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series, but not until the fifth day in the first series, in which the animal
received most proteid during the previous period. The actual amount of
proteid excreted per diem and per kilo, bodyweight was found by Voit

^ The amount of fat metabolised in the dog was found by Pettenkofer and Voit to be
le,ss during the first days than dm'ing the subsequent period.
-Hermann's "Handbuch," Bd. vi.



METABOLISM.

Urea Excretion in Grammes per Diem.



Day of
Inanition.


Series I.


Series II.


Series III.


1


60-1


26-5


13-8


2


24-9


18-6


11-5


3


19-1


15-7


10-2


4


17-3


14-9


12-2


5


12-3


14-8


12-1


6


13-3


12-8


12-6


7


12-5


12-9


11-3


8


10-1


12-1


10-7



to vary greatly with different dogs ; small animals metabolise more
proteid per kilo, than large : lean animals more than fat. Small dogs
have a larger proportionate sm'face, and relatively a smaller amount of
body-fat.^

Many similar observations have been made on fasting men. One
of these (Cetti) was under observation at different times and by
different observers. His weight was about 57 kilos. The amount of
urea excreted per diem, during the first ten days of fasting, was a Httle
over 20 grms., equivalent to from 10 to llgrms. N. Another (younger)
man, weighing about 60 kilos., was also found by I. Munk to excrete per
diem, during the first ten days of fasting, about 11 grms. N, representing
an average loss per diem of about 70 grms. proteid. In these cases there
was but little body-fat. In other individuals, in which there was abund-
ance of body-fat, the N excreted has been found to be much less. Thus
Succi (weight 63 kilos, at beginning, 52 kilos, at end of period) was found
by Luciani, during a thirty days' fast, to excrete on the tenth day
67 grms. ; on the twentieth, 4"3 grms. ; and on the last day 3 '2 grms. N ;
and Jacques (62 kilos.), observed by Noel Paton and Stockman, gave an
average daily loss of 5"29 N. Praussnitz determined the amount of N
excreted by ten persons during the second day of fasting, and found the
average, for a man weighing about 70 kilos., to be 13*7 grms., equivalent
to a loss of 90 grms. proteid per diem, or about 1"2 grms. per kilo,
body weight. This may therefore be regarded as representing the
amount which it is absolutely necessary to supply in the food, for the
maintenance of nitrogenous equilibrium.

In herbivora there may be an actual increase in the nitrogenous excreta
at the beginning of a starvation period, instead of a diminution ; due to
the fact that, under these circumstances, such animals, being reduced to living
upon their tissues, become practically carnivorous. As in carnivora, such
increase may become greater towards the end of inanition, in consequence of
the exhaustion of the fat of the body, and an increased destruction of the tissue
proteids.-

Now, the amount of urea in the urine during a fasting period of not
too long duration is probably a definite measure of the necessary de-
struction of tissue proteid which goes on within the body, and it may
therefore be taken as a result of such experiments, that the amount of
this metabolism is fairly constant. Such destruction occurs in spite of

1 Rubner, Ztsclir. f. Biol., Muuchen, 1883, Bd. xix. S. 535.

- Paibner, ihid., 1881, Bd. xvii. S. 214; Heymans, Bull. Acad. roy. d. sc. dc Belij.,
Bruxelles, 1896, p. 38.



ME TA B OLISM D URING INANITION. 889

the fact that there is still plenty of non-nitrogenous material (fat) able
to be drawn upon. The sudden increase which is sometimes met with
after a prolonged period of starvation is due no doubt to the fact that
by this time the noii-proteid materials of the body, which have been
up to that time used for the production of energy by their oxidation,
are now practically exhausted, and the whole energy and heat of the
body must necessarily be derived from the tissues themselves ; since
these are composed essentially of proteid, there is a considerable rise
of proteid metabolism.

The carbon dioxide exhaled from the lungs during starvation con-
tinues to be given off in proportion to the weight of the body, to the
work done, and in inverse proportion to the temperature of the environ-
ment. In a man weighing 71 kilos., Pettenkofer and Voit found that
during the first day of fasting 201'3 grms. C were given off by the respir-
ation, and 5"8 grms. by the urine, in which also 12'5 grms. N was elimin-
ated. This corresponded to a loss of 78 grms. proteid (370 grms. flesh)
and 215 grms. fat. The same man was found by Pettenkofer and Voit
to lose, when working on the first day of fasting, 75 grms. proteid (478
grms. flesh) and 380 grms. fat. The amount of oxygen taken in in the
two cases was 760 and 1072 grms. respectively, and the amount of water
exhaled 889 and 1777 grms. Pianke found on the second day of fasting,
in a fat subject weighing about 70 kilos., 8 grms. N and 3-7 grms. C in
the urine, and 180-9 grms. C given off' by the lungs ; corresponding to
50 grms. proteid (235 grms. flesh) and 204 grms. fat.

