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liver both in rabbits and cats, and that the sugar which is produced by it is
closely similar to, if not identical with, that formed in the " surviving " organ.*
A ferment converting glycogen into dextrose has also been obtained from
the liver by Artlius and Huber,-^ and by Bial,^ who states that it is identical
with and probably derived from the diastatic ferment of blood and lymph.'''

Puncture diabetes. — Bernard^ also discovered the fact that certain
lesions of the central nervous sj^stem, and especially a puncture in the
region of the floor of the fourth ventricle, which corresponds, as we now
know, very nearly to the position of the vasomotor centre, produces a con-
dition of glycosuria ; and that this is caused by a transformation of the
glycogen of the liver into sugar, which is then taken up by the hepatic
veins in so considerable a quantity, and increases so much the percentage
of sugar in the blood, as to cause its excretion by the kidney. That this
is the origin of the sugar in the so-called " puncture diabetes," is proved
by the fact that, if precautions are taken to render the liver devoid of
glycogen, as by a prolonged period of inanition,^ with or without severe
muscular activity, the glycosuria ordinarily resulting from puncture of
the fourth ventricle does not appear, nor does it occur in frogs with the
liver removed. It has been conjectured, with much probability, that

^ Koel Paton found that if the liver substance be bruised up in a mortar with sand, so as
to crush and thus destroy the liver cells, the change of glycogen into sugar does not occur
{TMl. Trans., London, 1894, vol. clxxxi. p. 233). But a repetition of his experiments by
Pavy ("Epicriticism," London, 1895. p. 79) has not yielded the same results, and, since
they were only few in number, they can hardly be accepted without further confirmation.
Paton has, moreover, in later experiments, himself failed to verify his earlier results
{Journ. Physiol., Cambridge and London, 1897, vol. xxii. p. 121).

^ " Le9ons sur le diabete," Paris, 1877.

^ Compt. rend. Acad. d. ,sc., Paris, tome xli. p. 461.

* There seems to be little doubt that this sugar is mainly if not entirely dextrose
(Seegen and Kratschmer, Arcli. f. d. ges. Physiol., Bonn, 1880, Bd. xxii. S. 214), but
according to Chittenden and Lambert {Stud. Lab. Physiol. Chem., New Haven, 1885)
there is some maltose. Kltlz and Vogel also found a certain amount of both maltose
and isomaltose in the fresh liver [Centralhl. f. d. med. Wissensch., Berlin, 1894, S. 769).
The remark that has been already made regarding the sugar found in blood applies to all
these determinations of liver sugar, namely, that what is actual)}^ determined is the
amount of reduction of cupric oxide, and that there may be, and undoubtedly are, other
substances present besides sugar which effect this reduction.

^ Arch, de j^hysiol. norm, etpath., Paris, 1892, p. 651.
« Arch./, d. f/cs. Physiol., Bonn, 1893, Bd. Iv. S. 434.
■^ See article "Blood," p. 160.

* " Le9ons sur la physiol. et la pathol. du systeme nerveux," Paris, 1858, tome i. p.
401. See also Kckhard, Beitr. z. Anat. u. Physiol. {Eckhard), Giessen, 1869, Bd. iv. S. i.
Kiihne found the same thing to happen in frogs (Liaug. Diss., Gottingen, 1856).

^ Luchsinger, loc. cit.



