(SANITIZED)UNCLASSIFIED SOVIET RESEARCH PAPERS ON DIABETES(SANITIZED)

• Document Type: CREST
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): CIA-RDP80T00246A010200100001-6
• Release Decision: RIPPUB
• Original Classification: C
• Document Page Count: 51
• Document Creation Date: December 22, 2016
• Document Release Date: June 30, 2009
• Sequence Number: 1
• Publication Date: April 6, 1960
• Content Type: REPORT

 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
New jd t cL on the Hole of Gamma Amhnobutri c Acid.
T C,1 ? ~u-K C.CL L~G Q^ti ~+h 3 ~t ~~c t B { /Jt oC F~ [,NC N
414
i7 `-a~'.y p S4 Uti? ~A'EV/~N i ffr.nenG4.. 4505
v Recent studies have focussed considerable
attention on gamma..aminobutric acid (GABA). It was discovered
in large amounts in mammalian brain by Roberts et "I,2)
and Awapra at al (3) In I950. The identity of this subetanceA
was proved by Udenfriend l4) in the same year. Widespread
investigations of GABA action followed the establishment by
Bazemore at al (5) and Hayashi at al (6) of its presence in
"Factor I", and the discovery of its inhibitory effect on
nervous activity. According to Mc..Lennan (7) Factor I contains
substances other than GABA the action of which is not always
identical with that ofFactor I . In another report the same
author (8) comes to the conclusion that GABA is absent from
brain containing Factor I. He postulates that GABA Is a frag_
ment of a larger molecule exeiating in Factor I to which he
ascribes inhibitory activity. Inspite of this, GABA generally
believed to play an Important role in the accomplishment of
inhibitory processes. Its effect on blood pressure, respiration
and cardiac rythm has been ascribed to its periferic ganglion
blocking action (9). Despite 'numerous Investigations the true
mechanism of GABA action on nervous processes Is not yet known.
Of spe'ial interest ii its effect on the structure and be.
haviour of synaptic membranes and on those of neurones. GABA
induces a repolatitation (or hyperpolarization) of cell mem.>
brane (10). Koshtoyantz and Kokina (II) have shown that GAB&
and B-alanine have a similar effect on membrane potentials of
organisms devoid of a nervous system, such as infusorla.
Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
According to Botatel & Fatt GABA excercises a similar effect 11 as that observed on the stimulation of the inhibitory fibres
of crustacean muscle. The increase in membrane conductance
observed under the action of GABA and inhibitory fibre stimula-
tion wds Interpreted as an Increased permeability to Cl.(I2).
Studies carried out by us in the course of
a number of years have shown that the hypoglycaemic effect
of insulin is not observed when it ip given on the develop.
1 1.~ ~~ { 1~ t cam. t co , t-~-aC
ment of eorticft? inhibitlo , obtained by extinguishing an
already established conditioned insulin hypoglycaemi 5,,I3-15).
Having In mind the role of GABA j inhibitory
processes and its action on membrane structure, and on the
other hand knowing that one of the main mechanisms underlying
the hypoglycsemic effect of insulin is an enhanced membrane
permeability to glucose (especially in muscle and fat tissue),-
it was interesting to study the effect of GABA on glucose
transport in muscle tissue.
Experiments were made on isolated, intact
rat diaphragm, which according to Kipnis and Cori (16) and
Randle and Smith (17) Is the most suitable object for the study
of glucose permeability into muscle. The diaphragm was obtained
from male rats of 80-120 gre wt. Incubation was carried out
under anaerobic conditions at 37?ror one hour in Krebs-Ringer
bicarbonate buffer at p1i-7.4.In our experiments it was shown
that in::this solution glucose uptake by rat diaghram was more
pronounced than that observed in the bicarbonate buffer used by
Randle (18). 96 by Rand qtylucose was added to IOmle,
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
m S
o* incubation medium to obtain a rinal concentration of 2.5mg
/ml . After incubation its amount was determined colortmetri..
tally by the Sorao3Yi modi.rication or Nelson's method. GABA
was added to the medium to obtain concentrations of 0.5 to 50
)Jg/ml, and crystalline protamine zinc insulin to make I0"3
-0.I units /ml. The results obtained are presented inTable I.
