(Laboratory Research Enterprises, Inc. Kalam- azoo, MI, USA). As control cases for ..... atic polypeptide (HPP) to a population of islet cells. Cell Tissue Res 156: ...
んοど5∫ J Tοメデ θ ο′r'α ′
67-7砺
/99フ
ABNORMAL PROLIFERATION OF PANCREATIC ENDOCRINE CELLS IN BEAGLE DOCS Osamu Katsuta andヽ linoru Tsuchitani Mitsubishi Kasei lnstitute oF Toxicological and Environmcntal Scicnces
lsao Narama lnstitute or Drug Sarcty,setsunan University
Abstract i
Of 164 dogs used in routine toxicity studies,scven male and three female Beagle dogs 6 to 17
months of age wcre Found to have spontaneous proLferation of pancreatic endocrine cells, consisted of various combinations of irrcgular―
The changes
shaped isiets,the budding oF endocrine cells rrom ductal
epithelia, beta cell nesidioblastosis conaposed of a fe、 v bcta cells, rocal adenOmatous proliferation of endocrine celis,and prominent ductulo― insular coコ nplexes The prOliferated cndocrine cells、 vere slightly vere interspcrsed、 vith ductular enlarged containing numerous minutc granules in their cytoplasm and、
cells
vas seen in beta and delta cells, and pancreatic lmmunocytochcmically, a moderate increase 、
polypeptide cells、 vere rrequently observcd in thc nesidioblastic lesions,suggesting that ncsidioblastosis might have occurred as a regenerative changc stimulated by the destruction oFexocrinc tissue
(J TOXicol
Patho1 5:67∼ 76,1992) Key wordsi
Dogs,Inlmunocytochemistry,Nesidioblastosis,Pancreas
This rcport describes the histopathology and Introduction
immunocytochemistry of ten canine cases
ln human pathology,nonneoplastic diffuse or hyperplasia of pancreatic islets,
disseH五 nated
known as nesidioblastosisl-17, waS arst described
as arising from pancreatic ducts or ductules in infants.
と
Using ilnmunohistocheolistry, Heits multifocal ductulo―
nesidioblastosis. ⅣIlaterials and Mcthods
И々Jttα な
,ど
と 716 found a combination of large cell clusters, Hlicro― adcnomatosis,and
of
insu―
Seven male and three femalc Beagle dogs,6 to
17=nonths old, taken frona nve toxicity studies
lar proliれ ration in seven infant patients with
(Table l)whiCh had used 164(94 male and 70
ncsidioblastosis with persistent hyperinsulnemic
female)dogS,Were examined retrospect市
hypoglyceHlia
anirnals werc imported fronl a coHllnercial breeder
Recently, the term ``nesidioblas‐
tosis"has been applied to a wide varicty or path‐
ely The
(Laboratory Research Enterpises, Inc Kalam―
ologic changes2,8,which have also been reported in
azoo,MI,USA).As control cases for immuno―
adults with5,15,16 and｀ Vithoutl,2,3,9,lS hypOglycer五 a.
histoche■listry two male and two femalc Beagle
In ani=nals,ho、 vever,only a fe、 v cases of spontane―
dogs bet、 veen 6 and 17 months old,、 vcre obtained
ous nesidioblastosis have been reported i these
仕om two direrent breeders,Toyo Research Ani―
、 vere in aged horscs10,in Cats19,and in dogs、 vith
mals, Inc. Shizuoka, Japan, and Ridglan Farms,
islet cell tuコ nor20.
Inc, Mt Horeb, Wis, USA. The animals were housed individuany in metal cages(78× 88× 78
勝 田 修 土谷 稔 奈 良 間 功 Accepted ior publication t January 14, 1992 Mailing addressi Osamu ttatsuta,Mitsubishi Kasei lnsti―
tute of Toxicological and Environmental Scienccs, Sunayama,Hasaki, Kashirna, Ibaraki 314-02,Japan
14
CHl)in cOnventional rooms air― conditioned at a temperature of 24± 2° C with 40%to 60%relative hunlidity and a 12-hour light/12-hour dark cycle
They were g市 en commercially available food(Lab
CANINE NESIDIOBLASTOSIs
68
Chow⑥ Puina Taiyo Co,TOkyo,Japan)and tap water α′ ′ カク脇 ilう
〃
iダ
The total numbers of endOcrine
cells in al1 0F the lobules of the pancreatic body
力ο】 οgッ αη′ ′ 櫂μク々ο力ねプ Oθ 力θ 解ねr′ノ ′ ′
rο
dure was followed by counteistaining with Mayer's
hcmatoxylin.
