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own figures show that the sugar of the blood, after having dimin-
ished during starvation continues to do so during subsequent feeding
exclusively on fats. Von Mering, Moritz and Praussnitz, Cremer
and Ritter, and now (1898) Kumagawa and Miura alike consider
that during phloridzin-poisoning, with its enormous loss of glucose,
fats do not give rise to carbohydrates.

Chauveau has been led to his conclusions as to the ability of the organism
to produce carbohydrates from fats chiefly by his own and by Regnault's and

* Among authorities now Hving, so far as I know, only Seegen, v. Noorden, Bunge,
Chauveau and Kaufmann, and Weiss accept the formation of carbohydrates from fats in
man.

13



1 86 DIABETES MELLITUS AND GLYCOSURIA.

Reiset's investigations on the marmot. This animal, when subjected to star-
vation in summer, dies after the loss of between 95 per cent, and 97 per cent.
of its fat, and then has scarcely any carbohydrate at all left in liver, muscles,
or blood. After hibernation the marmot has used up its fat, but the blood still
. contains glucose and the liver and muscles contain glycogen. Chauveau
asks how this could be, after such a time of continued abstinence from food,
with considerable expenditure for heat and circulation, if the carbohydrates
(glycogen and glucose) had not been formed from fat. Then Regnault and
Reiset had observed that the marmot may, during its sleep in hibernation,
increase in weight, and that it consumes considerably more oxygen than it
expires in carbonic acid, and Chauveau thinks that the fat has been changed
into glucose by oxidation according to the following equation :

2C57HJ10O6 + 670, = i6CgHi,06 + 18CO2 + I4H,0.
Stearin. Glucose. Carbonic Water.

Acid.

The question whether proteids directly produce vital force is not
to be answered at present. Voit, Brietske, Fick and Wislicenus,
and others found no increase in the nitrogen of the urine after
mechanical work. Pavy, Flint, Parkes, Argutinsky, Oppenheim,
and others arrived at opposite results, and Zuntz, too, after his
beautiful researches, has formed the opinion that proteids (and fats)
may directly contribute to the formation of vital force.

Finally, it is not impossible that a part of the proteids so utilized
is derived from carbohydrates. Pfliiger, Schenk, and others admit
a synthetic formation of proteids, as a station on the way to the
final production of vital force, to which formation carbohydrates
may contribute part of the nonnitrogenous constituents. So long
as we do not know more than we do at present of the fate of the
fats, we can not absolutely deny its participation in such a synthesis
of proteids.

Until further information is forthcoming it must be admitted that
proteids may form proteids, fats, and carbohydrates, that carbo-
hydrates may form carbohydrates and fats, but that fats are not
positively known to form anything but fat. On the other hand, we
have no right to deny positively the formation under some circum-
stances of carbohydrates from fat ; still less have we a right to
deny the synthesis of proteids, in which both carbohydrates and
fats may participate.

The sugar of the blood is proved to be glucose, and is found in
the serum.



METABOLISM AND NUTRITIVE NEEDS. 1 87

The quantity of sugar in the blood varies normally from
0. 10 to 0.15 per cent., and it may, perhaps, sometimes slightly
exceed these limits in either direction. The veins contain some-
what less than the collateral arteries. The portal vein, except after
the ingestion of large amounts of carbohydrate, contains less and
the hepatic veins contain more than do other vascular areas.
Unlike the glycogen of the liver, which varies enormously under
different dietetic conditions, the amount of sugar in the blood nor-
mally undergoes but comparatively shght variations. It increases
somewhat after the ingestion of large amounts of carbohydrate
(Claude Bernard, v. Mering) and after copious hemorrhage (Edel,
Schenk), and decreases during continued starvation (Bernard,
Bock and Hoffmann, Otto, Seegen, Chauveau), during the febrile
state, after extirpation of the liver, and as a result of poisoning
with phloridzin. The quantity of sugar in the blood is about
half of the quantity of fibrin, and the amount is not small consid-
ering that the sugar is being constantly produced and constantly
consumed. Seegen calculates that a human being produces and
consumes about lo grams of glucose per kilogram of bodily
weight in twenty-four hours. A German, Anglo-Saxon, or Scan-
dinavian of ordinary size thus manufactures and uses up between
700 and 800 grams.

The sugar of the blood is consumed in the different tissues of
the organism, but chiefly in the muscles ; and by its oxidation into
carbonic acid and water it forms the organism's largest, but prob-
ably not its only, source of vital power.