Table I-Comparison of the effect of insulin
(0. I unit /ml) and GABA ( 10 )J&/ml) on uptake of glucose by
isolated rat diaphragm under anaerobic conditions.
(Glucose uptake given in mg. per I gre of wet diaphragm).
Control GABA Insulin Insulin I unl}/mt-
IO JJg/ml 0, I unit/ml GABA IOmg.
~6~ 17t ~2i?40t'S8B t(o?5yjt3 z8i'56j1
* I I
o.) I (ii)
X T64. nu, btr U~ G4 bE i-rntr-4 a AR-- dq u, _ fn.
~ braectf,., 1,111L 0
The results obtained indicate that about
increase, In glucose uptake ensues rrom the addition of inau.
lin(O.I unit/ml). This is further enhanced by the addition of
glutosetnar,t ort ~,owwer,t4}ets date a+H~t oi~?aJtooQw.r
GABA (I0
lT)J
/)
g
m
. he most pronounce addition of GABA and
insulin, where glucose uptake by the diaphragm is increased
'abov'e times.
Being convinced that GABA in IOJTg/mL oonoen.
trations has a greater effect on glucose uptake by muscle
tissue than insulin, we tried the influence of various doses.
The results obtained with 0.5-50,0 pg/ ml amounts are given in
table 110
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6 __ ?
 Table II. The effect of decreasing concentrations or (}ABA
on glucose uptake by rat diaphragm.,
expressed in mg. Per I or. of fresh tissue.
50,4&/.%l
I0 IUSAJ I5pg/m1 IiJtg/ml I0,5 Pg/m1
g 92t i?zy 4.9
r i g - ?~s?5.22 ~Z.~?g.,~ I9 -5 quo Iti 's 2 ~~
(l o _
It is obvious that the effect of (3ABA on
41A., 40-4~
glucose uptake *mw not h the increase of its ooneent _
Oration. On the contrary smaller doses seem to have a grea..
ter influence. Thus , for instance 53tg.aeem to evoke a more
pronounced glucose uptake than that produced by I0 /Ig/ml, An
uptake equal to IOpge was obtained by I )Jg/m1. The consider.
able effect of GABA in such minimal doses is worthy of atten-
tion . Amounts as small as 0.5 ,(Jg/m1 inereaeeoglueose up.
take by about l.fZ_times. From table II it is obvious that
c. C'x C-x about tmo f01dSJ-a-
Here 4t glucose ;uptake of-
Knowing that insulin produces Its effect
in concentrations of ~ecr 'a.
h un1 t#/ml (IV and that its amount
in serum or normal animals and humans ict about 1U,
unl tj/ ml
(19), the erreot or such low concentrations or both insulin
and (}ABA (0.5..I )Tg/ml) were tested. It Has noticed that
I JJg of (MBA greatly enhanced Glucose transport, while 0.5pg
have an effect almost equal to that of r ' u~
Aunoit of insulin
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
In this series or experiments the amount of
glycogen in diaphragm was also determined by the method of
Morris (20). The results obtained are given in table III.
Table III. Glycogen content of rat diaphragm
in mg, per I gr. or wet tissue.
(6)
Insulin
00I unit/ml
2?I2? p6o
c)
GABA
I0/ ml
GABA.Insuiin
IO)zg/m1-0, I unit/m
25? 0OS
()
The data obtained indicate that insulin and
GABA considerably increase glycogen content of diaphragm,
A.
those obtained while studying glucose uptake by muscle tis..
sue froia the incubation medium.
