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and even an ounce; and the citrate of potash, six drachms; yet, I
have never succeeded in rendering the urine alkaline, or in any way
approaching this character."

Seegen was also prominent in the battle over the glycogenic hy-
pothesis. He laid down the principle that every prolonged glycosuria
should be considered an incipient diabetes. His therapy was retro-
grade in two points: he ignored the total quantity of protein and fat
ingested, and lie denied the value of exercise, in the belief that it was
based on a false theory.

Von Pettenkofer and Voit published the first study of the respiratory
metabolism of a diabetic patient. They made the interesting remark
that they dared not inflict much fasting on a diabetic, because of the
great hunger and the difliculty of rebuilding lost tissue. Their work
was originally supposed to show a subnormal oxygen consumption by
the diabetic. Reynoso had previously attributed diabetes to dimin-
ished respiration. Ebstein (1836-1912) devoted extensive labor to the
attempt to prove that as CO2 inhibits the diastase of saliva, pancreatic
juice, and organ extracts, so also it inhibits diastase in the living body,

="8 Cf. Editorial, J. Am. Med. Assn., 1913, Ix, 1159.

^'For earlier, less definite observations, cf. Griesinger, p. 59.



30 CHAPTER I

and that diabetes is due to abnormal diastatic activity resulting from
subnormal production of CO2 in the tissues. In treatment he advised
the usual diet, also carbonated waters. He (1) claimed priority as
being the first to point out the danger of coma when antidiabetic diet
is suddenly begun. He opposed inanition, but considered exercise
beneficial through increased CO2 production. Schnee and a few others
followed this doctrine.

Kussmaul, a pupil of von Frerichs, in 1874 gave the first detailed de-
scription of diabetic coma, distinguished it from pulmonary disease,
uremia, and other terminal processes, called attention to the char-
acteristic dyspnea, and from the physiological action of acetone ob-
served in man and animals cast doubt on acetone intoxication as the
cause of the condition.

After Bouchardat, the most powerful impetus to the rigid dietetic
treatment of diabetes came from Cantani (1837-1893). A pupil
of von Jaksch, he was at once a clinician and an enthusiastic chemist
and theorist. His preface preaches that, however great the achieve-
ments of morphologic pathology, it can show only the form, and never
the process at work; only chemistry can give the solution, and he pre-
sents his findings as a beginning in the pathology of metabolism. His
first chapter lays down the principle that metabolism is disturbed by
excess of any constituent in the diet, and if the excess is prolonged, the
disorder becomes permanent; diabetes and gout are examples. In an
analysis of 218 careful case histories, he showed that carbohydrate had
practically always predominated in the diet; but critics must observe
that Cantani practised in Rome. He believed the greater frequency
of the disease in Italy as compared with Germany and Austria to be
due to centuries of over-rich carbohydrate diet. When nervous shock
or other causes seem to bring on diabetes, he thought that the incipient
disease was generally present before. He admitted that a primary
predisposition must precede, because so many persons can live on
excessive carbohydrate diet and never develop diabetes. He con-
sidered the seat of diabetes to be in "the abdominal organs of diges-
tion, the chylopoietic glandular organs" ( (l), p. 363). Atrophy of
the pancreas present in some of his own cases and those in the litera-
ture was interpreted by him as the result and not the cause of diabetes.
He believed (p. 331) that sugar is mostly absorbed through the thoracic



HISTORY 31

duct and only a small portion enters the liver through the portal vein;
and (p. 257) quoting Kiihne's 1868 text-book of physiological chemis-
try against the glycogenic theory, he expressed surprise that a chemist
like Pavy should believe that the liver could change sugar into glyco-
gen. He thought it probable that the blood sugar in health fails to
pass into the urine because burned in the epithelial cells of the kid-
ney.'" Diabetic symptoms were attributed to the non-combustion of
sugar and its circulation in excess. He claimed to show (pp. 274r-275)
that the sugar of diabetic blood is a so called para-glucose, which is
reducing but non-polarizing and non-assimilable; the kidneys trans-
form it and excrete it in the urine as true glucose. He regarded ace-
tone formation and coma as due to the digestive disorder, and as acci-
dental in character. His treatment set an entirely new standard of
strictness; this was the essential contribution made by Cantani. He
isolated patients under lock and key, and allowed them absolutely no
food but lean meat and various fats. In the less severe cases, eggs,
liver, and shell-fish were permitted. For drink the patients received
water, plain or carbonated, and dilute alcohol for those accustomed to
Kquors, the total fluid intake being limited to one and one-half to two
and one-half liters per day. For flavoring were permitted acetic and
citric acids, and distillate of orange blossoms. Lactic acid was given
regularly as the best substitute for carbohydrate and to aid digestion;
Cantani deemed that by means of it he was enabled to keep patients
on a more rigid diet than any of his predecessors. The quantity of
protein was carefully limited; 500 gm. of cooked meat per day were
considered enough for any diabetic, and 300 to 400 gm. sufl&cient to
maintain strength. The value of vigorous muscular exercise was
recognized, and it was proved by clinical tests that glycosuria was thus
diminished or abolished without change in the diet. If the glycosuria
was not otherwise controlled, fast-days were imposed, as often as once
a week if necessary. On these days nothing was allowed but water, or
sometimes bouillon three times a day. The protocols show a sharp
drop in the glycosuria on fast-days.'^ The duration of this treatment