PUNCTURE DIABETES. 527

the condition of the liver which results from such puncture, and which
tends to cause this transformation of the glycogen into sugar, is due to
a disturbance of the hepatic circulation, and especially of the circula-
tion in the hepatic artery, thus indirectly producing an alteration in the
normal metabolism of the organ ; but this cannot be considered as con-
clusively proved, and it may be due to a direct interference with the
action of the nerves to the liver cells. Diabetes does not, however,
occur on section of the splanchnic nerves alone.^ But in all probalnlity
the vasomotor centre is stimulated by the puncture, for other forms of
stimulation of the vasomotor centre also tend to produce a temporary
diabetes, such as the prolonged stimulation ^ of most sensory or afferent
nerves {e.g. the sciatic, the central end of the vagus,^ and the depressor ^),
which are known so to influence the vasomotor centre as to produce
constriction or dilatation of the arteries of the body generally. It is
possible, therefore, that this may be the manner in which the effect is
produced in the liver, and that the glycsemia is due to the diminution
of the amount of oxygenated blood passing to the liver through the
hepatic artery, causing an excitation of the liver cells, and such conse-
quent alteration in their metabolic activity as ordinarily accompanies
excitation.^ Many drugs produce temporary diabetes, e.g. acids, such as
phosphoric, lactic, and hydrochloric, also strychnine, curari, phosphorus,
arsenic, carbon monoxide. Some of these may act by affecting the
circulation, others by producing a dyspnoeic condition of the liver cells,
others again may be direct stimulants to the hepatic cells.^

It must be looked upon as a strong argument in favour of the glycogenetic
theory of Bernard, that we find as a concomitant of the altered (increased?)
activity of the hepatic cells, both after removal of the liver from the body,
and after the diabetic puncture, such an increased production of sugar in the
organ. It is certainly easier to explain the occurrence of puncture diabetes as
an excess of the normal production of sugar in the liver, than as a phenomenon
entirely sid generis.

Action of the pancreas on carbohydrate metabolism. — Until
recently, it was not known that the pancreas had any more influence
upon metabolism than other glands of the same type, such as the
salivary glands. There had, however, been isolated instances recorded
in which disease of the pancreas was accompanied by a condition of
diabetes ; but this, for the most part, was ascribed to the implication of
the sympathetic ganglia, which are in anatomical relationship to the
pancreas, and no special importance was attached to the pancreas in
connection with the symptom.'' It was, however, shown in 1889, by

^ According to Kaufmann {Compt. rend. Soc. de hiol., Paris, 1894, p. 284), puncture
diabetes is not produced, if the nerves both to the pancreas and liver are cut ; but if one
set only is severed, it is found to occur.

2 Even that produced by sections, Kiilz, Arch. f. d. ges. Physiol. , Bonn, 1881, Bd. xxiv.
S. 97. Here also will be found references to previous papers on the subject.

^Bernard, ''Lemons sur le systeme nerveux," Paris, 1858, tome ii. ; Eckhard, Beitr.
z. Anat. u. Physiol. {Eckhard.), Giesen, Bd. viii.

* Filehne, Centralbl. f. d. vied. JFisscnsch. , Berlin, 1878, ISTo. 18.

^ Of. Araki, Ztschr. f. physiol. Chem., Strassburg, 1893, Bd. xvii.

^ References to the literature of some of these substances will be given later ; others will
be found in Kiilz, loc. cit., siqjra ; and in Neumeister, "Lehrbuch," AuH. 2, S. 328.

'' Since the discovery by v. Mering and Minkowski of the effects of total removal of the
pancreas, several cases of severe diabetes in man, associated with disease of that gland,
have been recorded (G. Hoppe-Seyler, Dcutsches Arch. f. klin. Med., Leipzig, 1893, Bd. Hi.
S. 171 ; Buss, Diss., Gottingcn, 189.'i). It must not be supposed, however, that this is at
all common. In most cases of diabetes no affection of the pancreas can be substantiated.



928 METABOLISM.

von Mering and Minkowski/ that complete removal of the pancreas in
the dog, cat, and pig,^ is inevitably followed by a very severe form of
diabetes, having the usual characters of that disease in man, namely, an
enormous increase in the excretion of water, and the appearance in the
urine, besides sugar, of aceto-acetic acid, acetone, and sometimes of oxy-
butyric acid. That this condition is not in any way due to the abolition
of the secretion of the gland, was further shown by the observation that
it does not occur if the duct of Wirsung be tied, or if it and its branches
be blocked by the injection of paraffin into them, and the gland left in
situ, nor even if a certain proportion of the gland be left, its secretion
being prevented from passing into the intestine ; nor does it occur if a
portion of the pancreas be detached from its normal position and trans-
planted elsewhere, either underneath the skin or in the peritoneal cavity,^
and the remainder of the organ subsequently removed, although diabetes
will appear in the severest form immediately after the removal of the
transplanted portion from its subcutaneous situation.