Muscle glycogen was also determined hiato..
chemloally by the method of Bawer. As shown in fig. I.3, a
greater accumulation of glycogen in muscle tissue takes place
in the presence of GABA (IO,ug/ml) than onthe idditlen of
insulin (O.I y'am' ml).
A similar Increase in glucose uptake by
muscular tissue was noticed on the administration of GABA
into the femoral artery under nembutal anaesthesia.
Blood samples for the determination of glucose
were taken simultaneously from the femoral artery and vein.
It was shown that the A..y difference is considerably inereasstl
from I-I0 minutes following its injection.
According to Soskin and Levin (21) Geiger et
Approved For Release 2009/06/30: CIA-RDP80T00246AO10200100001-6
noticeable rise in the amount of glycogen
A _Q nnae
 al (22) and Park at al (23) Insulin does not affect glucose
uptake by the brain. A few preliminary experiments seem to
point to an immediate effect of insulin on brain glucose
uptake namely within 2.5 minutes following its intracarotid
administration, prior to the development of Its hypoglycaemic
effect . From this point of view it waL; interesting to study
the effect of GABA on this process. 'Experiments were carried
out on previously operated dogs where a carotid loop was ob..
tained and the branches of the external jugular vein, all
except the posterior facial, were ligatured. In this way
blood taken from this vein came directly from the longitudi..
nal sinus of the brain. Blood samples for the determination
of glucose were taken from the carotid artery and jugular vein
following the injection of2.0..2,5 )go of GABA into the artery.
Table IV presents the results obtained.
Table IV.. The Effect of GABA on brain glucose uptake.A.V
difference in mg. %.
Prior to GABA injection
'S.17 t tie 8z
After GABA in eotion
m. 1 6m. 1 IOm.
13.84? H?81+ /{?12'
2.g~ g) 3.6g(g) 5 06 W
The results obtained indicate that on the
2nd minute following GABA administration brain glucose uptake
considerably increases until it gradually reaches its pre.
vious amount. This temporary increase In brain glucose uptake
is, most probably, due to its rapid distribution throughout
Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
the body,\except the brain; and its rapid excretion (24).
Data concerning the permeability of QABA
into the brain are contradictory , Marrazzi et al. (25) and
Hayashi at al (6) report an inhibitory effect on central
synaptic transmission following the infection of GABA into
the carotid artery, According to van-Golder and Elliott (24),
no increase in the content of JABA is observed in brain follovo-
ing Its intro peritoneal or intravenous administrations.
Elliott and Jasper (26) find that GABA passes from the blood
into the brain very sparingly. Others claim that it passes
only in areas of local destruction or the blooa brain barrier
(27). At present the enhanced permeability of brain towards
glucose caused by the administration of GABA cannot be ex...
plained . However, the Immediate effect of GAGA on the blood..
brain barrier , as well as its effect on brain glucose metabo.,
Liam and in this way the promotion of its uptakely cannot be
excluded. Experiments dealing with the mechanism of glucose
transport under the action of GAGA are now in progress In or
laboratory.
In connection with these experiments it was
interesting to study the effect of )3 alanlne on glucose up.
take by rat diaphragm. The experiments undertaken were similar
to those described above.
The results obtained are presented in table V
Table V -The Effect of B-alanine on glucose uptake by rat
diaphragm, mg.per 9n. of wet tissue.
b -alani ne &.alanj ne
I O ,ug/ml 20 u g/ml
8 o1 2-01 j2 51 t 2.06 5.9? ?,?95
 From data presented It is obvious that F;_alanine
In amounts of 10-20 jug/ml- considerably Inhibits glucose
uptake by muscle . In this respect it was interesting to
study the effect of B-?alanine on the promotionucose up.
take induced by GABA and Insulin. The results obtained are
presented in tables VI & VII.
Table Vi .. The Effect ofB-alanlne on glucose uptake of rat
diaphragm in the~resence of GABA in nag. per gme of wet tissue.
I
GAB&
IN g/nll. .