'" This idea has lately been supported by Reicher, by Pierce, and by Woodyatt.

'' Stokvis (1886) considered fast-days as having only experimental interest,
stating that in Cantani 's records, the glycosuria returned promptly in every case
and not one showed any clinical benefit.



32 CHAPTER I

is also a noteworthy step; the regular period was three months, and
it was extended to six or even nine months if necessary to achieve
sugar-freedom. After two months of absence of glycosuria, green
vegetables were begun; and later wine, cheese, nuts, sugar-poor fruits,
and finally small quantities of farinaceous foods were added. Notice
was taken of the different tolerance for different forms of carbohydrate
(p. 230). Glycerol'^ was found to produce a return of glycosuria in
sugar-free patients (p. 258). The urine was analyzed daily during
treatment, afterward once every week, then every two weeks. The
least trace of glycosuria (p. 229) called for one or two months of abso-
lute protein-fat diet. The patient who could return to moderate car-
bohydrate diet was considered genuinely cured. If a more generous
diet brought a return of glycosuria, it was regarded not as a relapse
but as a fresh attack, caused by the same excess in carbohydrate which
produced the diabetes in the first place. This determined insistence
upon sugar-freedom was Cantani's best contribution; but it was
marred by faults which have persisted since, namely, the high calory
fat diet, the beUef (p. 231) that gain in weight is one of the most
important benefits, and (p. 386) that a slight glycosuria is preferable
to undernutrition. Regarding his failures, Cantani believed (p. 356)
that as long as the pancreas alone, or perhaps the stomach alone, is
diseased, the diabetes is curable in all cases, but after the liver is in-
volved a cure is impossible. He acted (pp. 369-370) on the theory of
sparing a weakened organ. He held the modern view that diabetes
is a unit, and that the varying cases represent different degrees or
stages, not different diseases. He distinguished two groups: cases in
which sugar disappears on meat diet, and those in which it does not dis-
appear. He judged that the lowered temperature and the slowed
respiration were evidence of a diminished metabolism in diabetes. He
thought (p. 203) that diabetes is better borne by fat than by thin people
because of their lower metabolism, and that the greater severity of dia-
betes in young persons and children is explained by the higher metab-
olism. The diminution of glycosuria on fasting was held (p. 190)

^^ Glycerol in the treatment of diabetes was first used by Basham {Lancet,
January, 1854). It was especially advocated by Schultzen (Bed. klin. Woch.,
1872, No. 35) on the basis of an erroneous chemical theory. Cf. Naunyn ( (5), p.
441).



msTOEY 33

to prove that the diabetic's own tissues are not convertible into sugar,
though the glycosuria on meat diet shows that sugar can be formed from
ingested protein. The description (p. 302) of a case of cerebral tumor,
causing paralysis of the optic and oculomotor nerves, with poljTiria
and 3 per cent glycosuria, which cleared up after several months, while
the tumor progressed and caused death, may now receive probable
interpretation at the first mention of h5^ophyseal diabetes. The
infectious nature of tuberculosis being unknown, the development of
pulmonary tuberculosis in a diabetic was to Cantani (pp. 113, 233) a
sign that the glycosuria could never be abolished, that the breakdown
in metabolism was hopeless, and death inevitable.