For a considerable time, as a result of the oxidation of fat and body
proteid, the temperature of a fasting animal is maintained to about its
normal amount. Towards the end, however, of starvation, the temperature
begins to sink, and finally rapidly falls, the meaning of this being that
the animal has now practically exhausted all the nutriment which it
can take from the tissues, and that the amount of oxidation has become
reduced, so that the temperature is no longer capable of being main-
tained at normal. The change is also, in part, doubtless due to the
fact that the heat regulating functions of the nervous system are
beginning to break down in consequence of the deficiency of nutriment.
It has been suggested that an animal dying of starvation practically
dies of cold ; and it is undoubtedly true that the life of a starved animal
can be prolonged considerably by the employment of artificial warmth,
since this diminishes the amount of oxidation necessary for maintaining
the animal heat, and thus economises the energy-producing substances
within the body; but it is, of course, not possible for the artificial
warming of an animal to prolong life to any great extent under
circumstances of complete deprivation of food.

Numerous experiments have been made to determine the amount of
loss of the several organs and tissues of the body which have occurred
during starvation, and also the relative composition of such tissues and
organs as compared with those of a well-nourished animal. All such
experiments tend to show that the most essential organs of the body,
such as the heart and nervous system, live during a period of starvation
at the expense of the other tissues.^

1 Bidder and Schmidt, " Verdauungssafte u. Stoffwechsel," 1852; Bischoff' and Voit,
"Die Gesetze der Ernahi-ung des Fleischfressers," 1860; Pettenkofer and Voit, Ztsclir.
f. Biol., Miinchen, Bde. ii. and v. ; J. Ranke, " Die Ernalirung des Menschen," 1876 ; Voit,
" Ernahrung," Hermann's "Handbucli," 1881, Bd. vi.



Sgo



METABOLISM.



The first substances to disappear, as may well be supposed, are those which
are least essential to the maintenance of life, and we find accordingly that the
adipose tissue first begins to lose weight. Finally, at the end of starvation,
90 per cent., or more, of the fats of the body (except the fatty substances
which are found in the nervous system) have disappeared. At the same time
the glycogen which may have been stored in the liver and muscles also
begins to disappear ; but it is a long while, in some animals, before the last
traces of it are used up, especially the glycogen of muscle. Certain of the
organs especially become diminished in weight. Among these the first to
show a falling off" are the spleen and the glandular organs, especially those
concerned in digestion. Since there is very little secretion going on, these are
not called upon to exercise their normal functions. I^ext follows marked
diminution in the amount of the muscular substance, and this it is, no doubt,
which accounts for the muscular weakness which manifests itself. When all
the less essential organs have contributed as much as appears possible to the
maintenance of the normal condition of the blood, in order that it may suffi-
ciently nourish the most essential tissues, the latter, namely, the heart and
those of the nervous system, might next be expected to contribute their
quota. Apparently, as soon as this call is made, they fail to respond to it,
and the result is that death speedily supervenes.

Voit gives the following percentage loss for the several tissues and organs
in a cat killed after thirteen days' deprivation of food : —



Adipose tissue

Spleen

Liver

Testes

Muscles

Blood

Kidneys

Integument

Lungs

Litestines

Pancreas

Bones

Heart

Central nervous system

Tominaga^ has determined (by Kjehldal's method) the amount of N lost
from the several organs during a prolonged starvation period in rats and
rabbits, as follows : —



In 100 Parts of


In 100 Parts of


Fresh Organs.


Dry Organs.


. 97




. 67


63


. 54


57


. 40




. 31


30


. 27


18


. 26


21


. 21




. 18


19


. 18




. 17




. 14




. 3




. 3






Organ.


Bat.


Rabbit.


Spleen


98-48


67-06


Stomach and intestines








59-47


26-80


Muscles .








35-98


18-59


Heart








18-01


22-74


Brain








11-79


29-13


Liver








9-69


57-60


Kidneys . . .








3-48


24-80



The discrepancies in these results, both as compared with one another and
as compared Avith the loss in the dry organs as determined by Yoit, are so con-
siderable, that they cannot be accepted without confirmation.

1 Centrum, f. Physiol., Leipzig u. Wien, 1893, Bd. vii. S. 381.



NUTRITION WITH A PURELY PROTEID DIET. 891

The literature of the subject, since the article by Voit in Hermann's
"Handbuch" (1881), will be found mainly in the memoirs noted below.^

Nutrition with a purely Proteid Diet.

