E. A. (Edward Albert) Sharpey-Schäfer.

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Under certain circumstances it appears clear that the synthesis of
carbohydrate never passes beyond the stage of dextrose. Thus, in the
diabetes produced l^y successive doses of phloridzin there may be no
glycogen whatever in the liver and nmscles, and yet within the proteid-
fed and in the fasting animal large quantities of dextrose are formed
and eliminated with the m-ine.

Phloridzin is a glucoside obtained from the root-bark of certain
trees (ap]3le and cherry), but it does not act by virtue of its glucose
group, for the same action is got by the employment of the non-giucoside
phloretin which is obtained from phloridzin. If injected under the
skm, or taken into the ahmentary canal, either phloridzin or phloretin
produces within a very short time the appearance of sugar in the urine,
and this appearance of sugar in the urine is accompanied by a diminution
of the liver glycogen.^ The glycogen in the liver does not, however,
completely disappear as the result of a single dose of phloridzin ; both in
that organ and in the muscles a certain amount remains, but if a second

O ...

dose of phloridzin is given, glycosuria is again produced, and by repeating
the administration once or twice the glycogen can be completely removed
from the liver. Each successive dose of phloridzin will, however, cause
a fresh appearance of sugar in the urine even after complete removal of
glycogen from the hver, which shows that, although part of the sugar
which has appeared in consequence of the action of phloridzin may have
been produced from the glycogen in the hver, a part must be produced
in some other way. As by the employment of successive doses of this
drug all the appreciable glycogen in the body can be got rid of,* it is
almost certain that the sugar which then appears is derived from the
metabolism of proteid ; and this is rendered the more likely since it is

1 Arch, da med. expir. et dhmat. path., Paris, 1890, tome ii. p. 424.

2 Cf. PflUger, Arch./, d. rjes. Phydol., Bonn, 1888, Bd. xlii. S. 144.

^ V. Slering, Verhandl. d. Cong. f. w/icreJ/cfZ., Wiesbaden, 1887, S. 349 ; Ztschr.f. Jdin.
Med., Berlin, 1888, Bd. xiv. S. 405; 1889, Bd. xvi. S. 431. See also on phloridzin
diabetes, Cremer and Ritter, Ztsclir. f. Biol., Miinchen, 1892, Bd. xviii. S. 459, and Bd,
xix. S. 256 ; and Praussnitz, ibid. S. 168.

•* Klilz and Wright (Ztsclir. f. Biol., Miinchen, 1891, Bd. xxvii.) have shown that the
glycogen is not so readily got rid of as v. Mering supposed, and that as a matter of fact
there may still have been some glycogen left in the animals employed by v. Mering. These
authors state that phloridzin does not produce glycosuria in frogs. It did, however,
produce glycosuria in Inids (v. Mering, Verhandl. d. Cong. f. invereMecL, Wiesbaden, 1887),
in which pancreatic extirjiation failed to cause glj'cosuria ; it also increases tlie amount of
sugar in the urine of animals suffering from pancreatic diabetes (Minkowski, Arch. f. c:q}er.
Path. u. Pharmakol., Leipzig, 1893, Bd. xxxi. S. 148) ; and, further, Cremer has obtained
phloridzin diabetes in frogs by taking special measures to ensure the action of the drug
[Ztschr.f. Biol., Miinchen, 1892-3, Bd. xxix. S. 175).


noticed that the amount of nitrogen in the urine goes hand in hand with
the amount of sugar excreted.^ Further, it is found that if the glycogen
in the body be reduced as much as possible by a prolonged period of
starvation, followed by excessive muscular action, such as is caused by a
dose of strychnine, the administration of phloridzin will still cause
glycosuria ; much more sugar appearing under these circumstances in
the urine than can be accounted for by any glycogen which might remain
either in the liver or any other tissues of the body. It seems, therefore,
clear that the sugar must have been derived from proteid ; in this case
the proteids of the body itself. It may further be mentioned that Pick ^
has found that if the liver be rendered functionless by injecting dilute
sulphuric acid into the bile ducts, its glycogen disappears in twelve
hours, but phloridzin still produces glycosuria, although other agents
which usually cause glycosuria, such as carbon monoxide, fail to produce
this effect. As with the glycosuria produced by phloridzin, so also with
severe cases of natural diabetes in man, there appears to be no doubt
that a direct formation of sugar from proteid may occur without any
formation of glycogen. It may be supposed with some probability that
such a direct formation of sugar (mainly by the liver, for phloridzin
diabetes is produced in the absence of the liver),^ but also by other organs;*
and its passage into the blood may occur to some extent normally ; that
in fact a part of the carbohydrate produced from proteid may be at
once passed into the blood in the form of dextrose, and a part further
synthetised into glycogen and stored as such.^ We might then explain
phloridzin diabetes, and possibly certain severe cases of natural diabetes,
by supposing that the further synthesis into glycogen is in some way
interfered with, so that an excess of the carbohydrate formed is passed
into the blood in the form of sugar.