The authors who described gross lesions of the pancreas in diabetic
necropsies are named by Bouchard ( (1), p. 171) as follows: Cawley,
Elliotson, Bright, Bouchardat, Griesinger, Hartsen, Fles, von Reck-
linghausen, von Frerichs,Klebs, Harnack, Kuss, Cantani, Silver, Fried-
reich, Haas, Lecorche, Lancereaux.^' Zimmer in 1867 supposed that
carbohydrates are normally split to lactic acid in the intestine, but in
the absence of pancreatic juice the process stops at the stage of glucose,
with resulting glycosuria; but later he considered diabetes as a defect
of muscular metabolism. Popper (1868) assumed that diabetes is due
to lack of pancreatic juice, causing disturbance in fat digestion and
secondarily in glycogen storage in the liver. Lancereaux, a pupil of
Claude Bernard, described a form of diabetes characterized by sudden
onset, marked emaciation, polyphagia and polydipsia, characteristic
feces, and early death. He correctly interpreted this complex as
evidence of a pancreatic lesion. Hirschfeld later described similar
cases. But Lancereaux and his pupil Lapierre proceeded to assume
that all diabetes with emaciation is due to a gross pancreatic
lesion; to this diabete maigre or pancreatic diabetes they opposed the
type of diabete gras or fat diabetes, supposedly not pancreatic in ori-
gin. They also added later a "constitutional" or "arthritic" diabetes
and a "nervous" diabetes. This classification has been generally dis-
credited but still persists to some extent in France.

Baumel was the first to set up the hypothesis that all diabetes is

''Other literature is given by Sauerbeck, Rosenberger (p. 206), and Allen,
( (1), Chapter 21).



34 CHAPTER I

pancreatic in origin. When no gross or microscopic alterations could
be found, he assumed the presence of a nervous or circulatory disturb-
ance. Lack of pancreatic diastase was imagined to be the essential
factor, and the inhibition of secretion of pancreatic juice by stimula-
tion of the central end of the vagus was considered illustrative of
what might occur in diabetes of functional origin.

Bouchard followed Lancereaux in regarding diabetes with emacia-
tion as pancreatic in source. He upheld the doctrine of diminished
utilization as opposed to Bernard's view of simple overproduction of
sugar, and he classified diabetes among the diseases due to retardation
of metabolism.

Friedrich Theodor von Frerichs (1813-1885) published a work of
careful objective description, free from theories and preconceptions,
based on an experience of 400 cases and 55 necropsies. His preface
' states that he began with the exact science chemistry, passed thence to
physiology, and thence to the clinic, and writes now in the autumn of
life to present the fruits of nearly forty years' experience. The thor-
ough study and analysis of his cases, clinically, chemically, and patho-
logically, constitute the author's chief merit in extending the knowl-
edge of diabetes. He distinguished three forms of sudden diabetic
death; viz., cardiac failure, collapse, and the Kussmaul coma. To-
day it seems probable that all three are manifestations of acidosis.
By clinical experiments he made the acetone intoxication theory im-
probable. Ehrlich, with von Frerichs, investigated the glycogen in
'diabetes, not only post mortem but by liver puncture during life.
Ehrlich likewise discovered the so called glycogenic degeneration of
the renal tubules in diabetes.

Richard Schmitz of Neuenahr was the first to give conclusive dem-
onstration of complete recovery in a few cases of diabetes. Also,
among his 2320 cases he observed 26 in which the diabetes, in ab-
sence of any other discoverable cause, seemed so definitely to come
on after close association with another diabetic (through marriage or
otherwise) as to suggest an infectious transmission. Senator, Oppler
and C. Kiilz, and others have made it reasonably certain that such
cases represent mere coincidence.

Rudolph Eduard Kiilz (1845-1895) was a similar and even more
notable example of a painstaking, unbiased investigator. To him