The observations of v. Mering and Minkowski have been repeated
and extended by Minkowski himself and by many other physiologists.
The removal of the organ is less difficult than might be supposed, the
chief precaution to take being to interfere as little as possible with the
supply of blood to the duodenum. The complete removal is found
invariably to be immediately followed by a considerable increase of
sugar in the blood, where the amount of sugar may reach as high as 046
per cent., and its consequent appearance in the urine, in which the
amount may rise to as much as 8 per cent, or more. In the increased
amount in the blood pancreatic diabetes agrees with puncture diabetes,
and differs from phloridzin diabetes, in which, as already stated, the
amount of sugar in the blood is not increased, although there is a large
increase of sugar in the urine. Concomitantly with this increase of
sugar in the blood and its consequent appearance in the urine the
glycogen of the liver disappears.* When no carbohydrate is given with
the food, and even during prolonged fasting, the sugar continues to be
eliminated in considerable quantity; and since, under these circum-

1 Arch./, exper. Path. w. PJiarmalcoL, Leipzig, 1889, Bd. xxvi. ; see also Minkowski, ibid.,
1893, Bd. xxxi. S. 85. The experiments of v. :Mering and Minkowski have been repeated by
many observers, amongst whom may be mentioned especially Dominicis {Gior. interna?., d. -sc.
ined., Napoli, 1889), Hedon, Thiro'loix, Gley, and Lepine (numerous papers during the last
seven years in the Compt. rend. Acad. d. sc, Paris ; and in the Compt. rend. Soc. de
bioL, Paris; in the Arch, de p)hysiol. norm, et 'path., Paris; and Arch, de med. exptr.
et d'anat. 'path., Paris) ; Vaughan Harley, Journ. Anat. and Physiol., London, 1891, vol.
xxvi. ; Journ. Physiol., Cambridge and London, 1891, vol. xii. p). 391 ; Caparelli {Atti d.
Accad. Gioncnia disc, nat.in Catania., 1892, tome v.; Saudraeyer, Ztschr.f. Biol., Mlinchen,
1893, Bd. xxix. S. 86.

- The results in the rabbit were somewhat doulitful, and negative results were obtained
in birds and in the frog. AXdohoW [Ztschr. f. BioL, Mlinchen, 1892, Bd. xxviii.), however,
has obtained pancreatic glycosuria in the frog ; as has also Marcuse {Verhandl. d. pkysiol.
Gesellsch. zu Berlin, 1893-94, S. 98, in Arch. f. Physiol., Leipzig), who states that it fails
to occur if the liver he previously removed. This is also the case, according to Langen-
dorff {Arch. f. Physiol., Leipzig, 1887, S. 138), with the diabetes i)roduced by strychnine
and by puncture, but not with that produced by curari. Cf., however, Rohmann, Ccntralbl.
f. Physiol, Leipzig u. Wien, 1887, Bd. i. S. 122.

3 Thiroloix (" Le diabete pancreatique," Paris, 1892) at first obtained a contrary result,
but in later experiments (^rc/i. de physiol. norm, et palli., Paris, Oct. 1892) succeeded in
confirming the original statement of v. Mering and Minkowski.

•* According to Hedon {Arch, de physiol. norm, et path., Paris, 1893), theswgrar in the
liver may nevertheless be increased in pancreatic diabetes. The administration of
kevulose causes the rea[ii)earance of glycogen in the liver, although dextrose does not
(Minkowski, Arch. f. exper. Path. u. Pharmakol., Leipzig, 1893, Bd. xxxi.).