It must, however, be stated that the production of the severest forms
of diabetes above mentioned, and also that produced by removal of the
pancreas (see p. 927) and by the sugar-puncture (see p. 926), is still exceed-
ingly obscure. According to v. Mering and most other observers, there
is a fundamental difference between the diabetes caused by phloridzin
and that produced by pancreatic removal or sugar-puncture, in that in
the former there is no excess of sugar in the blood, — in fact the amount
may be less than normal/' — whereas in the two last-mentioned forms the

^ V. Mering, loc. cit., found the proportion of nrea to sugar in phloridzin diabetes = 1 : 2,
in cases of natural diabetes = 1 : 1. See also Moritz and Praussnitz, Ztsclir. f. Biol.,
Miinchen, 1891, Bd. xxvii. S. 81 ; Praussnitz, loc. cit.; Cremer and Ritter, Ztsclir. f. Biol.,
Mllnchen, 1893, Bd. xxix. S. 256. v. Mering and Minkowski {Arch. f. cxjoer. Path. u.
Pharmakol., Leipzig, 1889, Bd. xxvi.) found the proportion of sugar to nitrogen =3: 1 in
l^ancreatic diabetes.

'^ Arch. f. exper. Path. u. PharmaJcol., Leipzig, 1894, Bd. xxxiii. S. 305.

^ Thiel, Arch. f. exper. Path. u. PharmaJcol., Leipzig, 1887, Bd. xxiii.

■* Cornevin (Com2)t. rend. Acad. d. sc, Paris, 1895, tome cxvi. p. 263) has shown that
phloridzin causes a marked increase in the amount of sugar eliminated in the milk.

^ Seegen states that he obtained a formation of sugar (in excess of that produced by-
transformation of any glycogen present) in a mixture of chopped liver and arterial blood, to
which peptone had been added, and even with the addition of fat in place of peptone.
But his results have not been confirmed by other workers. Cf. Bbhm u. Hoffmann,
Arch. f. d. cjes. Physiol., Bonn, 1880, Bd. xxiii.; Girard, ihicl., Bd. xvi. S. 294;
Neumeister, Ztschr. f. i?io/., Miinchen, 1890, S. 346. The possibility of the formation of
carbohydrate from fat in animals, although not experimentally proved, must not be
ignored. For there is clear evidence that such a transformation may occur in germinating
seeds of plants (Siichs, "Text-Book of Botany," transl. by Bennett and Thiselton Dyer,
1875, p. 638), and if plant bioplasm is capable of effecting the transformation, animal
bioplasm might also be expected to have a similar power.

^ No diminution but an increase in the amount of blood-sugar was found by Pavy to


percentage of sugar in the blood is greatly increased. This seems to point to
the fact that phloridzin, besides any action it may have upon the metabolism
of carbohydrate in the liver and muscles, increases the permeability of the
kidney tubules to sugar, or causes the epithelium of the tubules to be more
susceptible to the presence of sugar in the blood, so that the kidney removes
sugar from that fluid more rapidly than under normal circumstances, and thus
the percentage is even diminished below normal.^ On the other hand, the
diminution in the percentage caused by such removal, even if it were in-
appreciable to chemical methods of analysis, might be supposed to excite the
sugar-producing tissues to increased activity, thus adding constantly more sugar
to the blood, to be again removed by the kidneys, and so on in a vicious circle.
On the other hand, Levene- has given reasons for believing that the
sugar in phloridzin diabetes may be produced in the kidneys, a view which
was previously expressed by IJschinsky (quoted by Levene). Thus, after
trying the renal blood vessels and then injecting phloridzin, there was no
accumulation of sugar in the blood ; indeed, the percentage of sugar in that
fluid was, if anything, diminished, Minkowski ^ had previously failed to find
an increase above the normal after ablation of the kidneys and injection of
phloridzin, and Schabad'^ obtained analogous results after tying the ureters.
Levene also finds that the amount of sugar in the kidneys is increased as the
result of giving phloridzin, and that under the same circumstances there is
rather more sugar in the blood of the renal vein than in that of the corre-
sponding artery. He admits, however, the probability that it is formed in
other organs as well as in the kidney. Minkowski ^ has put forward the
suggestion that phloridzin becomes split up in the kidney into phloretin and
sugar ; the latter becoming eliminated, and the former combining again with
sugar in the organism, and then again yielding this to the kidney, and so on.