1996
GAB:i'.. alanine
50,ug~ 20)j /mi
GABA 2QAj GABAIoaj,
Balnine a, Sal.to ?
BA i,j
1. zgMJ J
Table VII.. The Kffect of B..alanine on glucose uptake of rat
diaphragm in the presence of insulin In mge per gm. of wet
tissue.
Control
Insulin
B..alanine IOfJ/ B-alaninelo?8
alanin~/O
O.Iunit/ml
ina.O.Iunit/w4 ine.O.Iunit/
ins. 10_ u~'.,e
g.g~?l.3z
t9. 3 I28
l~?93?0.85 19?05*_o.45
I~
3
3) o
s)
From the table vi and VIty'ls obvious that
palanine considerably inhibits the effect of GABA on glucose
transport, while the action of insulin remains almost un.
changed.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
A number of investigators have demonstrated
that large concentrations of W_ amino acids (C2-C5 ) have
an inhibitory effect on nervous activity similar to OABA.
However, there are some indications that the previous
administrations of Baalanine inhibit the effect of (}ABA (2e),
In this respect the results obtained by us in regard to
P>alanine are of some interest. It may be concluded that the
action of B..alanine on the effect ofGABA is of a competetive
nature.
Hietochemical studies have shown that insulin and
GA BA increase the content of the basal substance of the oonneg
tiara tissue enveloping the muscle fiber
1. e..*hs acid
muoopolysaeoharides.) These have been detected through their
------------------------- ---
metachrometic staining property with toliudine blue and also
by the method of Halle (29), based on the affinity of the acid
mucopolysaceharides to absorb colloidal iron. The sections abe
subsequently embedded in potassium ferrocyanide and Prussian
Insulin and
lug of acid
ties of the
account for
at the sites of acid muoopolyaaeeharides.
GABA seem to produce depolimerization and swell.
mucopolysaccharid es. Such changes i+he proper..
main substance ofconnective tissue may partly
the increase.in muscle permeability to glucose.
This problem, however, needs further study.
The following question arises; Has GABA any
role in the transport of glucose or any other substance in th e
organism? The results of our experiments seem to be in accord
with such an idea. GABA in minimal amounts such as 0.5 pp~ml,
1
induce a marked increase in glucose uptake by muscle and in
Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 CIA-RDP80T00246A010200100001-6
- 10 -
Its glycogen content. With the exception of the brain, other
organs contain very small amounts of GABA (from 0.2-I0 }tg/gr,
of tissue) (30). These small amounts, however , according to
our experiments, seem to have a considerable effect on gluooal
uptake. The question, whether insulin may produce its effect
on glucose transport in muscle through the enhancement of
GABA formation remains to be answered. Our experiments demons
trate the inhibitory effect of P..alanine on the increased
glucose uptake produced by GABA. Such an effect of P.alnine
was not observed in respect to insult.. In this connection
the action of and insu.lib on glucose uptake by brain is
of interestt~. too. As mentioned above, GABA enhanced the pene-
tration of glucose into brain after Zmin. following its injeo.
tion?Insulin seems to have a similar effect:
4,1001, 4 3-- glucose uptake by muscle through different mechanisms. The
1n.Su -C~ln whk final elucidation or this problem, however, remains to be
% LA LA-- \ V'von.
According to a number of investigatbra, as
for instance, Gravioto et al. (31), Dawson (32) and van.
Gelder and Elliot (33) in insulin hypoglycaemia, the amount
of CIABA in brain is decreased. This Is obviously due to the
fact that during insulin hypoglyoaesla brain consumes almost
no glucose, thus the formation of GABA by way of glutamio
acid cannot take place.
It is generally accepted that insulin does
not affect the glucose metabolism of brain . However, !n
muscle tissue ,by promoting glucose transport and oxidation,
it Increases the formation of glint aoid through the tri.
 oarboxylio acid cycle . The main route of GAGA formation is
through the decarboxylatlon of giutamio acid by the action
of the corresponding deoarboxylase~the activity of which is
very high In brain and very insignificant in other tissues.