PANCREAS AND CARBOHYDRATE METABOLISM. 929

stances, its amount, as in the case of phloridzin glycosuria, rises and
falls with the amount of nitrogen in the urine (see p. 921), it may
be assumed that it is derived in these cases also from the splitting of
proteids.

The exact amount of the pancreas which it is necessary to leave in
order to prevent the occurrence of glycosuria cannot be exactly given,
but a comparatively small amount is sufficient. If somewhat less than
this minimum be removed, diabetes of a less severe type than that
following complete removal may occur. There is, however, a tendency
for it to become more severe in process of time, probably from a certain
amount of atrophy occurring in the pancreatic tissue which has been
left.i

Cause of 'pancreatic diabetes. — It appears probable that the pancreas
exerts its iniiuence upon carbohydrate metabolism, either by promoting
the formation of glycogen in the liver from the dextrose taken to it by
the portal blood, or by furthering the oxidation of dextrose in the tissues
generally. In either case the effect would be the prevention of the
accumulation of dextrose in the blood, so that the percentage of sugar
in this tl uid would be kept down to its normal, small amount. Whether
this is brought about by the direct action of the organ upon dextrose
which reaches it with the blood, or whether it acts indirectly in promot-
ing the metabolism of dextrose by an internally secreted material, which
passes out from the organ into the blood and tissues, is a question which
it is impossible at present to give an answer to. Diabetes which results
from removal of the pancreas, is not necessarily due to an increased
glycogenesis from transformation of glycogen (although this is the cause
of the glycosuria w^hich first makes its appearance), for it will continue
after the glycogen has completely disappeared from the liver and muscles.
Moreover, the amount of sugar which is passed is altogether too great
to be accounted for by the amount of glycogen present in the body.
Nor is it due to a diminished consumption of sugar by the tissues.^
It has been suggested that it is caused by the absence of the glyco-
lytic ferment, which is described as being usually present in the blood.
L(fpine ^ has supposed that the pancreas forms such a glycolytic ferment,
which effects the splitting of sugar prior to its oxidation in the tissues.
But Minkowski * has shown that the blood of an animal deprived of its
pancreas still possesses just as much power of glycolysis as a normal
animal. Kausch,^ who succeeded in producing diabetes in ducks and
geese by pancreatic extirpation, also found that, after removal of the
liver in the diabetic animal, moderate amounts of sugar were still con-
sumed in the tissues. Pancreatic glycosuria diminishes or disappears
during fever.^

The symptoms are not allayed by giving raw pancreas with the
food, as those of thyroidectomy are by feeding with raw thyroid. Nor

^ Cf. Hedon, Compt. rend. Acad. d. sc, Paris, 1893, tome clvi. p. 649 ; and Thiroloix,
Arch, de physiol. norm. et2}cith.. Paris, 1892.

^ Kaufmann, Covvpt. rend. Acad. d. sc, Paris, 1894, tome cxviii. p. 656; Arch, dejihysiol.
norm, etpath., Paris, 1896, p. 151.

^ " Le ferment glycolytique et la pathogi^nie du diabete, " Paris, 1891. Lupine's theory
is supported by Vauglian Harley {Brit. Med. Journ., London, 27th August 1892), and
has been criticised by, amongst others, Spitzer {Berl. Min. JFchnschr., 1894, S. 949).

•* Arch. f. exper. Path. u. Pharmakol., Leipzig, 1893, Bd. xxxi.

5 Ibid., 1896, Bd. xxxvii. S. 274 ; and 1897, Bd. xxxix. S. 219.

^ Kaufmann, Comiit. rend. Soc. de hioL, Paris, 1896, p. 227. Fever was found by Poore
to diminish sugar in natural diabetes {Trans. Clin. Soc. London, 1894).

VOL. 1,-59



93°



METABOLISM.



are they due to any toxic substance accumulating in the blood (from
which it might be supposed to be normally removed by the pancreas),
as has been thought to be the case in the analogous instances of thyroid
and suprarenal extirpation, for the blood of an animal rendered diabetic
by pancreatic removal is not found to render a normal animal diabetic.