Glycogenesis — Theory of Bernard. — ^As regards the fate of
the carbohydrates of the food, there is no doubt that, whether they
inevitably go through the stage of glycogen or not, they ultimately
undergo oxidation into carbon dioxide, and removal in the form of this
substance and water. The carbohydrate of the food directly increases
the amount of carbon dioxide given off, and in proportion to the amount
of such food taken. This elimination of carbon dioxide is not immediate,
for most of the carbohydrate taken in is in the first instance stored,
and only becomes oxidised gradually, as the needs of the organism
demand. The view which has been most commonly held with regard to
the method of transformation of the stored carbohydrate into the
products of its oxidation, originated with Bernard. Having found that
the blood of the hepatic vein constantly contains more sugar than
the blood of the portal vein, except during the absorption of food,
he concluded that the glycogen which he had discovered in the
liver,^ and which is no doubt the chief store of carbohydrate material in

occur in cats to which phloridzin had been administered ("Proc. Physiol. Soc," Nov. 14,
1896, Journ. Physiol., Cambridge and Loudon, vol. xx.), and he therefore denies that
diminished glycsemia is a feature of this form of diabetes.

' V. Mering, loc. cit. ; Minkowski, " Untersuch. 11. d. Diabetes mellitus," Leipzig, 1893 ;
Zuntz, Arch. f. Physiol., Leipzig, 1895, S. 570.

'Journ. Physiol., Cambridge and London, 1894-95, vol. xvii. p. 259.

^ Loc. cit.

* Vrach., St. Petersburg, 1892, No. 49, quoted from Minkowski.

* Op. cit., p. 152.

"The fact that sugar is formed in the liver was discovered by Bernard in 1848
{Compt. rend. Acad. d. sc, Paris, 1848, tome xxvii. pp. 249, 253, 514 ; " Nouvelle fonction
du foie, etc.," Paris, 1853), but the substance (glycogen), from which it is produce(l was
not found until 1857 (by Bernard, and also independently by Hensen). For a full list of
Bernard's writings on this subject, see " L'oiuvre de Claude Bernard," Paris, 1881,


the body, gives off such material into the blood in the form of dextrose.
This dextrose is taken to the tissues and is used by them, becoming
oxidised within them. Whether this oxidation occurs outside the actual
bioplasm, or whether the dextrose which is taken to the bioplasm
becomes first of all built up into its molecules and then split up
and oxidised, and whether the products of its oxidation leave the
muscles in their ultimate forms, are questions which we need not
now consider. In either case the effect of such oxidation is to produce
energy (in the form of heat and mechanical work).

This view of Bernard's has, on the whole, met with general favour among
physiologists. Some there are, indeed, who have so far proceeded beyond
Bernard, as to assert that the whole energy of the body is derived from the
oxidation of carbohydrate. Such carbohydrate, which is taken to the tissues
in the blood in the form of glucose, is assumed to be formed either from the
stored carbohydrate of the liver, as Bernard supposed, or independently of this
from proteid, or even from fatty materials in the liver cells, and being carried
to the tissues to be taken up by them, oxidised within them, and thus become
the immediate source of the energy of the body, whether this takes the
form of heat or work. It is in fact assumed that the main result of
metabolism within the body is the production in one part, and the destruction
in another, of carbohydrate. Such a view has been cliiefly contended for by
Seegen ^ and Chaiiveau, who hold that even the proteid material of the food,
at least its non-nitrogenous part, must ultimately become converted into
carbohydrate before it can become oxidised in the tissues (see p. 914).

It is obvious that Bernard's theory is, in the main, dependent upon the
circumstance that sugar is continually being passed from the liver into the
hepatic blood, even during starvation, and this, in fact, has been directly
affirmed by Bernard and others. Even in the fasting animal, sugar is found in
the blood, except at the extreme end of an inanition period ; and, according to
the analyses of Seegen, it always occurs in larger amount in the hepatic blood,
whatever be the nature of the food, whether proteid, fat, or carbohydrate,
than in blood from any other source. This occurrence of dextrose in
larger proportion in the hepatic blood than in the rest of the blood of the
body, if it were completely and satisfactorily determined, would be a fact of
fundamental importance, and Avould go very far to establish Bernard's theory
upon a firm basis. But there are reasons for believing that such an excess of
sugar as has been found by Seegen and other observers is not present
under absolutely normal conditions. Seegen's experiments were made without
anaesthetics, and it is a well-established fact that any operation upon an
animal, which involves the production of pain, will immediately produce
a transformation of the glycogen of the liver into sugar, and the appearance of
an excess of sugar in the hepatic blood.- It is, in fact, admitted by Seegen

^ " Die Zuckerbildung im Thierkorper," Berlin, 1890, S. 218, and numerous papers in
the Arch. f. d. ges. Physiol., Bonn, and in the Ccntrcdbl. f. Physiol., Leipzig u. Wieu.

