THE ISLETS OF LANGERHANS
IN PANCREATIC
FIBROSIS
By Yngve Larsson, M.D.
Paediatric Clinic of Karolinska Institutet at Kronprinsessan Locisas Barns/ukhus, Stockholm, Sweden
PEDIATRICs, June 1958
893
D
IABETES MELL1TUS rarely occurs incon-junction with cystic fibrosis of the
pancreas in children. This is noteworthy
when one considers the anatomic relations
of the endocrine and exocrine portions of
the pancreas which are reviewed in this
paper. The effects of experimentally
pro-duced fibrosis of the pancreas on the islets
of Langerhans are reported.
BACKGROUND
OF PRESENT
INVESTIGATION
A close morphologic relation exists
be-tween the two organ systems of the
pan-creas, the exocrine and the endocrine. Both
are developed from the same
undifferenti-ated, ambipotent duct cells; the insular
system is distributed diffusely in the organ
in direct contact with acinar elements, and
no distinct separatory capsule or membrane
is present. A striking feature is that, on the
whole, these intimate anatomic relations
lack any functional or clinical homobogue.
A coincident disturbance of both
func-tions is rare and is, in fact, seen only in
cer-tain severe, destructive pancreatic lesions,
particularly carcinoma and advanced
chronic pancreatitis, with or without
lithia-sis. Under such conditions, the insular
ap-paratus may be damaged, so that diabetes
appears; cases of this nature have been
described by Barron’ and by Lagerlof,2
among others. According to Cliffton,1
Rich-man4 and Zimmermann,5 diabetes occurs in
12 to 13% of cases of carcinoma of the
pancreas, in about 25% of cases of chronic
pancreatitis and in about 11% of cases of
acute pancreatitis. In contrast to this,
hy-perplasia or hyperfunction of the islets has
been described in exocrine pancreatic
dam-age. Thus, it was reported by Terbruggen
(Submitted October 7, accepted November 21, 1957.) ADDRESS: Polhemsgatan 30, Stockholm K, Sweden.
in two cases of carcinoma of the pancreas,
by Brinck and Sponholz7 in one case of
pancreatic lithiasis, and by Ranstrdm8 in a
remarkable case in which a 64-year-old man
became free from diabetes in connection
with chronic pancreatitis.
From the pediatric point of view, it is
especially interesting to note how extremely
seldom diabetes occurs in cystic fibrosis of
the pancreas despite the extensive
destruc-tion of pancreatic parenchyma
characteriz-ing this disease. Thus, in Andersen’s#{176} first
publication (1938), comprising 49 cases,
there was no instance of diabetes. Later,
however, Bodian1#{176} reported 1 case of
dia-betes in a series of 116 cases, and
men-tioned 1 patient with a temporary diabetic
type glucose tolerance test. In a series
more than twice as large, Shwachman et
al.h1 found three cases of diabetes, with
onset at 4, 13 and 14 years of age,
respec-tively. These authors nevertheless stated
that the appearance of diabetes in a patient
with cystic fibrosis of the pancreas implies
merely “the superimposition of one serious
disease on another.” In the series of di
Sant’Agnese,12 comprising 397 patients,
there was only 1 case of diabetes.
The glucose tolerance, determined by
the oral tolerance test, also seems to be
normal in cystic fibrosis of the pancreas.
For example, in Bodian’sbo series, only 1 of
20 patients had low glucose tolerance, and
in the series of Lowe et al.,13 only 3 of 35
patients. It is probable that in such
excep-tions, the decreased glucose tolerance is
due more to such factors as undernutrition,
liver damage and disturbances in
absorp-tion than to impairment of insular
func-tion. A normal glucose tolerance curve in
for making a differential diagnosis between
this condition and celiac disease, in which
the curve often is flattened.”
If the clinical picture thus supports the
concept of a generally normally functioning
islet tissue in cystic fibrosis of the pancreas,
the results of histologic investigations are
more discrepant. It is true that in most
clini-cal reports brief mention is made of the
islet tissue presenting a normal appearance,
and this view is shared by Andersen9 and
by
May,14 but more systematic studies haverevealed definite structural changes.