HISTORY 35

diabetes was a mystery, toward the solution of which theorizing was
futile and only the gathering of the most complete and exact data
possible could be valuable.'^ In journal articles Kiilz published many
laboratory investigations, especially concerning glycogen. Also,
he discovered the oxybutyric acid in diabetic urine simultaneously
with Minkowski, and was first to observe it to be levorotatory. His
clinical experience of twenty-five years covered 1 100 carefully studied
cases of diabetes, of which 711 were chosen for publication. Probably
no other man ever did so much to clarify the subject by proving all
things and holding fast that which was good. His experiments were
the last which finally ended the error of excess of fluid output over
intake in diabetes. He found sugar absent from the sweat. He
showed the uselessness of lactic acid and the harmfulness of glycerol.
He proved the absolutely negative effects of various drugs, notably
sodium bicarbonate and arsenic, for diminishing glycosuria, aside from
the illness and digestive upsets produced; this lesson of KUlz con-
cerning Fowler's solution still needs to be learned by many today.
He demonstrated with exactness that Carlsbad water has no effect
upon diabetes. Although no valid evidence has ever shown that any
kind of water anj^where has specific influence upon diabetes, this
superstition is still so prevalent among both physicians and patients
that diabetics continue to flock by thousands to mineral springs like
pilgrims to medieval shrines. Kiilz disapproved of the methods of
Bouchardat, who jumped at truths without pausing to prove them;
and much of his constructive work actually consisted in establishing
on a substantial basis the suggestions of the brilliant Frenchman. He
tested the tolerance of many patients for many forms of carbohydrate,
finding ( (2), p. 528) that the assimilation is better for green vege-
tables than for the equivalent of starch in other forms; and that lac-
tose, levulose, and even cane sugar are often better borne than glu-
cose, but results are variable and levulose is often harmful and utilized
no better than starch. He was unable to formulate any fixed rule
whether glycosuria is increased by alcohol or not. By careful com-

^* Preface to "Beitrage:" "Main Bestreben ging vor Allem dahin, moglichst
exacte Beobachtungen zu liefern. In wieweit mir dies gelungen ist, in wie weit
diese Untersuchungen geeignet sind, unsere Kenntnisse von diesem in vieler
Beziehung noch so rathselhaften Leiden zu erweitern, mag die Kritik entscheiden."



36 CHAPTER I

parison between periods of days of rest and corresponding periods
with exercise, he reached the conclusion that e!xercise is beneficial in
strong patients with mild diabetes; in severe diabetes, where sugar
is excreted on carbohydrate-free diet, exercise may diminish glyco-
suria, sometimes only transitorily, or it may have no effect; and
in weak individuals with severe diabetes, there was no benefit
from exercise.'^ The great experience of Ktilz was probably the most
powerful factor in establishing the modern view of the unity of dia-
betes. His cases were classified in three groups; first, a mild group,
becoming sugar-free on strict diet; second, a "mixed" or intermediate
group; and third, the group of severe cases, with glycosuria continu-
ing on restricted diet. The numerous careful case records showed
such an abundance of gradations and transitions between these groups,
from the mildest to the most severe, that fixed distinctions between
types of diabetes were shown to be impossible. Kiilz made no use of
undernutrition or fasting. He treated severe cases by gradual with-
drawal of carbohydrate to avoid coma, reduced protein not below 110
gm. daily, and was one of the first to calculate diets according to the
caloric requirement. He was the first to introduce the practice of
systematically testing the carbohydrate tolerance of each patient.
Rumpf" claims as the greatest merit of the Kiilz system the inaugu-
ration of individually planned diets instead of indiscriminating general
rules. Notwithstanding the universal adoption of this plan by special-
ists and the better informed physicians, it is a regrettable fact that
the majority of the profession have not yet come up to the standard of
Kiilz, and the majority of diabetics still receive treatment by means of
printed hsts of "allowed" and "forbidden" foods. Kulz founded a
numerous and influential school. Of the three editors of his posthu-
mous work, Aldehoff is known for various clinical and experimental
studies, Sandmeyer chiefly for the diabetes produced in dogs by pan-
creatic atrophy, and Rumpf as a prominent clinician, who made early
studies of dextrose-nitrogen ratios in human patients (1, 2, 3), and

^' This was not only the most thorough investigation of exercise in human dia-
betes, but also an important independent discovery, for Kiilz did not know of any
previous use of exercise till after completion of his experiments.

'¬Ђ Preface to Kiilz (2).



HISTORY 37

first (3) warned against loss of body fluid as an important factor in
bringing on coma.

Joseph Friedrich von Mering (1849-1908) was trained under von
Frerichs and Hoppe-Seyler. Though a clinician of high standing, his
fame rests upon his numerous experimental works, among which may
be mentioned his metabolism studies with Zuntz, the discovery (1886)
of phloridzin glycosuria, and the discovery with Minkowski (1889)
of pancreatic diabetes in dogs.