- Seegen calculates that in man from 500 to 1000 grms. of dextrose may pass into
the blood from the liver in twenty-four hours. But since his calculations are based upon
experiments made upon animals in an abnoimal condition so far as the carbohydrate
metabolism is concerned, these numbers cannot be accepted. Cf. Abeles, Med. Jahrh.,
Wien, 1886, S. 383; I. Munk, Berl. Min. JFchnschr., 1890, S. 595; also Pfiliger,
Arch. f. d. ges. Physiol., Bonn, 1891, Bd. 1. S. 330, 396 ; Mosse, ibid., 1896, Bd. Ixiii. S.
613 ; Zuntz, Centralbl. f. Physiol., Leipzig u. Wien, 1896, S. 561. The blood is obtained
either directly from one of the liepatic veins, or by passing a catheter up into the inferior
cava, this vein being then blocked just below the reception of the hepatic veins by the
inflation of an india-rubber bag ; or a tube is passed down from the jugular vein through
the right auricle into the inferior cava, and its bent end is made to enter one of the
hepatic veins.


himself, that when the blood from the hepatic vein is collected under
conditions of anaesthesia, the difierence between the percentage amount of
sugar in the hepatic blood and that in ordinary arterial blood becomes
greatly diminished, if it does not altogether disappear.^

Bernard's views have been combated strenuously by Pavy,^ whose
method of experimentation is not open to the same objection as that
of Seegen and others who have found a constant excess of sugar in
the hepatic blood. Pavy takes blood from the animal immediately
after it has been killed by a blow upon the head, and before there
has been time for any change to have occurred in the liver, and he
finds that blood which is collected under these circumstances from
the inferior vena cava (including, therefore, the blood which has passed
out from the liver) never shows any appreciable excess of reducing
substances over blood obtained from other parts of the body. Eesults
similar to those of Pavy have also been obtained, although under
somewhat different conditions, by other observers.

We are therefore landed in this difficulty, as the result of the
imperfection of our present methods, that we cannot be sure whether
the blood of the hepatic vein does or does not, normally, contain an
excess of sugar. If it does, we are bound to assume that sugar is
being continually passed off from the liver into the general blood of the
body, and since this sugar does not j)ass off by the urine, it can only be
available for the nutrition of the tissues, and the production of energy
by oxidation. If sugar does not pass from the liver into the blood, we
should require to find some form in which the glycogen, which is
undoubtedly stored up in the liver, is got rid of, and also to find some
meaning for its presence there and in the muscles.

It has been suggested by Pavy^ that such stored glycogen may
become converted into fat. There is no doubt that carbohydrate
food does become converted in the body into fat, and there are
many instances of the formation of fat from carbohydrate material in
plants ; it is therefore not altogether wanting in probability, that the
glycogen which is stored up in the liver cells and muscles may also
become converted into fat. Such fat may be assumed to be gradually
removed by the blood and carried to the different organs, and in them
ultimately oxidised to carbonic acid and water.

Another supposition, which we have already considered, is that it
becomes directly oxidised, and produces heat. As most of the
oxidation of the body occurs in the muscles, and as the muscles retain
their glycogen in starvation longer than the liver, although the latter
organ contains normally a much larger proportion, it seems very
probable that the glycogen passes from the liver to the muscles. This
cannot be as glycogen, for glycogen is not present in blood plasma, and

1 CentralU.f. Physiol., Leipzig u. W^ien, 1896-97, Bd. x. S. 497, 822.

^ "The Physiology of the Carbohydrates," London, 1894. Here other papers by the
same author are referred to.