As early as 1926, Gross15 found distinct
signs of an increase in the number of islets
in 7 of 27 cases of atrophy of the pancreas,
and similar islet hyperplasia was described
by Benoit.16 Baggenstoss and Kennedylt
ob-served abnormalities in 12 of 14 cases, with
the islet cells loosely arranged in bands,
and in some cases intercellular edema as
well. Torgersen18 found communications
between the islets and the duct system in
five cases, and interpreted this anomaly as
a postfetally persisting embryonic stage of
development. According to Bodian,b0 the
islets are qualitatively normal, but they
seem to lie closer together than usual,
prob-ably owing to atrophy of the acinar tissue.
In older children, however, Bodianl0 noted
a definite decrease in the number of islets.
SchultzeJena19 also found a reduction in
the total islet area to the lower portion of
the normal range.
A methodical quantitative study of the
insular apparatus in 10 cases of cystic
fibro-sis of the pancreas was reported by
Meis-sner.2#{176}It showed that the number of islets
per surface unit was greater than normal,
whereas the size of the individual islet was
smaller. This was explained partly by there
being a greater formation than normally
of new islets, deriving from the epithelium
of the cystically dilated ducts, and partly
by the small islets being prevented by
fibro-sis from becoming confluent, and forming
larger complexes. The newly-formed islet
proliferations consisted mainly of silver
cells (alpha cells) but Meissner2#{176} did not
regard it as probable that these cells were
functionally equivalent to fully (lifferenti-ItC(l alpha cells. Seifert’ stu(lied tile
rela-tive proportion of alpha and beta cells in
12 cases of cystic fibrosis of the pancreas,
and found a higher alpha count than
nor-mally. He considered this embryonic
fea-ture to be in agreement with the general
immaturity characterizing the pancreas in
this disease.
The islet tissue has also been the object
of numerous studies in experimental
fibro-sis of the pancreas, after division and
liga-tion of the pancreatic duct. The results of
the various workers are not, however,
in-variably in agreement. For example, as
early as 1902, Laguesse and de Ia Roche2l
found, in an investigation on the guinea
pig, that the islet tissue increased in size,
with concurrent atrophy of the exocrine
tissue, and that the whole organ assumed
an embryonic nature. Similarly,
Herx-heimer23 observed considerable insular
hy-pertrophy after ligation of the pancreatic
duct in hens. The effect was particularly
evident in one animal that died of
hypo-glycemia one month after operation. On
the basis of such findings, Mansfeldl4 and
later De Tak#{225}tsand Cuthbert25 and Koster
et al.26 performed ligation of the pancreas
in diabetic patients, but with completely
negative results.
Both Allen27 and Best28 found, on the
contrary, in experiments on dogs, no
indi-cations of islet hypertrophy, but atrophy
and destruction of islet tissue instead. In
some cases it was so extensive that the
animal became mildly diabetic 3 to 4
months after operation. The cause of these
divergences in opinion may be sought in
species differences. Another explanation
may be that, after ligation of the duct, both
degenerative and regenerative processes
occur concurrently in the pancreas. Thus,
in the rabbit, Bensley29 observed signs both
of atrophy of older, larger islets and of
progressive new formation of islets from
the duct epithelium.
his-Blood
sugarmg/IOO ml
normal child
tbrse children oth catic fibro3se
of the pancreas
FIG. 1.Intravenous glucose tolerance test in normal child and in three patients with cystic fibrosis of the pancreas.
tobogic technique was used in these studies.
This is one of tile reasons for which the
present investigation was made.
PRESENT INVESTIGATION
Clinical Observations
The normal glucose tolerance in cystic
fibrosis of the pancreas demonstrated in
earlier investigations referred only to that
in oral tolerance tests. As already pointed
out, this is dependent on secondary factors,
such as absorption, nutritional state and
liver function. Consequently, it seemed of
interest to evaluate the glucose tolerance by
an intravenous test, which gives a more
gen-nine picture of the ability of the tissues to
take up a certain excess of glucose from
the blood stream.
An intravenous tolerance test, with 0.4
gm of glucose per kilogram of body weight
in 25% solution, was therefore made in three
patients with cystic fibrosis of the pancreas.
The injection was terminated within 5
minutes. The results can be inferred from
Figure 1, which shows that no difference
was present between the glucose tolerance
in these three cases and in a normal
con-trol. Thus, the intravenous tolerance does
not differ from that demonstrated earlier in
cystic fibrosis by means of oral tolerance
tests.
Experimental Observations
METHODS: The experimental animals
con-sisted of adult white rabbits of both sexes. The
glucose tolerance was determined by an
intra-venous tolerance test, the dose of glucose
be-ing 0.4 gm/kg of body weight in 25% solution.