The sugar of the blood causes reduction of copper- and bismuth-solutions ;
undergoes fermentation, with the generation of alcohol, carbonic acid, etc. ;
forms with potassium a combination, out of which it may be driven by car-
bonic acid (Seegen, Ludwig, Abeles) ; deflects the ray of polarized light to the
right (Ewald) ; and yields glycosazone with phenyl-hydrazin-chlorate and
sodium acetate (Pickhardt). Thus, there is no doubt that it is glucose. To
this rule there may, however, be rare exceptions ; it seems probable that in
cases in which the sugar in the urine is another saccharid — .?. ^., levulose —
the sugar of the blood is also constituted by this saccharid.

Otto proved the sugar of the blood to be contained in the serum by intro-
ducing in Hoppe-Seyler's equation for the valuation of blood-corpuscles from
the quantity of plasma and fibrin (in two cases) the figures of the sugar instead
of the figures of the fibrin, arriving at nearly the same figures as Hoppe-
Seyler's equation gave. Calculating with the aid of Hoppe-Seyler's equation,



i88



DIABETES MELLITUS AND GLYCOSURIA.



he found in one case 64.65 per cent, of plasma and 35.35 per cent, of red
blood-corpuscles ; and with his own equation he found the corresponding
figures to be 64.29 and 35.71. In a second case the analogous figures were
67.88 and 32.12, and 67.96 and 32.04. The figures representing fibrin and
sugar were as follows :





Cases.


Blood.


Plasma.




Fibrin.


Sugar.


Fibrin.


Sugar.


I,


0.205 psi' cent.


O.I 16 per cent.


0.317 per cent.


0.182 per cent.


2,




0.311 "


0.123


0.458 "


0.181



Naunyn states the normal quantity of sugar in the blood as about o.i per cent.
— rather somewhat below (from 0.08 to 0.09) than above this figure ; Bernard
found between 0.09 and 0.117 per cent. ; Seegen, between 0.12 and 0.19, and
as an average in ten cases, nearly 0.17 per cent. ; Otto, nearly 0.12 per cent. ;
V. Mering (in the serum), between 0.13 and 0.14 per cent. ; Frerichs, between
0.12 and 0.30 (!!!) per cent. All of these figures refer to man. In the rab-
bit Otto found between 0.09 and o.ii per cent.; Barral, in the dog, between
0.08 and 0.17 per cent. ; Otto, in the dog, o.ii per cent. The highest of these
figures include not only the sugar, but all reducing-substances in the blood
(kreatinin, uric acid, etc.), and thus represent too high a value for the glucose.
Otto corrected this error, which, besides, shows a wrong relation between the
quantity of sugar in the arteries and that in the veins, the reducing, nonsac-
charine substances being present in greater quantity in the veins than in the
arteries. Otto found in the dog, in blood from the femoral artery, a reduction
before fermentation of 0.160 per cent., and after fermentation of 0.034 per cent.,
the amount of glucose thus equaling 0.126 per cent. ; in blood from the femoral
vein of the same dog a reduction before fermentation of 0.158 per cent., and
after fermentation of 0.039 P^i" cent., the amount of glucose thus equaling
0.1 19 per cent. (The blood was taken simultaneously from both vessels.)
After hemorrhage the reduction is increased. Otto considered this to be an
effect of the increase of nonsaccharine reducing-substances. Bernard had
mentioned this increase as due to the presence of an increased amount of
glucose, and Schenk,* in opposition to Otto, maintains that the whole increase
is due to the presence of glucose.

The excess of glucose in the arteries over that in the veins is small ; accord-
ing to Otto, the proportion is 12 : 11; according to Barral, 100 : 92.7. As already
mentioned, the hepatic veins generally contain most, and the portal vein least
sugar of all vessels. The great difference, however, that has so often been
found is i7i part the effect of a marked increase in the production of sugar
in the liver from nervous causes during the experiment. Mosse, who arranged
his experiments with a view to the elimination of this influence, found only



*" Pfliiger's Archiv," 1894.



METABOLISM AND NUTRITIVE NEEDS.



189



0.107 per cent, of glucose in the hepatic veins; the portal vein rarely contains
less than 0.08 or 0.09 per cent. After the ingestion of large amounts of carbo-
hydrate the portal vein may contain as much as 0.4 per cent., and much more
than the hepatic veins (v. Mering).

The accompanying table, showing the results of Seegen's experiments, illus-
trates the influence of diet on the amount of glycogen in the liver and the
amount of glucose in the blood. The figures representing the amount of
glucose in the hepatic veins probably are much too high, from the influence of
the experiment on the nerves ; and all the figures relating to glucose in reality
represent both glucose and other reducing-substances. Nevertheless, I con-
sider the relations of this conscientious experimenter's figures to be of great
value. The observations were made upon dogs that had been subjected to
starvation for eight days, and were then fed exclusively on one of the several
kinds of food named. I would call attention to the most important fact that
both glucose and glycogen reach their lowest figures when the period of pre-
liminary starvation is followed by a period in which the only food is fat.