'^ IhicL, pp. 245 to 252. In connection with tlie question of sugar production by the
liver, it may be mentioned that removal of this organ or cutting off its blood supply in
rabbits (Book and HoH'mann, " Exper. Studien li. Diabetes," Berlin, 1874), dogs (Seegen,
"Die Zuckerbildung," and Tanyl and v. Harley, Ardi. f. d. ges. Physiol., Bonn, 1895,
Bd. Ixi. S. 551), geese (Minkowski, Arch. f. expcr. Path. u. PharmukoL, Leipzig, 1882,
Bd. XX. S. 41), is followed by either disajipearance or marked diminution of the sugar of the


what little there is in the blood is in the white corpuscles — a property
they share with most other protoplasmic structures. It is therefore
natural to conclude, even if we cannot show the fact conclusively
by analysis, that it passes from the liver to the muscles in the form of
grape-sugar. The extra amount of sugar in the hepatic blood might Ije
so small as easily to fall within the limits of experimental error, and
yet sufficient to transport a very large amount of carbohydrate in the
course of twenty-four hours. ^ Nor can it be said that we have any
means of exactly estimating the amount of sugar in the blood at all.
What has been estimated hitherto in the blood is not sugar alone, but
substances which reduce cupric salts. That a part of these substances
consists of glucose, is shown by the reaction with phenylhydrazine.
But it must not be forgotten that there occur in the blood other
substances which, although not glucose, also reduce metallic salts ; nor
can we say what proportion these hold to the glucose in the blood.
Hence any mere determinations of the reducing substances do not give
us a direct measure of the amount of glucose, and it is impossible to
admit as proven any theory which is entirely built up upon observations
of the amount of reduction yielded by the blood, on the assumption that
such reduction is exclusively produced by glucose. If, therefore, we
accept Bernard's theory, it must be understood that the evidence in its
favour is mainly of an indirect character. There exists an analogy in
the case of plants, in which the stored insoluble carbohydrate (starch) is
conveyed from one part to another in the form of soluble sugars. And
it must further be looked upon as a powerful argument in favour of
Bernard's hypothesis, that under certain circumstances there is rapidly
produced a very appreciable transformation of the liver glycogen into
dextrose. This occurs as the result of stimulation of almost any sensory
nerve, as the result of interference with the hepatic circulation,^ and as
the result of administration of many drugs. And it also occurs, as was
found by Bernard early in his investigation of the subject, very rapidly
after death, especially if the liver be kept at the body temperature. On
the other hand, this transformation can be prevented by subjecting the
liver, immediately after the animal is killed, to a sufficient amount of
heat, as by throwing it in pieces into boiling water, or of cold, as by
ice-cold salt solution,^ or by a freezing mixture.* It has been held
that this transformation, which occurs during the " survival " of the
liver cells, is due to a continuance of such chemical processes as occur
in the cells during life, and which lead to the change of their glycogen
into sugar, just as the chemical changes which occur in muscle which is
passing into rigor are generally similar to those produced during the

1 Foster, "Text-Book of Physiology," 1889, pt. 2, 5th edition, p. 726.

^ For these reasons conclusions should be drawn very cautiously from such experiments
as those of the brothers Cavazzani {Centralhl. f. Physiol., Leipzig u. Wien, 1894, Bd. viii.
S. 33), who obtained disappearance of glycogen in the liver, and increase of sugar in the
hepatic blood, on stimulation of the coeliac plexus. The same remark applies to the results
obtained by Morat and Dufourt by excitation of the vagus {Arch, dc physiol. norm, et path.,
Paris, 1894, pp. 631 and 371).

^ Dastre states that a tempei'ature of 55° C. is sufficient to destroy the amylolytic action,
and that prolonged exposure to ice-cold salt solution has the same effect. He argues
from this that the action is not that of a ferment, but of cell protoplasm {Arch. dc2')hysiol.
norm, et path., Paris, 1888, p. 69). On the other hand, Nasse found that liver digested
with chloroform water has a free amylolytic action, which must in that case be due to a
ferment {Rostoclmr Ztg., 1889, No. 105). See also Salkowski, Centralhl. f. d. med.
Wissensch., Berlin, 1889, No. 13).

** Pavy, " Physiology of Carbohydrates," p. 134.


activity of the muscular tissue ; and accordingly anything, such as the
sudden application of heat, able to instantly kill the liver cells stops
such change.^ On the other hand, it may also be that the trans-
formation is caused by an amylolytic ferment, which is produced by
the cells. This view was in fact held by Bernard,^ but he afterwards
supposed that the ferment was derived from the blood.^

It has been denied that such a ferment can be obtained from the liver, and
it has therefore been contended that the transformation of glycogen into sugar
must be produced by the direct metabolic action of the cell protoplasm. It
has also been argued that, since the sugar Avhich is produced by the digestive
amylolytic ferments is maltose, and not dextrose, the production of dextrose in
the surviving liver cannot be due to a ferment. Pavy, however, has shown
that an active amylolytic ferment is obtainable from the alcohol hardened

Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 129 of 147)