.
,`μ
were
counted
■licroscOpically
under
× 200
Tissues ttom the head,body,and tail of 10%
magnincation,and the number of positive cells fOr
formahn― nxed pancreases were embedded in
each iHununOstaining was compared with that in
paramn.sections(5-μ m thickness)were made
unaIFected control cases,
and stained with hematoxyhn and eosin (】 IE),
ーtests、vere used for the statistical evalu‐ Student's サ
aldehyde― fuchsin, Or by Criinelius' silver impreg―
ation of direren∝
nation method.
dogs,
An indirect peroxidase―
anti― per‐
Non― paired t、 vO― sided
s bet、 veen
aFIccted and control
oxidase(PAP)method21 waS applied, using antisera to porcine insulin, glucagon or sOmatos‐
Results
tatin and synthetic human pancreatic polypcptide
No clinical signs Of remarkable andingS in
(PP),as well as a cOmmercial kit(BiO Cenex
either hcmatO10gy or blood fasting glucose levels
Laborato五 es,Dublin,CA, USA).ThiS prOce‐
were observed in any of the ten dogs exanined
Table l
Sex,Age,B100d Glucose COn∝ ntration,and PrOnles of Toxicity Studies in Ten Beagle Dogs Examined For AbnormaI PrOnferation of Pancreatic Endocine Cells Pronle of Toxicity Study
Case
Sex
No.
Age
Glucose(mg/dl)
(mOnth)
Dose Volume
Female l
Male†
Cheniical Compound
Duration
Administration
(Week)
Route
2
Orally
AfFected Dogs
I 2
M M
6
Ｍ
3
High
1040
11
910
12
102,0
High
Ｍ 一 Ｆ
7
102.0
Low Low Low
Ｍ
6
Low
960(97.0± 91)
Ｍ
5
5,3)*
12
11
4
1090(1128±
8
Calcium antagonist 0 Synthetic Pyrethroid
Orally
insecticide
20
12
1010(Not examined)
Low
Orally
Antihyperlipidemic
drug 30
8
13
F
80.0(86.5± 35)
Middle
Cephalosporinic
31‡
Intravcnously
antibiotics Ｍ Ｆ
9
17
94.0(963± 74)
Low
17
100.0
Middle
20 AntipoHakiuria
52
Orally
agent
Control Dogs
l 2 3
4
M F M
F
6
102.0
Control
6
98.0
ContrOl
17
930
Control
17
1040
Control
Orally
Orally
ⅢMean value± standard deviation of the control group.
I Number oF dOgs used For the study.
‡Administcred for 26 weeks and follOwing 5 weeks∝ ssation
of treatment
Katsuta,Tsuchitani,and Narama
(Table l).
tributed around the proliferated ductules(Fig,4),
At necropsy the pancreas appeared
nOrmal in color, but was reduced in size and 、 veight
No gross lesions
69
someti=nes for血 ing so― called ductulo_insular cOm―
plexes(Fig.5)that COntained atrophied acinar
、 vere detected in any
other organs.
cells as 、 vell as undirerentiated pseudo― ductular
Microscopic examination revealed irregular―
cells.
In two cases examined(caSes Nos.l and 8),
shaped islets,ductulo― insular complexes,budding of endocrine cells,beta cell nesidioblastosis coHl‐
the adenOmatous foci of proliferated endOcrine
posed of only a few beta cells, and focal
cells and ductules werc、 vell― delineated by a thin
adenomatosis in all cases except one(case No,7),
layer of collagen abers from the adiaCent tissue
which showed only focal adenomatosis(Table 2).
(Fig.6). In anOther case (case No.7), such
The changes were most severe in the body of the pancreas Various― sized and irregularly outlined
innltratiOn oflymphocytes and with some nbrosis
adenomatous lesions were associated 、 vith the
islet cen aggregatiOns were dispersed diffusely
ln most cases examined, the acinar structure
(Fig.1),Seemingly formed by the fusion or merg‐
was metamorphosed in association with the
ing of two or three islets(Fig.2).A number of
nesidioblastic changes in the rnargin of the 10bules
endocrine cells in these abnormal islets had oval or
(Fig,7) Acinar cells were atrophied,degenerat‐
spindle― shaped nuclei,、 vere slightly enlarged,and
ed,and irregular― shaped,and had a reduced nuHト
containcd numerous lninute granules in their cyto‐
ber of zymogen granules,、 vith innltration of a re、 v
plasm.