The facts clearly show that the diabetes which results from pancreatic
extirpation is not the result of any interference with the sympathetic nerves
in the neighbourhood of the organ, nor is it due to the arrest of the passage
of the secretion of the gland into the intestine, but is exchisively the result
of the removal of something belonging to the gland which acts in independ-
ence of its functions in connection with digestion. Since we find in the
pancreas, if we compare its structure with similar glands such as the salivary,
that the only important difference is the occurrence in the parenchyma of the
pancreas of certain cell islands of an epithelium-like appearance richly supplied
with blood vessels, and entirely unconnected with alveoli or gland ducts, it
seems reasonable to suppose that the influence, whatever it may be, which the
pancreas exerts upon carbohydrate metabolism, and which results in the
excessive formation of sugar on its removal, is due to this particular tissue.^

That the salivary glands have no such influence upon metabolism as the
pancreas was shown by !Fehr,2 and also conclusively by Minkowski,^ who, after
removal in dogs of all the salivary glands, including the orbital glands, found
no appreciable efiects either upon carbohydrate or any other form of metabolism
to follow the removal. I have myself, in conjunction with Moore, repeated this
experiment in a dog, removing in successive operations all the salivary glands
upon both sides, leaving, however, the orbital glands. The animal remained
in perfect health for several months, and no disturbances coidd be determined
in either carbohydrate or proteid metabolism.*

Metabolism of Fat.

Is the fat of the body directly derived from the fat of the food ?

— That the fat of the body should be derived from the fat of the food
seems at first sight extremely probable. But, on consideration, it will
appear that before it is laid down as the fat of the tissues it would
probably undergo a change. For the fat of different animals has by
no means the same composition. Whereas some, such as the dog and
man, have a large amount of olein in their adipose tissue, and conse-
quently their fat has a comparatively low melting point, others, such as
the sheep, have a large proportion of stearin, and the fat of such animals
has a relatively high melting point.

Now, if a clog or a man is fed upon sheep's flesh and fat, the fat
which is laid up in the body has not a different composition from that
which it ordinarily possesses. That is to say, a man living upon mutton
will have his body-fat, not of the consistency of mutton suet, but of the
ordinary consistency of the fat of the human body, having a melting
point far lower and containing a much larger amount of olein in its
composition.

If, therefore, the fat of the food is laid down as the fat of the body,
it must undergo important modifications. It is possible to suppose that
only such portions of the fat of the food as would make fat of the

^ Schiifer, "On Internal Secretions," Brit. Med. Journ., London, August 1895.

^ Inaug. Diss., Giessen, 1862 (quoted from Minkowski).

"Arch./, exper. Path. u. Pharmakol., Leipzig, 1893, Bd. xxxi. S. 141.

■* " Proc. Physiol. Soc," Journ. Physiol., Cambridge and London, 1896, vol. xix. p. xiii.



METABOLISM OF FAT. 931

composition normal to the particular species of animal, are laid down
directly, and that other portions, such as the excess of stearin which
occurs in mutton fat, become broken down completely, and either directly
oxidised, or the products of their decomposition again built up to form
the normal fat. It has indeed been conclusively proved that the fat of
the food may be to a certain extent laid down unaltered in the body-
fat. Dogs which have been starved for a considerable time, so that
practically the whole of the body-fat has become removed, will, if fed
upon an excess of mutton fat and sufficient proteid, lay down a body-fat
of a melting point and composition very similar to mutton-fat. This
shows that at least a portion of the fat introduced with the food has
been, for a time at any rate, laid down directly as body-fat.^

It has been further shown that dogs to which there has been
administered, along with their food, forms of fat which do not ordinarily
occur in the animal economy, will lay down a certain amount of this
along with their body-fat. This has been determined for spermaceti,
linseed oil, and rape oil.^ That in pigs the fat of the body may also be
derived from the fat of the food, was shown in some of the experiments
by Lawes and Gilbert.^

Formation of fats from fatty acids. — The question of the form
in which fats are absorbed has been already considered in a previous article
dealing with that subject, and it has there been shown that the fats of the food
are in large part not absorbed in the form of fat, but in that of fatty acid,
into which and glycerin they are broken up by the fat-sphtting ferment of
the pancreatic juice ; and that they undergo a subsequent synthesis into fat
by combination with glycerin in the columnar epithelial cells of the small
intestine.