The injection was terminated within 1 minute.
The concentration of sugar in the blood was
determined before the injection and 5, 10, 15, 30, 45, 60, 75 and 90 minutes after its end.
Under ether anesthesia, the pancreatic duct
was ligated at its opening into the duodenum. The size of the islet tissue was determined
with a quantitative histologic technique, on
sections of the serial-sectioned organ at
inter-vals of 1,200 microns. The islet size was
de-termined by measuring with a planimeter the
cut surface of a sample containing at least 200
islets from each animal. The total number of
islets in each section was found by systematic
counting. The relation between alpha and beta
cells was determined by a differential count of at least 1,000 islet cells from each animal. The sections were granule-stained according to
the method of Comori,3#{176} with chromalum
Blood
sugar
mg/ioo
ml100
0
5 1015
A detailed description and discussion of the
methods used have i)een published
else-where.31
RESU LTS
In nine animals, a glucose tolerance test
was made an average 65 days after ligation
of the pancreatic duct. It can be seen from
Figure 2 that, with one exception, the
glu-cose tolerance in these animals lay entirely
within the normal range of variation
ob-tained in a group of 55 untreated animals.
The exception was an animal which
exhib-ited a completely pathologic curve of
“dia-betic” type, with a fasting value of 208
mg/100 ml, a maximum value of 302 mgI
100 ml 10 minutes after injection, and a
final value of 226 mg/100 ml 90 minutes
after injection. This animal had marked
glycosuria for several weeks which,
how-ever, gradually disappeared.
The experiments were ended an average
73 days after operation. The animals had
stood the operation well, showed no signs
of illness, and had all gained in weight.
At necropsy, complete atrophy of the
pan-creas was found in every case. The
paren-chyma had been replaced by connective
tis-sue with plentiful fat. Microscopically,
numerous, often cysticably dilated ducts
were seen, with proliferation of epithelium
but no acinar cells. Between these ducts,
islets of Langerhans were observed, with
an appearance entirely differing from the
FIG. 2. Intravenous glucose tolerance in nine rabbits with fibrosis of the pancreas. The heavy lines denote the 95% limits of variation in a group of 55 untreated
ARTICLES
normal (Figs. 3-6).
The relatively large islets, which occur
fairly regularly in normal cases, were only
infrequently seen. In those present, the
cells were tightly packed, without the loose
interstitial capillary network normally
vis-ible. One had the impression that these
originally large islets had been compressed
by the cirrhotic connective tissue (Fig. 3).
Small islets, on the other hand, were more
numerous. They were often assembled in
groups close to each other, as if they had
originally belonged to a single, large islet,
which had been split by the connective
Fic. 3 (Upper). Rabbit pancreas after ligation of pancreatic duct. A “compressed” islet is surrounded by cirrhotic connective tissue. (Gomori stain, x500.)
Fic. 4 (Lower). Rabbit pancreas after ligation of pancreatic duct. Numerous small
tissue into smaller ones (Fig. 4). Beside the
epithelium of the ducts, large numbers of
small islets were observed; they consisted
of only two or three cells, and often lay
in direct contact with the duct cells in the
same way as in the fetus, where islet cells
are formed from the duct epithelium (Figs.
5 and 6). In general, the microscopic
ap-pearance resembled that of the fetal
pan-creas, but also that seen in cystic fibrosis
of the pancreas in man.
The results of quantitative analysis of the
FIG. 5 (Upper). Rabbit pancreas after ligation of pancreatic duct. Suggested new
formation of islet cells from duct epithelium. (Gomori stain, x500.)
Fm. 6 (Lower). Rabbit pancreas after ligation of pancreatic duct. Numerous small
Islet volume/kg BW
mm3
4.
3
2
No. of animals
Beta cell volume
A.
Untreated rabbitsRabbits with ligated
Alpha cell volume
.
pancreatic ductL,. 10 9 8 11 16
D.
Biliory fistulo rabbit.E.