Argyrophilic cells were not increased in
lymphocytes.
number
A single or several endocrine cells、 vere
pr筍 CCted
into the pronferatcd ducts (Fig 3).
By i=nmunocytochemistry, 81ucagon― positivc alpha cens were often seen centrally or dilfusely in
Smali clusters of endocrine cells were often dis―
the islets in both arFected and non― arFccted pan―
Table 2, Summary of Microscopic Findings in Dogs Examined for Abnormal PronferatiOn Of Pancreatic Endocrine Cclls Nesidioblastosis
Case No
lrregular
Ductuloinsular
Conaplex
Budding
B Cell
Focal
Nesidioblastosis
Adenomatosis
Acinar
Atrophy
十
十
十
十
＋
十
＋
AIFected Dogs
Ductal Proliferation
＋
十
０
＋
十
■
＋
十
十
０
＋
十
十
十
＋
十
０
０
０
汁
＋
＋
十
０
＋
＋
＋
＋
十
＋
０
十
十
＋
＋
十
十
＋
０
０
０
０
＋
十
十
＋
十
叶
＋
＋
＋
０
十
十
＋
＋
０
十
０
＋
＋
十
十
Control Dogs 1
0
0
0
0
0
0
0
2
0
0
0
0
0
0
0
3
0
0
0
0
0
0
0
4
0
0
0
0
0
0
0
ホ十 =slight change
l+=mOderate changc ‡叶=SeVere change SO=negative change
CANINE NESIDIOBLASTOSIs
70
Fig l
Pancreasi Case No 9
、 vhich arc degencrated
VariOus―
sizcd and irregular― shaped islets in the oxOcrinc tissue,somc or
lmmunopcroxidase stain for insuln,counterstaining withヽ
yhn,× 125
Fig 2 Pancreasi Case No 8 1rregular― shapcd islets IOOked as iF thcy had cOnidcd lm_ munoperoxidase stain for insulin,cOuntcrstain―
ing with Mayer's hematoxylin,×
190
Fig 3 Pancrcasi Case No 10 Beta cells(arrOw) budding rrom ductular epithclia lm【 nunOper― oxidase stain for insulin, cOunterstaining 、 vith Maycr's hematoxylin, × 385
creas,while insulin― positive beta cells、 vere located
(Figs 3)4) Sman aggregates of beta cells were
peripherany (Fig 8), and somatostatin― positivc
frequently encountered in the vicinity of ducts or
delta cens were randonily distributcd within most
ductules,
of the large islets,
In the normal pancreas,single
There 、 vcre slightly to mOderatcly increased
or several PP― positivc cens、 vere more frequently
numbers of PP― positive cells in the ductal prolifer‐
secn in contact、 vith acini or ducts in the periphery
ative lcsions, ductulo― insular cOmplexes, and in
of islets of the tail(lcrt lobc)than in the other
thc periphery of rnetamorphosed islets(Fig,9).
reglons,
In the attccted pancrcas, most of thc abnor― mally prOliferated cndocrine cells 、 vere beta cclls
,t
layer's hcmatox―
Quantitat市 e assessment for relat市 e propoト
tion Of cen types(dircrential endOcrinc cell counts)by inllnunocytocheHistry rcvcalcd that,in
Katsuta,Tsuchitani,and Narama
71
Fig.4 Pancrcas; Case No.10 Small clusters of endocrinc cells ciosely associated with ductules or intercatated ductules lmrnunoperoxidase stain for insuin,counterstaining with Mayer's hematoxy― lin,× 385
Fig 5
Pancreas;Case No 8
Ductulo insular complex Note pronferated ductular cells(arrOW)and
atrophic acinar cells(arrOwhead). H,E.,×
control cases,about 5,220(3,000 to 10,000)endO‐ crine cells、 vere counted in the body region of the
pancreas(Table 3).