On the other hand, the extensive distribution of GABL indi.?
cartes that its formation in other ways cannot be exetndede
The, restu to obtained by us, together with
data from the literature, indicate that GABA has a widespread
effect in animal organisms and that its function cannot be
restricted to that of an inhibitory transmitters MoKhann and
Tower (34) question 9e the role of GABA as a factor taking
part in thcmediation of inhibitory impulses They find that
its presence in brain In large quantities and its high turn-
over-rate are not indicative of its role as a neuro..humor.
They suggest that GA BA affects brain function by participating
in Its energetic metabolism.
The question oonoernig the neuro.humoral
action of (MBA lies out of the scope of this report,+ -hvwVVW
But it is evident that the role of GABA in the organism oan>
not be confined to this It may participate in the energetic
metabolism of the brain not only by way of the trieapboxylio
acid cycle but also through the promotion of glucose penetra..
tion into nerve Dells. The results of our experiments seem
to point to a possible role or GABA in the metabolism of
organs besides the brain and raise new questions ooneerning
this substance which is widely distributed in planto and
microorganisms as well.
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
I. S. Roberts, & S. Frankel, J,131o1. Chem, 187, 55. (1950).
2. #. Roberts, 3. Frankel, P.J. Harman, Proo. Soo .Szper. Blol
a, lied.. 74083 (1950).
3. J.Awapara, A.J. Landua , R.Fuerst, J.Biol. Chem. 187,35,(I9500
4. B.Udenfriend, J. Blol. Chem, 187, 65 (I950)?
5. A.W.Bazemore ,K,A.C. Elliott, E.Floley, Nature, 178,I052,
1956, J,Neurochem, 1,334(1957)
6. Hayashl,r. NaG~a1,4t.Abstr. Commune Into Physiol. Congro
p.4I0 (I956)0 T. Hayashi, R.Shuhara,
p.410-II.
7. H.MoLennan, J.Physiol, 139. 79 (1957)
8. H.MoLennan, Nature 181. 18079 1958
9. H.C.3tanton, F.H. ioodhouse, Feder. Proc., 18. 448, 1959.
IO. S.rM.Huffler, C. Edwards ,J Neuropysiol., 21, 586(1958)
12. J. Soistell a, Y. Fatt, J. Physiol., 144, 176, 1958
I3?
14.
15.
16. O.M. Kipnis.a C.r'.eori, J B1ol .Chem., 224, 681 (1957)
17. P.J. Randle as G.H. lim1th, Biochem,J. 70, 490 (1958)
I8. Y. J.Randle a. G. H. Smith, Bioohem.J, 70, 501 (1958)
19. A.F. 4111ebrands, J. Groen, Advances intern. ,'4ed. 6,331 1954
20. D.3.C4orris , Selene* 107. 254 1948
219 S.Loskin . R.Levine, Carbohydrate metabolism 1952.
22. "felger :+. :Haynes J. Taylor R. :4, a. :Aeralli M. Am J. Physiol
177, 138 . 1954
23. Park C. R. Johnson L.li* dri 3ht J.H. as Batsel H. Am. J. Physiol
191 13, 1957
24. N.P4. Van Goldner , K.A. C. s!lliott, J. Neurochemistry, 3,
139, 1958
25. Marrazzi, A.s. Hart s'.R. J.M. Rodriquez, :;eienoe, I27, 284
I958.
 26, K.ti.C. :s'Iliott, H.H. Jasper, Physiol Rev. 39, 383 , 1959
27. D. P. Purpura, M. Girado, T. G. Smith as J.A. Gomez, Proo.
Soc. Exper. Biol . A. Med. 97
348,(1956) E.E. G. Cline
Neurophysiol, 10, 677 (1958)
28. Stanton, F.H. Woodhouse , Feder, Proc. I6, 448 , 1959
29. C.W. Halle, Nature, 157, 802 1946
30.H.H. Tallan, S. Moore, W. H. Slain, J, Biol. Chem, 211
927, 1954
31.Cravioto , R.O. Massieu, G. JJ Izquirdo, Proo. Soo. Exper.