Under the circumstances we have been considering, namely, complete
deprivation of food, the nitrogen excreted must come from the nitrogen
of the tissues, and it might be supposed that if we supply a starving
animal with food containing the exact amount of nitrogen (in the form
of proteid) which it is losing, we should be able to entirely prevent such
waste of the tissues, and that any loss then occurring would arise solely
from non-proteid substances. This, however, is not the case. For if
this experiment is performed, it is found that the animal loses more
nitrogen than we give it. The whole of the nitrogen of the added
proteid appears in the urine as urea, and in addition there is a certain
amount, although not as much as during complete starvation, of tissue
nitrogen still present in the urine. In order to keep up nitrogenous
equilibrium, Voit found that it was necessary to give two and a half
times as much proteid as the animal had metabolised during fasting.
This result, which is at first sight somewhat unexpected, is due to the
fact that the ingestion of proteid food directly excites the tissues to
increased metabolic activity, so that tissue proteid itself still becomes
split up and oxidised.

How and why the activity of the living tissues is thus stimulated
by increased proteid pabulum is a problem as to which we are entirely
in the dark. Non-proteid substances do not produce this effect. On the
contrary, the giving of gelatin, carbohydrates, and fat has, as we have
seen, a sparing effect upon proteid metabolism, and tends to diminish
the amount of tissue proteid which is becoming broken down. This is
also shown very conclusively in Voit's experiments on dogs which had
been kept in a condition of N-equilibrium with proteid food. The con-
dition of N-equilibrium could be produced with a far smaller amount
of proteid, provided that for the amount removed an adequate quantity
of fat or carbohydrate was added to the diet.^

If to a starving animal, instead of what would appear to be just a
sufficient amount of proteid, an excess be given, a point is at length
reached at which the building-up process exceeds the breaking-down,
and the tissues, and therefore the body generally, gain in weight.
This increase in body weight, due to the laying on of tissue, proceeds
to a certain point with any constant amount of added proteid, until
a balance between the N laid on and the N lost is struck, when a
condition of N-equilibrium is again obtained. A further increase of

^Lnciani, "Fisiol. d. digiuno," German translation, "Das Hunger," 1889; Richet,
"L'inanition,"Travaux, 1893, tome ii.; Tucsek, Centralhl.f. d.mcd. fFissewscZi., Berlin, 1885,
S. 69 ; Lehmann, Muller, Senator, Zuntz, I. Munk, and others, Berl. Min. JVchnschr., 1887,
S. 425 ; and Virdioiifs Archiv, 1893, Bd. cxxxi., Suppl.-Heft ; I. Munk, Centralhl. f. d.
med. TVissensch., Berlin, 1889, S. 833; Noel Paton and Stockman, Proc. Boy. Soc. Min.,
1889, p. 121 ; Praussnitz, Milnchen. med. JFchnschr., 1891, No. 18; a,iid Ztschr. f. Biol.,
Miinchen, 1893, Bd. xi. S. 151 ; R. May, ibid., 1893, Bd. xii. S. 29 ; I. Munk, Arch. f.
d. ges. Physiol., Bonn, 1894, Bd. Iviii. S. 309 ; Johansson, Landgren, Sonden and
Tigerstedt, SJcandin. Arch. f. Physiol., Leipzig, 1896, Bd. vii. S. 29; C. Voit, Ztschr.
f. Biol., Miinchen, 1894, Bd. xxx. S. 510 (comparison of weight of organs in well-nourished
and starved dogs). See also on this subject, Lukjanow, ZtscJir. f. physiol. Chem.,
Strassburg, 1889, Bd. xiii. S. 339.

^ Voit, op. cit.



892 METABOLISM.

proteid food will now again produce an increase of tissue and of body
weight, until again a condition of N-equilibrium is established. And
this may apparently be carried up to the limit of the power of digestion
of the animal for proteid food, so that ultimately fifteen times as much
proteid may be metabohsed as in the condition of inanition.^ On the
other hand, diminution of the amount of proteid food tends in the same
way to gradually establish N-equihbrium on a lower level, and with a
diminished body weight ; the animal losing flesh until such equilibrium
becomes established, and then maintaining itself, provided the IST ingested
be constant, at a constant but lower level of N-equilibrium. In short,
" N- equilibrium is possible with the most different amounts of proteid
in the food." ^

The fact that the amount of urea excreted is directly dependent
upon the amount of proteid ingested, is well illustrated by the
following observations of Voit upon a dog fed on lean meat ; the
numbers are grms. : —

Meat per diem . 300 600 900 1200 1500 1800 2000 2500
Urea per diem . 32 49 68 88 106 128 144 173

About 80-85 per cent, of the ingested proteid is usually oxidated
and eliminated, and only about 15-20 per cent, is laid on.