Food.



Glucose.



Carotid.



Portal Vein.



Hepatic Vein.



Glycogen

IN

Liver.



None,

Fat,

Muscle,

Starch, .

Cane-sugar, ....
Cane-sugar and dex-
trin,



0.157 per cent.
0.128 "

0-I55 "
0.165 "
0.165 "

0.176 "



o. 147 per cent.
0.I14 "
o. 141 "
0.147 "
0.186 "

0.258 "



0.269 P^"" cent.
0.217 "
0.281 "
0.261 "
0.265 "

0.327 <'



1.67 per cent.
0.93 "

3-7

6.0 "

9.4



Chauveau and Kaufmann, in 1886, brought to light important facts in con-
nection with the consumption of glucose in the muscles. They determined the
amount ,of both carbonic acid and glucose in the blood from the masseter
muscle and from the parotid gland, having previously made a corresponding
analysis of the blood in the carotid. This artery supplies the muscle and
the gland with about the same amount of blood, which in both is about three
times as large during functional activity as during repose. During functional
activity the muscle consumed about 5^ times as much glucose as the gland
and produced about five times as much carbonic acid. The muscle in exercise
produced about 3^ times as much carbonic acid as in repose, and also con-
sumed about 3>^ times as much glucose. With the gland, the figures during
functional activity and in repose were as 87 : 60 with regard to the production
of carbonic acid, and as 90 ; 70 with regard to the consumption of glucose.

Quinquaud found from 0.12 to 0.15 per cent, of glucose in the femoral vein
before, but only 0.07 per cent, after strong faradization.



As soon as the sugar in the blood reaches a certain amount,
which Claude Bernard found to be about 0.25 per cent, in the dog,



IQO DIABETES MELLITUS AND GLYCOSURIA.

it begins to pass over into the urine. Lepine, immediately after the
beginning of the glycosuria in diabetic dogs (following extirpation
of the pancreas), found between 0.19 and 0.24 per cent, of glucose
in the blood. Seegen's figures indicate that glycosuria in man may
exist with less glycemia than 0.20 per cent. Still, there seems to
be a certain interval between the ordinary glycemia, which only
rarely exceeds 0.15 per cent., and the decided hyperglycemia, in
connection with which glycosuria begins. Thus, we find glyco-
suria often absent in states that bring about hyperglycemia — £■ g-,
asphyxia. Carcinoma is usually (Freund), though not constantly
(Matrai), attended with hyperglycemia, but is often found without
glycosuria. In cases of simple glycosuria only the highest degrees
of glycemia give rise to glycosuria, which appears for only a short
part of the day some time after meals. In cases of diabetes there
is always hyperglycemia in the severe and often in the light stage.
It rarely exceeds 0.4 per cent., but much higher figures are occa-
sionally reached. Pavy found 0.57 and Hoppe-Seyler 0.9 per
cent, of glucose in the blood. Investigations have proved that
the glycosuria bears no fixed relation to hyperglycemia (Seegen,
Lepine, and others). Seegen found 3.8 per cent, of sugar in the
urine and 0.182 per cent, in the blood ; and afterward, in the same
(mild) case, 0.6 per cent, in the urine and o. 181 per cent, in the
blood. In a severe case during the observance of a strict diet he
found 0.6 per cent, in the urine and 0.19 per cent, in the blood.
We thus see that the hyperglycemia, even with considerable gly-
cosuria, may be quite moderate. Still, the hyperglycemia consti-
tutes the real '^ nocens'' — the sugar in the urine, which alone we
are generally able to observe, is of small account. A moderate
hyperglycemia, however, is certainly capable of only a moderate
noxious influence. We are terrified on finding a glycosuria of 3.8
per cent, in a patient, but should be much less alarmed if told at
the same time that it resulted from a hyperglycemia of only 0.18
per cent. Every one understands at once that if it is normal for
the blood to contain 0.12 per cent., or even 0.15 per cent, of glu-
cose, it does not constitute a very great danger for it to contain
0.18 per cent, of glucose.

I now arrive at that much-discussed question whether hypergly-
cemia and glycosuria — i. e., diabetes mellitus — arise from an in-



METABOLISM AND NUTRITIVE NEEDS. I9I

creased production or from a decreased consumption of sugar, or
from both of these causes.