Biol. a Mod, 78, 876 , 1951
32. Dawson, R. i4. Bioohime et Biophys. Acta, 31, 548, 1953
33. N.M. Van Geldner, K. A. C. Elliott, S.A.C. Elliott,
H.H. Jasper, Physiol. Rev., 39, 383,1959
34. M.Mc Khann a. D. Tower, Am. J. Physiol, 196, 36, 1959.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
Brain Gluoose Uptake During Its Various
Functional states*
(Based on the investie-tiens of w w author and soworkers-
yoghtan V.H., Khaahatrian Q.S., Kkhetan gel**
>
arc, L:. Bert ir. cxtei L ^ir;1.l.'r to eact, other, th(, ro:ssi' ility
trl:,c:.. t
.~L .r , .. :?u :nL 2 u~tiar:'~ !
' 1 . tea, ;,d~% ?
- s tre.s L? a hr?Zi n
?)ro.-u? e Ir' rV_~sr._ 3'?'.U+Intb cif
c ol.^:.tcrol~:r.. :}.t> ray
aLE~ro:scl.cru:;.} : :- a; `.oro.:ctcri~:c1 _3 are 1.1 L'elY to dovolon. rLs
s own it. t :3 fi tro, on !,he .:oval^n";cnt of ccrtl cal intil hition
t..er?u 1 c,r r: cc~ntrar,
'asr.tton of c::olesterol. t.ttr?
lrtvoaLt;~r,1.:~r.:; 1:. i1c to al .:o ti.1t varlo.r' con: tituontr of the
br-Li.nynvoivc:? 1r I t,-, ac*.4 v1 t,;~, 1: t.:r: cta:.c oP Iowef ,vl ioose
u? tike 1.:. -Lrt.i..?;' ter.
ro . o re:;.il ;s of our extiert::onts l t :nay be
cunclu aJ L .aL 'ur?in._ cortlcul inhiti'lion there is a rovorsal
of :aeLabolI c nr?oce_ r.e i n brain Li sne, ?Nni. ch enables tho
synL..es1 of tr,o :;ut:::tanco;: !itilized .zurin-r its activity.
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
 ~a? ~aotoa ?g GrEa~it???ull~saz
H. Ch.-Buaiatian.
r;229acd on the Investigatioae of the author and soworkers.
Yeghlen V. Be , Aduntz (}. Th., hoihaaaiesian A.8.0
Yessalan N.A., Khachatrian G.8., Mkaeian S.Y.9
Haragooslan C.a., Organd,ian M.G., Oydjian 0.
IIovaesian Q. G* and Hagopian J.
One of the important problems of biochommise
try to the study of the sortisal regulation of mmetabolle pro,"
ceases in effector organs, as well as the study of the bioehe?
mical prosecaea underlying oortioal excitation and inhibitions
A number of investigations have been undertaken in our labor
tory to study this problem.
In the preaortt ropoa?t, I sh&A i Give the n
otlto obtalmed come raing the effect of cortical activjty
rct olio proooso?a in effector org sa Usua1aya dl fore f c-
t1aaal states of tho brain are obtath d by the ad?i2Aet ca
of Otlaulsatins aad inhibiting Agnt
an our OXPOR~CCQt3 We L."20
vo ai lnQC from tho woo of auob ffie2Moa Ezn?VIaG t to
o~
gorto area not faro? fron no 91Qo afg?oto of %honr ouzo
Me inveotlcption of tho LaoP oontnzoE oQ
tiro b 2 la hoot car?g oat t MO tho Mao of U10 u, '30
oordbtaor ed rzflozooo thiol Too fat }ao l bj ovooo
t L :,a r lotabtCaAY by Oars t ho noc-r c o Soto - pL ~o~o c ~~
L=OO QO sr' Otrzn as U20 G 4 1?Cafl #Z Q{~~s?L~~ a ~tltC 7 00 by o r^ ^,<
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
more perfect form pf adaptation to shaages in the surroundings.