Biliary stasis rabbitsislet tissue showed that the mean islet area
in the group of animals with ligated ducts
amounted to 1,467 2, whereas in an
un-treated group of controls it was more than
twice as large, i.e., 3,599 2#{149} The difference is significant. This decrease in islet area was
compensated to some extent by an increase
in the number of islets as compared to that
in the controls, but the difference is not
sig-nificant. A conception of the total size of
the islet tissue was obtained by calculating
the islet volume per kilogram of body
weight. In the duct-ligated group, the mean
value of this islet volume was 1.35 mm3,
as compared to 2.98 mm3 in a normal group,
this difference also being significant. Thus,
the islet volume in the animals with
pan-creatic fibrosis was scarcely half the normal.
The smallest islet volume in the whole
group, 0.45 mm3, was noted in the animal
with “diabetic” glucose tolerance and
gly-cosuria. This animal also had the highest
incidence of alpha cells, i.e., 31.1%.
Other-wise, no significant change was observed
in the relative incidence of alpha and beta
cells. Thus, in both the operated animals
and the controls, the incidence of alpha
cells was around 20%. The values for both
islet volume and alpha cell incidence are
recorded in Figure 7, groups A-B.
DISCUSSION
The fact that diabetes did not appear
despite the decrease in islet volume after
ligation of the duct can presumably be
ex-plained by the great reserve capacity of
the islet tissue. By way of comparison, it
can be mentioned that the islet volume in
a group of alloxan-diabetic insulin-treated
rabbits studied with the same method
amounted to only 0.48 mm3/kg of body
weight (Fig. 7, group C). Furthermore, in
such animals, a considerable dominance of
alpha cells was present, the incidence being
about 70%.
It is possible, by means of certain
experi-C.
Allo,an-diabetic rabbitsF.
Pair-fed controlsFic. 7. Volume of pancreatic islet tissue, calculated per kilogram of body weight
mental interventions, to produce pancreatic
conditions that are the reverse of those now
reported in experimental atrophy of the
pancreas. Hypertrophy of the gland occurs
if the bile flow to the intestine is
inter-rupted by creation of a biliary fistula, or
by ligation of the common duct only. The
results of such experiments have been
re-ported in an earlier publication.3’ If the
islet tissue of such animals is analyzed, it is
found that, parallel to growth of the whole
organ, the islet tissue has also increased n
size. The islet volume in groups of such
animals with hypertrophy of the pancreas
is apparent from Figure 7, groups D-E. In
these cases, the change in islet tissue is due
more to an increase in the number of islets
than to an increase in the average islet
area.
Thus, these experiments indicate that the
endocrine part of the pancreas is
structur-ally dependent on the exocrine part, i.e.,
it decreases in size when the acinar
paren-chyma atrophies, and increases in size with
hypertrophy of this parenchyma. This
rela-tion is not entirely unexpected, in view of
the common embryology of both pancreatic
tisues. The experimental results also imply
that the ambipotency of the duct
epith-elium existing during fetal life may, under
certain conditions, appear postnatally as
well.
In addition to the quantitative change in
islet tissue occurring after ligation of the
pancreatic duct, a qualitative change
ap-pears. It is, in fact, impossible to produce
diabetes by administration of alloxan to
such animals with fibrosis of the pancreas,
as can be done in normal animals. This
resistance to alloxan was first described by
Walpole and Innes.32 Although many
the-ories have been put forward to explain this
resistance, it seems most probable that it
is associated with the return to an
imma-ture, prenatal structure which characterizes
the islet tissue after ligation of the duct.
This view is supported by the investigations
of Shultz and Duke,33 who demonstrated
that the animal in utero and the newborn
animal are alloxan-resistant. Further
evi-dence is provided by the studies of Hughes
and Hughes,34 who found young beta cells
to be more resistant to alloxan than older
ones. Moreover, Hultquist and Thorell,35
on the basis of studies with ultraviolet
mi-croscopy, postulated the existence of
func-tional differences between islet cells of
fetus and adult, even when with ordinary
granule-staining techniques they appeared to be identical.
SUMMARY
A survey is given of earlier views on the
occurrence of diabetes and decreased
glu-cose tolerance in cystic fibrosis of the
pan-creas, as well as on the structure of the
islet tissue in this disease and in
experi-mental fibrosis of the pancreas.
Intravenous glucose tolerance tests were
performed in three patients with cystic
fibrosis. of the pancreas, and normal
glu-cose tolerance curves obtained.
Fibrosis of the pancreas was produced
experimentally in rabbits by ligation of
the pancreatic duct. In eight of nine such
animals, the glucose tolerance was normal.