The first essential difference in metabolism between the normal
and the diabetic individual is met with in the liver, which exhibits
a decreased capability of storing glycogen. The opinion is held
by many that this deficiency of forming glycogen — which may
afterward be used for producing fat, or, in case of need, may be left
to the blood as glucose — is the immediate cause of diabetes. The
liver is incapable either of keeping the formed glycogen in that
state or of transforming enough of the glucose derived from the
food into glycogen, and thus it produces or permits too large quan-
tities of glucose to escape into the circulation. Claude Bernard
believed the increased production of sugar in the liver to be a result
of hyperemia and of the action of the diastatic ferment in the blood
in attacking the glycogen too vigorously — ^^ V augmentation de
rapidite de la circidation du foie accrdit la glycemie."

Others — e. g., Zimmer — sought to find the root of the evil in the
muscles and in an impaired consumption of the sugar of the blood.
When in these latter days it was discovered that extirpation of the
pancreas causes diabetes, and that extirpation of the thyroid gland
causes myxedema, Brown-Sequard formulated the theory of an
" internal " secretion of the glands in addition to that which had
hitherto alone been observed. The profession, as already men-
tioned, for a large part adopted the view that the pamcreas, through
an internal secretion, sends into the blood some substance necessary
to the combustion and the utilization of the sugar.

Claude Bernard was familiar with this " glycolytic ferment," or,
as Nommes calls it, the "glycolysine." It is this ferment that
drives the sugar out of the extravasated blood in about twenty-
four hours. Bernard used acetic acid, carbolic acid, or sodium
sulphate to prevent or retard this disappearance, Lepine has pro-
posed as a unit of glycolytic power the relative quantity of sugar
that disappears from the blood in one hour at a temperature of 38°
C. (100.4° F.). The normal unit is about twenty per cent, of the
whole amount. According to Lepine and Barral, the glycolytic
power — which seems to be subject to great variations within the
normal — is quite low at a temperature of 15° C. (66° F.), but it
increases then for a while with the higher temperature, and is very



192 DIABETES MELLITUS AND GLYCOSURIA.

Strong at 40° C. (104° F.). At 52° C. (125.6° F.) it suddenly
decreases, and is annihilated at 54° C. (129.2° F.). Lepine and
his disciples have made extensive researches upon the glycolytic
ferment, which, according to that observer, is partly, but not ex-
clusively, formed in the pancreas, and is delivered to the blood and
the lymph ; it is, further, chiefly, but not exclusively, fixed in the
Avhite blood-corpuscles. Spitzer found the glycolysis effected both
by the red and the white blood-corpuscles. The process is one of
oxidation, oxygen being taken up and carbonic acid produced (Kraus,
Spitzer). Barral found that oxygen and ozone slightly increase, while
rarefied air, carbonic acid, and carbon monoxid diminish the glyco-
lytic power. Acidity also lessens and finally annihilates the glyco-
lytic power. This is also the effect of antipyrin (Lepine and Barral,
Brouardel and Loye), of sodium carbonate, of morphin, and of vale-
rian (Butte). Colenbrander made the observation that the glyco-
lysis is destroyed by the extract of leeches. Curare augments it
somewhat (Butte). The glycolysis is about as energetic after as
before defibrination (Dastre).

Lepine considers that there is a certain alternation between the
"internal" secretion (of the glycolytic ferment) and the external
secretion (of the pancreatic juice) in the pancreas. By irritation of
the peripheral stump of the pneumogastric nerve Lepine caused
increased secretion of pancreatic juice, and found that at the same
time the blood from the pancreatic vein had almost entirely lost
its glycolytic power, which afterward returned, when the external
secretion had moderated.

After ligation of the pancreatic duct the glycolytic ferment in the
blood is increased, probably as a result of pressure on the glandu-
lar cells in consequence of stasis.

In cases of diabetes the glycolytic ferment in the blood is
markedly diminished, according to Lepine and many others ; there-
fore less sugar is consumed in the tissues, and hyperglycemia, with
its various consequences — /. e., diabetes — arises.

Lepine and Metroz * found that in normal blood — at 37° C.
(98.6° F.) — the sugar had decreased, as a result of glycolysis,
from 0.13 per cent, to o. 10 per cent.; i. e., the blood had lost

* " Compt. Rend.," 1893.



METABOLISM AND NUTRITIVE NEEDS. 1 93

23 per cent, of its sugar. In diabetic blood under the same
circumstances the glycolysis may bring down the sugar from
0.32 to 0.29 per cent., and the loss amounts to less than 10 per
cent. Not only the relative, but also the absolute, loss of sugar is
smaller in diabetic than in normal blood ; but relative loss is the
one to be taken into consideration. Lepine and Metroz have found
that a liter of normal blood customarily loses in the course of an
hour about 0.20 gram of sugar, but that an addition of glucose to
this same blood may cause the loss, under otherwise the same cir-
cumstances, to amount to 0.60 gram.