Bernhard Naunyn (born 1839) was the pupil of Lieberkiihn, Reich-
ert, and von Frerichs. Though the author of a number of researches,
they include no important discovery. His position as the foremost
diabetic authority of the time rests upon his influence for the advance-
ment of both clinical and experimental knowledge; upon his judgment,
his teaching, and his pupils; upon the fact that from his great Strass-
burg school have come the soundest theories, the most fruitful inves-
tigations, and the most effective treatment. In birth, it is to be noted
that Naunyn preceded Kiilz, and was only two years younger than
Cantani. He came into this field in the pioneer period when the
principle of dietetic management was generally recognized, but the
average practice, especially in regard to severe cases, was still a mass
1 of ignorance and inefficiency. As late as 1886, Naunyn (1) stood as
the champion of strict carbohydrate-free diet in a German medical
congress where most of the speakers opposed it. As one of the few
early German followers of the Cantani system, he maintained its
feasibility and ultimate benefit, and locked patients in their rooms for
five months when necessary for sugar-freedom. With experience, he
gradually introduced modifications, until the rigid and inhuman
method, which a majority of physicians and patients would never
adopt, became a rational individualized treatment, with a diet reckoned
according to the tolerance and caloric requirements of each patient.
The work of various pupils requires mention in this connection. Im-
portant investigations of metabolism established the basis for this
treatment, the inost notable being that of Weintraud, who proved that,
instead of having an increased food requirement, diabetics could main-
tain equilibrium of weight and nitrogen on a diet as low as or a little
lower than the normal. Minkowski discovered with von Mering the



38 CHAPTER I

diabetes following total pancreatectomy in dogs," and established
the doctrine of the internal secretion of the pancreas, as well as the
first clear conception of a dextrose-nitrogen ratio. After the early
acetone investigations and Gerhardt's discovery of the ferric chloride
reaction had failed to reveal the cause of coma, the Naunyn school
accomplished almost the entire development of the subject of clinical
acidosis in the following sequence. Hallervorden (1880) discovered
the high ammonia excretion, confirming an earlier discredited observa-
ton of Boussingault. Stadelmann (1883) established the presence in
the urine of considerable quantities of a non-volatile acid supposed to
be a-crotonic, correlated the condition with Walter's previous acid
intoxication experiments, and theoretically suggested the treatment
with intravenous alkali infusions. Minkowski proved the excreted
acid to be /S-oxybutyric, and demonstrated the presence of this acid
in the blood and a diminished carbon dioxide content of the blood.
He, also Naunyn and Magnus-Levy, applied the alkali therapy in
practice, and the latter carried out chemical and metabolism studies
which made him the recognized authority in this field. Naunyn intro-
duced the word acidosis, saying in definition ( (4), p. 15): "With this
name I designate the formation of /8-oxybutyric acid in metabolism."
The Naunyn school have consistently maintained that this acidosis
is an acid intoxication in the sense of Walter's experiments. They
demonstrated striking temporary benefits from the alkali therapy,
particularly in diminishing the danger of the change from mixed to
carbohydrate-free diet; but the practical results were never equal to
the theoretical expectations. With Naunyn, also, acidosis became
the principal criterion of severity for the clinical classification of cases.
As regards other theories, the Naunyn school have upheld the deficient
utilization as opposed to the simple overproduction of sugar in dia-
betes. They have clearly recognized the necessary distinction be-

" This is commonly supposed to have been an intentional following up of the
observations of Cawley, Bouchardat, and others. But according to Dr. A. E.
Taylor (personal conmumication) the epoch-making discovery was accidental.
Dogs depancreatized for another purpose were in a courtyard with other dogs.
Naunyn, perhaps mindful of the part played by insects in the history of diabetes,
asked, "Have you tested the urine for sugar?" "No." "Doit. For where these
dogs pass urine, the flies settle."



HISTORY 39

tween diabetes and non-diabetic glycosurias." Naunyn was next
after Klemperer to recognize clinical renal glycosuria. Though
observing that "the course of the disease is as variable as can be
conceived," he nevertheless upholds the essential unity of diabetes,
finding in heredity a link which often connects cases of the most varied
types. In regard to the etiology, he considers that "it is certain that
disease of. the nervous system and of the pancreas can produce dia-
betes;" other causes seem more doubtful. The nervous disorder
supposedly acts indirectly by setting up a functional disturbance in
the pancreas or other organs directly concerned. Underlying every-;
thing in most cases is, in his opinion, the diabetic "Anlage" or inherited;
constitutional predisposition. Naunyn has particularly supported;
the conception of diabetes as a functional deficiency, to be treated by
sparing the weakened function. He wisely emphasized the impor-



Online LibraryFrederick M. (Frederick Madison) AllenTotal dietary regulation in the treatment of diabetes → online text (page 4 of 76)