On the Building-up and Breaking-down of the Bodystuffs.

The food of animals consists, besides water and a certain amount of
inorganic salts, of organic constituents, nitrogenous (some of which must
be proteid) and non-nitrogenous. The food of the higher plants, on
the other hand, consists normally of inorganic materials, some of which
must be nitrogenous ; and, as has been long recognised, plants have the
power of buildmg up from these materials complex organic substances,
such as proteids, carbohydrates, and fats, whereas animals have not this
power ; the materials biult up by plants serving as the food of animals.
Hence arose the belief that it was an essential difference , between the
plant and animal organisation, that the one possessed extensive
powers of effecting syntheses, whereas the other had practically no
powers of synthesis, but must receive its materials already synthetised,
either directly from plants or indirectly from plants through the bodies
of other animals, such materials being subsequently broken down into
simpler materials, which, after being oxidised within the tissues, are got
rid of in such simple forms as lu'ea, water, carbon dioxide, and salts.

These views have undergone considerable modification of late years,
since we are now familiar with numerous instances of syntheses occur-
ring in animals. The first well-established case of the kind was
determined by Wohler in 1824. Wohler found that when benzoic acid
is taken with the food, it appears as hippuric acid in the urine. Now,
hippuric acid is formed synthetically from benzoic acid and glycine.

^ C. Voit, Hermann's " Haudbuch,'' Bd. vi. S. 105. Voit's dog, weighing 35 kilos.,
was able to maintain N-equilibrium with as little as 500 and as mnch as 2500 grms.
flesh, containing 548 grms. dry proteid. With larger amounts than this, digestion was
interfered with. The same fact is still more strikingly shown by the experiments of
Pfiiiger, who kept a large dog in a condition of nitrogenous equiliV)rium on an almost
exclusively proteid diet. A man weighing 70 kilos, is, as a rule, unable to digest more
than 1500 grms. of lean meat per diem.

^ C. A^oit, loc. cit., S. 111.



BUILDING- UP AND BREAKING-DO WN BODYSTUFFS. 893

It is produced when these two substances are allowed to act upon one
another at a high temperature, and under pressure, as when they are
heated together for some hours in a glass tube to a temperature of 160°
C, or more simply by heating monochloracetic acid with benzamide : —

CACO.NH2+CH2Cl.COOH=(CcH5CO)NH.CH2.COOH+HCl

(benzamide) (monochloracetic acid) (liippnric acid)

This synthesis of hippuric acid in vitro was speedily followed by that of
urea (Wohler, 1828).

The synthesis of hippuric acid was proved by Bunge and Schmiede-
berg to occur in dogs exclusively in the kidney, and may be produced
even at the temperature of the room, by passing oxygenated blood
containing benzoic acid, or a benzoate, and glycine through the blood
vessels of the organ, or even by allowing such blood to stand for a
while in contact with the minced kidney of a fresh-killed animal.
When, however, the kidney cells are destroyed, as by being pounded with
sand in a mortar, no hippuric acid is produced. If benzoic acid be
given by the mouth, hippuric acid appears in the urine ; the glycine for
the synthesis is furnished by the tissues. If the kidneys are previously
extirpated, no hippuric acid is found in any of the organs after the
exhibition of benzoic acid ; but if the ureters are merely hgatured,
hippuric acid is found in abundance.

In frogs and rabbits the synthesis of hippuric acid is not confined to the
kidneys, but is found to occur after the extirpation of these organs.^

Other syntheses besides that of hippuric acid, which are known to
occur in the anunal body, are that of urea in the liver, from ammonium
carbonate and ammonium carbamate ; that of uric acid in the bird's Kver,
also from ammonia compounds ; that of glycogen, from glucose in the
liver, and also in muscles and in many other tissues ; that of proteids,
from peptones in the mucous membrane of the alimentary canal ; that of
fats, from fatty acids and glycerin in the intestinal mucous membrane ;
that of fats from carbohydrates, or from the elements of the broken-down
carbohydrate molecule ; and also, in all probability, that of fats from the
non-nitrogenous moiety of the broken-down proteid molecule. It is clear
from these instances that the importance of syntheses in the animal
economy cannot be overrated, and although the most striking feature in
animal metabolism is the breaking down of complex substances into
others of more simple form, yet even in the case of these broken-down
products there is frequently a subsequent synthesis before they are got
rid of from the body. Instances of this occur in the case of several urinary
products, such as hippuric acid, urea, and uric acid.-