Lepine observed chyle from the thoracic duct of a normal dog
injected in the veins of a diabetic dog diminish for a short time the
glycosuria. Lepine and Barral, by adding such chyle to a solution
of glucose in water, also produced "glycolysis," with loss of glu-
cose. They also found the normal difference between arterial and
venous blood decreased in diabetes. By driving the blood through
the extirpated kidney of a dog in Jacoby's apparatus they proved
that loss of sugar takes place in the tissues independently of ner-
vous influences.* For the details of the extensive researches of
Lepine and his disciples I must refer to his own treatises.

Hedon also, by a series of investigations, has tried to establish a
defective glycolysis in cases of diabetes and to exclude an increased
production of sugar in the liver. He maintains that on separating
the liver from the circulation the sugar disappears (by glycolysis)
from normal, but not from diabetic, blood. Minkowski submits that
this last fact may depend upon an abnormal transformation into
glucose of the glycogen of the muscles. For other results of
Hedon's researches also I must refer to the original communica-
tions.

Several experimenters, and especially Minkowski, have come to
other conclusions than those of Lepine. Minkowski found the
glycolysis in the blood of a diabetic dog to be quite normal, and he
was not able to reduce the glycosuria by injections of glycolytic
ferment or of pancreatic extract ; he points out that the experiments
with Jacoby's apparatus do not exclude postmortem changes —
Qui z'ivra, verra !

* Barral, " Sucre du Sang," Paris, 1890.



194 DIABETES MELLITUS AND GLYCOSURIA.

Lepine also mentions a '' pouvoir saccliariferant'' of the blood.
While the '' pouvoir glycolytigue " ceases at 54° C. (129.2° F.),
the saccharification, which is effected in the serum, is at its best at
from 56° to 58° C. (132.8° to 136.4° F.), and gives rise to the pro-
duction of about one gram of sugar to the kilogram of blood. The
material for this production of glucose is, according to Lepine {vide
Seegen), left by peptones. The '^ pouvoir sacchariferant," like the
" potcvoir glycolytigue," is increased by acute, but reduced by slow,
asphyxia.

Lepine, while laying the greatest stress on reduced " glycolysis "
and diminished consumption of sugar as a cause of diabetes, pru-
dently does not deny an increased production of glucose as an addi-
tional cause. It is interesting to note Kaufmann's plea * for the
view at which he and Chauveau have arrived as a result of numerous
experiments. The production of sugar is, according to Kaufmann,
like the oxidation in the lungs, a regulative function of one organ.
The consumption of sugar, on the other hand, is a common quality
of the different tissues, which consume sugar in order to be able to
perform their functions, but which do not perform their functions
for the purpose of consuming sugar. When a deviation from the
normal takes place, it is more reasonable to look for the cause in the
organ among whose functions is the production and distribution of
sugar — i. e., the liver — than in those organs that have only indirectly
anything to do with the sugar. In hibernating animals, in spite of
their comparatively profound muscular repose, one does not find
hyperglycemia but hypoglycemia, and only when they return to
muscular activity does the sugar in the blood reach its full amount.
In this instance production is seen to depend on consumption.
Chauveau and Kaufmann, in 1893, demonstrated the fact that the
sugar increases in organs, especially in muscles, when they are
occupied in their functions. By administering large amounts of
glucose or by injections of glucose into the portal vein one may
induce a glycosuria that manifestly has nothing to do with
diminished consumption, but with the overstraining of the liver's
capability of transforming and storing glucose in the form of
glycogen. This capability is reduced in cirrhosis of the liver ; this

* " Sem. Med.," January l6, 1895.



METABOLISM AND NUTRITIVE NEEDS. 1 95

is the cause of the frequency of glycosuria in connection with that
disease. Kaufmann further calls attention to Dastre's view that in
cases of asphyctic glycosuria the asphyctic blood causes an abnor-
mally large production of sugar in the Hver by stimulating the
organ to increased activity. In the course of glycosuria due to
other poisons (curare, morphin, and anesthetics in general) there is
certainly a reduction in oxidation and in consumption ; but the
glycosuria is not caused by this, being often developed during the
stage of excitement, before the decrease of oxidation and consump-
tion ; under these conditions also the glycosuria results from
increased production. After Bernard's puncture, with the develop-



Online LibraryEmil KleenOn diabetes mellitus and glycosuria → online text (page 20 of 38)