In dOgs、 vith nesidioblastosis
423
Discusslon
ln the present study, 10 of 164 (6.1%)caSes
the relative number of alpha cens was significantly
sho、 vcd
decreascd(21.6± 2.6%in control pancreas versus
the pancreas.
16.0± 42%in
aFfected pancreas).Ahhough there
between the occurrence of nesidioblastosis and the
was no signincant change in the number of beta
experilnental treatlnent,although the anilnals、 vere
and delta cells,PP― positive cells were numerically
taken froni toxicologic studies,
increased in arected pancreas as compared with the normal pancreas,
various degrees of rnicroscopic changes in There seemed to be no relationship
These histologic changes rnay be considered to be nesidioblastosis2,8,20
The Fusion of two islets
vere charac― and enlarged cytoplasm and nucle17 、
「
CANINE NESIDIOBLASTOSIS
72
Fig 6 Pancreasi Casc No 8
HE,×
Fig 7
Focal adenomatous iesion consisting or cndocrinc and ductulal cc‖
s
423
Pancrcasi Casc No l
Distorted cxocrinc tissuc
Note acinar atrophy
、 vith irregモ llar― shapcd
acini An cxOcrinc apoptosis is sccn(arrO w) HE,× 423
tcristic andingS
Budding clumps of ductal cpith―
incrcascd numbcr oF PP― positivc cens ln dogs,
elia,composed of alpha and bcta cells,havc bccn
thesc cclls havc bcen fcportcd tO bc rrequcnt only
dcscribcd in Othcr animal specics18,19, as、 vcn as in
in the right lobc22 and processus uncinatus23,24
1,14)16
1n
suCh Clumps 、 vcrc oftcn Ob― scrvcd in cases in the prescnt study,although here
the prcsent cascs,including thc cOntrols,PP― posi tivc cclls、 vcrc orten obscrved in the body and thc
thcy consistcd Only of bcta cells
relativc number of alpha cells was significantly
tail region(leA lobc)Of thc organ ln nOrmal human pancrcas,PP― positive cells are rcportcd tO
decrcased, it、 vas thOught that this、 ハ /as duc to thc
usuaHy constitute from 0 5% to 20% or thc total
modcrately incrcased numbcrs of othcr ccH types
islct cell populationll,22
humans9,4-7,9,ユ
Although thc
The rnost intcrcsting nnding was thc relaと ively
1n thc prcsent sttudy,
,vhilc thc proporttion of PP―
positivc ccns in thc
Katsuta,Tsuchitani,and Narama
a
73
b
Fig,8
Pancreasi Control No 3 Normal islets Beta cells(Fig 8a)are 10Cated peripherally,while alpha ce■ s(Fig.8b)are 10Cated centraHy lmmunoperoxidase stain for insulin (Fig 8a)and giucagon(Fig 8b),counterstaining with Mayer's hematoxylin,× 297
Fig,9 Pancreasi Case No l Moderate increase of pancreatic polypeptide ceJs in a lesion shOwing acinar degeneration and ductular prOliferation lmlnunopcroxidase stain for pancreatic pOlypep‐ tide,counterstaining with Mayer's hematoxylin, ×423
body region was 10.5± 3.2%in unalfected cases,it
diabetics25, aS Well as in alloxan― diabetic26 and
varied from 8.3%to 22.5%(average,14.3± 4,7%)
hyperinsulineH五 c obese27 ratS,
in affected cases.
occurrence of PP― positive cell hyperplasia in these
The proliferation of these cells
At present, the
was conspicuous in the ductal lesions as well as in
conditions is unexplained,but it has been hypoth‐
ductu10_insular complexes,
esized to be a nonspecinc response to pancreatic
Such proliferation of
PP― pOsitive cells has been reported in some human
endocrine pancreatic tumorsll,12, and in juvenlle
itturyll.