As Bunge ^ remarks : " There are two reasons why these synthetic
processes in the animal body have excited the interest of physio-
logists and chemists. In the first place, they were in contradiction
to the long dominant doctrine of Liebig, as to the contrast be-
tween the metabolic processes in plants and animals ; * and, in the

^ Bunge and Schmiedeberg, Arch. f. exjKr. Path. u. PJbccrmakol., Leipzig, 1876, Bd. vi.
S. 233 ; Hoffman, ibid., 1877, Bd. vii. S. 239 ; Kochs, Arch. f. d. ges. Physiol., Bonn, 1879,
Bd. XX. S. 64 ; Salomon., Ztschr. f. 2Jhysiol. Chem., Strassburg, Bd. iii. S. 365.

" On the importance of synthetic processes in animal metabolism, see Pfliiger, Arch.f. d.
ges. Physiol., Bonn, 1888, Bd. xlii. S. 144. ^ "Lelirbuch," 1894, S. 288.

* ISTevertheless, the main distinction propounded by Liebig, that most jalants are able
to obtain their nitrogen, and to build it up into proteid from inorganic materials, wbereas
animals do not possess this power, still holds good.



894 METABOLISM.

second place, the methods of synthesis in animal (and vegetable)
organisms are still an misolved problem, in spite of the fact that
it is the rapid progress in our knowledge of the syntheses of organic
combinations which constitutes the greatest triumph of modern
chemistry. Chemists are already able artificially to build up atom for
atom out of their elements a series of organic compounds, some of a very
complicated nature. We no longer doubt that all the rest, even the
most complex, will be thus produced. Nevertheless the processes
employed in no way represent the synthetic processes of the living cell,
for all artificial syntheses can only be achieved by the application of
forces and agents which can never play a part in vital processes, such as
extreme pressure, high temperature, concentrated mineral acids, and free
chlorine — agents which are immediately fatal to any living cell."

It must nevertheless be admitted, in spite of the numerous instances
of syntheses of organic compounds which have accumulated of late years,
that, so far as the formation of bioplasm is concerned, the only material
from which the animal organism is capable of forming it is proteid, and
this proteid must be present as such in the food. No doubt the ultimate
change of the circulatory or blood proteids to the proteid of bioplasm must
depend upon a special synthesis, but we are necessarily completely ignor-
ant as to the manner in which such synthesis occurs, since we are ignorant
of the actual chemical constitution of both living tissue and dead proteid.

With respect to the breaking-down of the bodystuffs in the process
of metabolism, there are reasons for believing that this consists of two
phases, namely, a splitting of the complex molecules into simpler mole-
cules, and an oxidation of some or all of the simpler substances thus
arising. It is probable that in the metabolism of proteid these two
phases usually, if not invariably, occur at different times, and even in
different places in the body ; for example, the materials derived from
the splitting up of the metabolised proteids of muscle do not all leave
the muscle in a fully oxidated condition, but are, in part at least, in
the form of oxidisable substances, such as lactic acid. Doubtless, in
the formation of the ultimate products, oxidation is the prominent
feature, for these products, in the form in which they leave the body, are,
as compared with the materials that enter the tissues, unquestionably
in a condition of oxidation, in some cases of complete oxidation. There
is, however, no distinct evidence that the process of splitting of the
complex molecules is necessarily immediately combined with that of
oxidation. On the other hand, there is reason to think that such
splitting may occur without immediate oxidation ; for example, the
splitting of proteids, which are taken in the food, into urea and non-
nitrogenous substances. For, in a dog fed with proteid, the urea was
found by Feder to make its appearance in the urine within fourteen
hours after feeding, whereas the removal of the remainder of the proteid
molecule in the form of carbon dioxide and water did not occur for
twenty-four hours after, so that the splitting of the proteid molecule
must have occurred at one time, and its complete oxidation at another.^

It is found that any conditions which tend to diminish the normal
oxidations of the body generally, or of the individual tissues (such as
the ingestion of prussic acid or the cutting off or diminution of the
arterial supply to an organ), cause such substances as lactic acid and
dextrose, which are probably products of proteid and carbohydrate
i C. Voit, Ztschr.f. Biol., Miinchen, 1891-2, Bd. xxviii. S. 292.



METABOLIC ACTIVITY OF TISSUES AND ORGANS. 895

metabolism respectively, to appear in larger amount than usual in the



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