Histologically, the pancreas exhibited total
acinar atrophy, with cystic dilatation of
the ducts, between which numerous small
islets of Langerhans of fetal type were
com-pressed. The general picture was similar to that seen in the fetus and in cystic fibrosis
of the pancreas. Quantitative
determina-tions of the islet volume showed a great reduction in size of the is!et tissue, due
chiefly to a marked decrease in area of the
individual islets. The alpha-to-beta cell
relations were, however, normal.
The results are discussed, and compared
with those in alloxan-diabetic animals and
with animals with experimentally produced
hypertrophy of the pancreas. In the latter
the islet tissue hypertrophies as well (Fig.
7).
The prenatal relations between the
exo-crine and endocrine tissues of the pancreas
may also exist postnatally. The resistance
to the diabetogenic effect of alloxan present
in animals with the pancreatic duct ligated
fetal structure of the islet tissue in acinar fibrosis.
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1. Barron, M. : The relation of the islets of
Langerhans to diabetes with special
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pan-creatic disease studied by means of
secretin. Acta med. scandinav., suppl. 128, 1942.
3. Clifton, E. E. : Carcinoma of the pancreas.
Am.
J.
Med., 21:760, 1956.4. Richman, A. : Acute pancreatitis. Am.
J.
Med., 21:246, 1956.
5. Zimmermann, B. : Diabetes and gross
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J.
Clin. Endocrinol., 14:481, 1954.6. Terbruggen, A. : Untersuchungen #{252}ber
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bei Diabetes mellitus und
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7. Brinck,
J.,
and Sponholz, G. : Hypogly-k#{228}mie und Pankreassteine. DeutscheZtschr. Verdauungskr., 1:3, 1938.
8. Ranstr#{246}m, S. : Insular regeneration med
spontant l#{228}ktdiabetes vid kronisk pan-kreatit. Nord. med., 18:969, 1943.
9. Andersen, D. H.: Cystic fibrosis of the
pancreas and its relation to celiac
dis-ease. Am.
J.
Dis. Child., 56:344, 1938.10. Bodian, M.: Fibrocystic Disease of the
Pancreas: A Congenital Disorder of
Mucus Production-Mucosis. New York,
Grune, 1953.
11. Shwachman, H., Leubner, H., and Catzel,
P.: Mucoviscidosis. Advances Pediat.,
7:249, 1955.
12. di Sant’Agnese, P. A.: Cystic fibrosis of
the pancreas. Am.
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Med., 21:406,1956.
13. Lowe, C. U., May, C. D., and Reed, S. C.:
Fibrosis of the pancreas in infants and
children. Am.
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Dis. Child., 78:349,1949.
14. May, C. D.: Cystic Fibrosis of the Pancreas
in Infants and Children. Springfield, Thomas, 1954.
15. Gross, F.: Pankreasatrophien im Sauglings-und Kindesalter. Jahrb. Kinderh., 112: 251, 1926.
16. Benoit, W.: Hyperinsulinismus bei einge-borener Atresie des Pankreasganges.
Endokrinologie, 16:313, 1936.
17. Baggenstoss, A. H., and Kennedy, R. L.
J.:
Fibrocystic disease of the pancreas: Study of fourteen cases. Am.
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Clin.Path., 15:64, 1945.
18. Torgersen, 0. : Islets of Langerhans in
fibrocystic disease of the pancreas. A
hitherto undescribed abnormality? Acta
path. et microbiol. scandinav., 25:124,
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19. Schultze-Jena, B.S. : Personal
communica-tion to Shwachman et 1
20. Meissner, H. : Uber den Inselapparat bei cystischer Pankreasfibrose und morpho-logisch verwandten Zust#{228}nden des
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21. Seifert, G. : Zur Orthologie und Pathologie des qualitativen Inselzellbildes (nach Bensley-Terbr#{252}ggen). Arch. path. Anat., 325:379, 1954.
22. Laguesse, E., and Gontier de la Roche, A.:
Les ilots de Langerhans dans le
pan-cr#{233}asdu cobaye apr#{232}sligature. Compt. rend. Soc. biol., 54:854, 1902.
23. Herxheimer, G. : Pankreas-zellinseln und
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24. Mansfeld, G. : Versuche zu einer chirur-gischen Behandlung des Diabetes. KIm.
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25. De Tak#{225}ts, G., and Cuthbert, F. P. :
Sur-gical attempts at increasing sugar
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26. Koster, H., Collens, W. S., and Geshwin,
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Mass ligation of the pancreas nearthe head in diabetes mellitus. Proc. Soc.