Hawkins
て αと20 eXanlined the normal pan― ,ど
CANINE NESIDIOBLASTOSIS
74
Table 3 Quantitat"e lmmunohistochemical Analysis Or lslet cells in Dogs Examincd for AbnormaI Prohrcration of Pancreatic Endocrine Cclls Dirferential Count of Endocrine Cell(%)
Casc No Beta Ccll
Alpha Ccll*
Delta Ccll
Pancrcatic POlypcptidc ccll
Afrected Dogs
164
109
(1367)
( 906)
63.0
1
(5246)￨ 2 3
4
720
120
(4825)
( 901)
54.8
179
15,8
( 544)
( 481)
( 352)
549
105 (412) 134 (715) H.2 (484)
121
225
( 473)
(884) 194
56.3
620 (2666)
7
8
9 10
Mean vali】 c
8.5
(1669)
(3000) 6
75 (526)
(515) 115
(2154) 5
97 ( 806)
109 (582)
(1032)
162 (696) 156 (655)
10.6
( 457)
514
240
(2159)
(1007)
(381)
63.0 (2282)
193 (699)
( 340)
90 94
515
17.0
155
(2742)
( 904)
( 824)
83 (301) 160 (857) 148
546
181
125
(1510)
( 502)
( 345)
(4H)
114± 27
143」 L47
58.4=L65
16.0±
42
+sta ndard deviation
Control Dogs 1
2
3
4
Mean value +standard
590
187
(5849)
(1855)
648
201
(4323)
(1345)
89
13.4
( 884)
(1327)
89
62
(589)
(417) 123 (536) 100
521
240
H6
(2253)
(1039)
( 500)
548
237
H5
(2535)
(1096)
(531)
( 460)
216± 26
102=L1 5
105± 32
57,7±
55
dcviation キSignincant decrease(Pく (005, analysis or non_paired t、 vo― sidcd Student's
―test) ど
I Number oF posit"e cells,
creases of large breeds of dogs over 6 years Old,
Junction, cither adiacent tO or entrapped nbrous capSule.
revealing that alpha cells werc 10cated peripherally
in the islet, whereas the beta cells werc located
centrally.
The pathOgenesis of human nesidiOblastosis
In thc present study on Bcagle dogs
inverse localization of endocrine cells was seen in
both
normal
and
aFFected
pancreases
、 vith a
has been discussed by lnany authorsl-9,11,13-10,whO
havc suggested histogenic errOr of the endocrinc
The
pancreas beyond birth and during infancy6 and
adenomatous foci 、 ve observed in three cases, in‐ cluding case No.7, resembled the nonneoplastic
exaggcrated or prolonged persistence of fctal insu―
nesidioblastic clusters dcscribed by Ha、 vkins て
1n adults, cystic abrosisl,
α′20ぅ in 20 cases of primary islct cell tumor.
syndrome9,11, pancreatic duct obstructionl, and
Those fOci appeared at the pancreatic― mesenteric
other stirnuh8 might play a signincant rolc in the
,チ
lar tissuc3,7,14; pOssibly due to genetic defects6,13,15
zollinger―
1311isOn's
Katsuta,Tsuchitani,and Narama
progression of nesidiOblastosis,
In aged rats,
cells were suggcsted to be regenerative28,20.
pathology in hyperinsulinemic hypOglycemia of infancy
ductal proliferation and neogenesis Of endocrine In
511-513, 1982.
9 K16ppel,G,Willemer,S,Stamm)B,Hacki,wH,and
crine tissue nlight be induced by a hormone that
Heitz,PU I Pancreatic tesions and hormonal pronlc
compensates for decreased function18.
