulation, but conditions
causing pain alone will reasonably explain it. As we have already
seen, strong stimulation of sensory fibres causes the discharge of
impulses along the splanchnic nerves, and incidentally calls forth an
increased secretion of the adrenal glands. In glycosuria resulting
from painful stimulation, as well as in emotional glycosuria, the
adrenal glands may be essential factors.
Later the evidence will be given that sugar is the optimum source
of muscular energy. In passing, we may note that the liberation
of sugar at a time when great muscular exertion is likely to be
demanded of the organism may be interpreted as a highly interesting
instance of biological adaptation.
REFERENCES
[Footnote 47: Kleen: On Diabetes Mellitus and Glycosuria,
Philadelphia, 1900, pp. 22, 37-39.]
[Footnote 48: Naunyn: Der Diabetes Mellitus, Vienna, 1898, p. 72.]
[Footnote 49: Schultze: Verhandlungen der Gesellschaft deutscher
Naturforscher und Aerzte, Cologne, 1908, ii, p. 358.]
[Footnote 50: Zeitschrift für Heilkunde, 1902, xxiii, Abtheilung
iii, pp. 14, 19.]
[Footnote 51: Mita: Monatshefte für Psychiatrie und Neurologie,
1912, xxxii, p. 159.]
[Footnote 52: Folin, Denis and Smillie: Journal of Biological
Chemistry, 1914, xvii, p. 519.]
[Footnote 53: Arndt: Zeitschrift für Nervenheilkunde, 1897, x, p.
436.]
[Footnote 54: Naunyn: _Loc. cit._, p. 73; Hirschfeld: Die
Zuckerkrankheit, Leipzig, 1902, p. 45.]
[Footnote 55: Waterman and Smit: Archiv für die gesammte Physiologie,
1908, cxxiv, p. 205.]
[Footnote 56: Henderson and Underhill: American Journal of
Physiology, 1911, xxviii, p. 276.]
[Footnote 57: Böhm and Hoffmann: Archiv für experimentelle Pathologie
und Pharmakologie, 1878, viii, p. 295.]
[Footnote 58: Eckhard: Zeitschrift für Biologie, 1903, xliv, p.
408.]
[Footnote 59: Loewy and Rosenberg: Biochemische Zeitschrift, 1913,
lvi, p. 114.]
[Footnote 60: See Abderhalden: Handbuch der biochemischen
Arbeitsmethoden, Berlin, 1910, ii, p. 181.]
[Footnote 61: Scott: American Journal of Physiology, 1914, xxxiv,
p. 283.]
[Footnote 62: Cited by Scott: _Loc. cit._, p. 296.]
[Footnote 63: Rolly and Oppermann: Biochemische Zeitschrift, 1913,
xlix, p. 201. Jacobsen: _Ibid._, 1913, li, p. 449. Hirsch and
Reinbach: Zeitschrift für physiologische Chemie, 1913, lxxxvii, p.
122.]
[Footnote 64: Cited by Kleen: _Loc. cit._, p. 37.]
[Footnote 65: Folin, Denis and Smillie: _Loc. cit._, p. 520.]
[Footnote 66: See Macleod: American Journal of Physiology, 1907,
xix, p. 405, also for other references to literature.]
[Footnote 67: See Meyer: Comptes rendus de la Société de Biologie,
1906, lviii, p. 1123; Nishi: Archiv für experimentelle Pathologie
und Pharmakologie, 1909, lxi, p. 416.]
[Footnote 68: Gautrelet and Thomas: Comptes rendus de la Société
de Biologie, 1909, lxvii, p. 233; and Macleod: Proceedings of the
Society for Experimental Biology and Medicine, 1911, viii, p. 110
(true for left adrenal and left splanchnic).]
[Footnote 69: Wertheimer and Battez: Archives Internationales de
Physiologie, 1910, ix, p. 392.]