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29. Bensley, R. R.: Structure and relationships
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34. Hughes, H., and Hughes, C. E. : The
effects of prolonged administration of
small doses of alloxan upon the islet
tis-sue of the rat pancreas. Brit.
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Exper. Path., 25:126, 1944.35. Hultquist, G. T., and Thorell, B. :
Cyto-logical changes during the embryonal
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1953.
SUMMARIO
IN INTERLINGUA
Le
Insulas
Dc
Langerhans
in
Fibrosis
Pancreatic
Le intime relationes anatomic inter le pastes
exo- e endocrin del pancreas es, in general,
disproviste de homologo functional o clinic. Ii
es solmente in certe sever lesiones destructive
del pancreas que le apparato insular es
corn-promittite de maniera que diabete se manifesta.
In fibrosis cystic del pancreas, diabete appare
rarmente in despecto de extense destruction
del parenchyma pancreatic e in despecto del
facto que alterationes in le histos del
insulas-per exemplo reduction del dirnensiones insular
e immaturitate general-pote occurrer in fibrosis
cystic del pancreas. In previe investigationes del dirnensiones del histos insular, basate super
fibrosis pancreatic de production experimental,
le resultatos ha essite contradictori.
Tests del tolerantia de glucosa intravenose esseva effectuate in tres patientes pediatric con fibrosis cystic del pancreas. Le tolerantia in iste
casos esseva normal (Fig. 1).
Fibrosis pancreatic esseva producite in 9
conilios adulte per medio del ligation del ducto pancreatic. Post un intervallo medie de 65 dies,
le tolerantia de glucosa esseva determinate per
un test intravenose. Un del animales exhibiva
un typo “diabetic” de curva del tolerantia. In le altere anirnales le curvas esseva normal (Fig. 2).
Le animales remaneva in bon condition e
ganiava in peso. Illos esseva occidite post un
intervallo medie de 73 dies a partir del tempore
quando le ligation del ducto habeva essite
effectuate. Atrophia complete del pancreas
esseva trovate in omne casos.
Microscopica-mente, numerose ductos a dilatation cystic
esseva vidite, con proliferation del epithelio
sed nulle cellulas acinar. Le histo insular pre-sentava un apparentia anormal (Figs. 3-6).
Grande insulas esseva infrequente, e quando
tales esseva presente, le cellulas esseva paecate densemente sin le laxe rete capillari interstitial que es normalmente visibile. Del altere latere,
micre insulas esseva plus frequente. In multe
casos illos consisteva de solmente alicun cellulas
que se trovava in contacto directe con le
cellu-las ductal, in le mesme maniera como in le
feto quando cellulas de insula es formate ab
le epithelio de ducto. Assi le apparentia
micro-scopic resimilava le apparentia del pancreas
fetal e etiam le apparentia del pancreas afficite de fibrosis cystic in humanos.
Le dimension del histo insular esseva
evalu-tate per medio del quantitative technica
histologic: le grandor e le numero del insulas esseva determinate e etiam le relation numeric
inter cellulas alpha e beta. Le resultatos mon-strava que le volumine insular in iste animales con fibrosis pancreatic esseva a pena un
medie-tate del norma (Fig. 7). Le incidentia relative de cellulas alpha e beta esseva normal.
Pro objectivos de comparation, le volumine
insular esseva determinate con le mesme
methodo in animales alloxano-diabetic sub
tractamento con insulina. In tal animales le
volumine insular esseva ancora plus micre e
amontava a solmente circa un sexto del
volu-mine normal.
In altere experimentos, hypertrophia del
portiones exocrin del pancreas esseva producite
per interrumper le fluxo de bile verso le
intestino. In tal animales le histo insular esseva
augmentate in volumine, parallel al crescentia del organo integre.
Iste experimentos indica que le parte
endo-cnn del pancreas depende structuralmente del
parte exocrin e que le ambipotentia del
epi-thelio de ducto que existe durante le vita fetal
pote, sub certe conditiones, manifestar se etiam a un periodo postnatal.
In animales con fibrosis pancreatic il esseva
impossibile producer diabete per le
administra-tion de alloxano. Iste resistentia a afloxano ha
previemente essite observate. Illo es
probabile-mente associate con le immatur structura fetal