or pancreatic tumors in multiplc endocrine neoPIasia
In the present study,all the anilnals came from
the same breeder, and there is the possibility of The nesidiOblastic lesions, how―
evcr, were associated 、 vith atrophy)degeneration,
type I
as with inaanlmatory ccn innltration in the intcr―
1l
Larsson,LI: Two distinct types or islet abnOrmaト itics assOciated with endocrine pancreatic tumours
12
Larsson,LI,Schwartz,T,Lundqvist,C,Chance,RE,
Virchows Arch[A]376:209-219, 1977 Sundler, F,Rehfeld,JF,Grimelius, L, Fahrenkrug,
It is possible that when the pancre‐
」, SchaFralitzky, de MuckadeH O, and Moon, N:
atic parcnchyma is damaged or dcstroycd during
Occurrencc of hurnan pancreatic polypeptidc in pancreatic endOcrine tumors t pOssiblc irnplication in thc watery diarrhea syndrOme Arn J Patho1 85: 675-684, 1976
the Fetal or infant period,thc islet cells proliferate
as a regenerative change
The proliferation of
PP― positive cens that we obscrved■ light support this hypothesis
13 Schwartz,SS,Rich,BH,Lucky,AW,Straus,FH II, Gonen,B)Wolfsdort J,Thorp,FW,Burington,JD, Madden,JD,Rubenstcin,AH,and Rosenicld,RL: Familial ncsidioblastosisl scvere neonatal hypo―
Иθ々〃ο,ν ル′ ′ ,Tθ ″ rS f ｀ vc thank Professor Chitoshi ltakura,
Department =θ of Comparative Pathology, Faculty of Veter― inary Medicine,IIoに kaido University,fOr his comments on the man uscript, We atso thank Proressor Kosaku Fttiwara, Departrnent of Veterinary Pathology II,Nthon Univcrsity Vctcrinary SchOol, for his advice in preparing the manu― script
glycemia in twO families J Pediatr 95i 44-53, 1979
14
Hyperinsulinemic hypogtyccm ia of the neonate as―
oF the pancreas
HoHandcr, D, and Wilhams, RH i Familial nesidioblastosis as the predominant manirestation of
multiple endocrine adenomatosis
Brown, RE and Madge,GE I Cystic abrosis and nesidioblastosis
Arch Path01 92: 53-57, 1971
16
Am J Clin Patho1 84: 534-541, 1985 TF:Nesidioblastosis and other islet cell abnormaト ities in hyperinsutincmic hypoglycemia of child―
Hum Pathol ll1 641-649, 1980
NS I Nesidiodysplasia
and
nesidioblastosis
17
the syndrome of hyperinsulinemic hypoglycemia
18
Arch Surg l16: 575-580, 1981
cher,TF:Immunohistbchemical morphomctry of pancreatic endocrine cells in diabctic, nOrmog― lycaemic glucOse― intolerant and normal cats J
Comp Patho1 96: 357-369, 1986
20 Hawkins, KL,Summers,BA,Kuhttda, FP,and Smith, CA: Imrnunocytochcmistry or normal pan―
6 Heitz,PU,K16ppel,G,Hackl,wH,Polaに ,JM,and Pearse, A(3E: Nesidioblastosis i the pathologic basis of persistent hyperinsuLnemic hypoglycemia in iniantsi morphOlogic and quantitative analysis of
seven cases based on specinc immunostaining and clectron microscopy
Diabetes 26: 632-642, 1977.
7 Jarfe,R,Hashida,Y,and Yunis, EJ I Pancreatic
Furuoka,H,Shirakawa,T,Taniyama,H,Ohishi,H,
19 0'bien,TD,Hayden,Dヽ V,Johnson,KH,and Flet―
Harness,JK,Ceelhoed,GW,Thompson,Nヽ V,Nishi― yama,RH,FaJans,SS,KraFt,RO,Howard,DR,and dilemma
Yakovac,ヽ VC)Bakcr,L,and Hummeler,K I Beta
Satoh,H,and ltakura C t Histogenesis or neoforma― tion in thc endocrine pancreas of aging horses Vet Patho1 26: 40-46, 1989
Pcdiatr Pathol l: 7-31, 1983
Clark, KA: Nesidioblastosis in adultsi a surgical
Arn J Clin Pathol
cell nesidioblastosis in idiopathic hypOglycemia oF inrancy J Pediatr 79: 226-231, 1971
of vith
cell hyperplasia and dcgranulation of
exocrine cens Or the pancrcas 7': 14-24, 1983
4 Gould,VE,Memoli,VA,Dardi,LE,and Gould, infancy: structural and functional correlations、
」r: Hyperinsulinemic hypoglycemia in adults
with islet―
pathologic Features and in vitro pancreatic studies
Dahms,BB,Landing,BH,Blaskovics,M)and Roe,
Weidenheim, KM, IIinchey)ヽ VW, and Campbcn,
WG
pancreatic islet ce‖ hypcrplasia in an adulti clinico―
hood
Am J Med 52:
211-227, 1972
and Enis, DW i Nesidioblastosis and muhifocal
5
Ann Surg 191i 182-186, 1980
15 Vance,JE,Stoll,RW,Kitabchi,AE,Buchanan,KD,
2 Campbell,IL,Harrison,LC,Ley,C」 ,Colman,PG,
3
Shermeta,DW,Mendelsohn,C,and Haller)JA Jr: sociatcd、vith persistent fctal histology and function
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CANINE NESIDIOBLASTOSIs
76
atic polypeptide(HPP)tO a population ofislet ce■
s
26
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