That such synthesis is possible even in the absence of glycerin given with
the food, is shown by the experiments of I. Munk, who found that when a
dog was fed upon fatty acids in place of the fats of its ordinary food, just as
much fat was absorbed into the chyle and was laid down in the body as if
it had been fed with the complete fat. The columnar epithelial cells become
filled with fat globules, as after a meal containing actual fats ; and the synthesis
of fatty acid and glycerin to form fat must therefore have occurred in these
cells, which must themselves have produced, in some way which is not under-
stood, the glycerin necessary for the synthesis.*

Are fats formed from carbohydrate ? — This is a question of great
practical importance, seeing that carbohydrate foods are the cheapest forms
of nutriment, and that the fattening of animals is an important branch of
agricultural industry. The experience of all rearers of animals for market
points to the fact that carbohydrates do produce fat. Sheep and oxen
fed purely upon grass, which contains hardly any fat and but little
proteid in proportion to the carbohydrate present, lay on a large amount
of fat, and the artificial foods which are used for fattening purposes

1 Lebedeff, Central.hl. f. d. med. Wusensch., Berlin, 1882, S. 129 ; Ztschr. f. physiol.
Chem., Strassburg, 1882, Bd. vi. S. 149 ; Arch. f. d. ges. Plmjsiol., Bonn, 1883, Bd. xxxi.
S. 11 ; I. Munk, Arch. f. Physiol, Leipzig, 1883, S. 273 {Verhmidl. d. physiol.
Gesellsch. zu Berlin) ; Firchow's Archiv, 1884, Bd. xcv. S. 407.

- Radziewski, Virchovfs Archiv, 1868, Bd. xliii. S. 286; Lebedeff", lac. ciL; I. Munk,
loc. cit. See also Minkowski, Arch. f. exper. Path. u. Phcvnnakol., Leipzig, 1886, Bd. xxi.
S. 373, and L Munk and Rosenstein, Virchow's Archiv, 1891, Bd. cxxii. S. 230, for evidence
tliat foreign fats pass into the chyle.

^ See note 2 on next page.

* For further details regarding these and similar experiments, see article on "Fat
Absorption," p. 443.



932



METABOLISM.



also for the most part contain, in addition to a certain amount of
proteid, a large proportion of carbohydrate. In spite, however, of this
almost universal experience, it has been held by C. Yoit ^ that the
carbohydrates of the food are not directly transformed into the fat of
the body, but that they only act in promoting the fattening of animals
by sparing the oxidation of proteid, so that the non-nitrogenous portion
of the proteid molecule may become transformed into fat. It has been,
in fact, altogether denied by Voit that the carbohydrates themselves can
be transformed by the animal economy into fat, in spite of the well-
established fact that in plants there frequently occurs, especially in the
ripening of many seeds, a considerable transformation of carbohydrate
material into fat. The question was, however, brought to the test of
direct experiment by Lawes and Gilbert.^ These observers took two
pigs of the same litter, killed one as a control, and determined the total
amount of fat in its body, and kept another one alive for some weeks,
feeding it with proteid and an excess of carbohydrate food, and
determming the exact amount of proteid in such food, then killed it,
and determined the total amount of fat in its body. They found that
the amount of fat which had been added on during the time could not
be accounted for by supposing it to be derived from the proteids of
the food, since there was not sufficient proteid in the food during the



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 130 of 147)