They develop in association with an unconditioned, inborn refem
lox. When a stimulus, which in itself is absolutely neutral, is
repeatedly applied simultaneously with an unconditioned stimn?
lung the two corresponding cortical centres are activated at the
same time and a temporary nervous association develops between
the two. Thus, the hitherto neutral stimulus acquires stimula..
tive properties, and is transformed into a sonditisned stimulus,
the application of which evokes the same changes as the unsondlm
tioned stimulus. In this respect, the changes that are brought
about in the organism by conditioned reflexes may be regarded as
the result of cortical activity.
Pavlov discovered further a functional state
of the brain cortex, which he named conditioned or internal Inm
hibition. It may be also called cortical inhibition. Unlike the
inborn inhibitory processes of the central nervous system, cor.
tieal inhibition In acquired and therefore of a temporary shares..
ter. One of the methods used by Pavlov for developing cortical
inhibition was the extinction of an already established Bondio
tioned reflex, which is attained through the repeated adainis..
trations of the conditioned stimulus itself.
In our investigations, in studying the sorti.
sal regulation of metabolic processes in effector organs, we
have attained activated and inhibited states of the cerebral cor-
te4y developing conditionea reflexes and then extinguishing then
through the daily administrations of the conditioned stimulus.
The unconditioned stimuli used in these studies were the antram
venous Injections of epinephrine and insulin, the administration
 o~n eaue~n9 /
of food rich in sugar and the elestris stimulation of the skin.
In oases where the unconditioned stimulus consisted in injecting
a substance, the conditioned stimulus used was the act of the in.
jeetion itself, where a neutral substance, lush as an isotonic
solution of sodium chloride, was uced.In the other experiments,
the conditioned stimulus was the sounding of a buzzer. During
these studies, the following ingredients have been determineds.
blood glucose, pyruvate, lactate, inorganic phosphorus, sateehol
amines, histamine, glutathione, glutamia and aspartie aside, gin.
tamine and ammonium , as well as the various components of the
blood clotting system. Changes in renal function have also been
followed.
After a number of simultaneous dally administra.
Lions of the unconditioned and conditioned stimuli when the sondi.
tioned stimulus atone was applied, it called forth, as was expeem
ted, the same changes as those brought about on the administration
of the unconditioned stimulus. This proved that the changes conw
corned were brought about by cortical activity. Then followed the
extinction of the reflex, during which period a gradual fading of
the changes studied was noticed. On continuing the administration
of the conditioned stimuli, with the purpose of developing sortsm
cal inhibition, there came a time when not only no changes were obw
served regarding the ingredients in question, but even a reversal
of the effects was noticed.
The results of our investigations clearly Indio
cats that during the development of cortical inhibition, the cotes
boiic processes in the effector organs go in the oppoolto Q mcc~
tion, as compared with those obtained during cortis?1 caativItyo
 .4~
To illustrate this fast numerous examples may be pro.
dused from our experiments. In fig. I, for instance, we see
FIG I.
the effect of epinephrine and that of the conditioned stinum
lus , on blood glucose level. Epinephrine , given In amounts of
O.8 mg,. brings about a noticeable rise in blood.sugar level.
after about ten trials, the injection of an altogether neutral
substance such as saline solution, brings about the same in..
crease in blood glucose as was brought about by epinephrine .
This effect, however , gradually fades away and after the third
application is no more noticed. On subsequent administrations
of the conditioned stimulus alone, a state of internal inhibie
tion develops gradually and a reversed effect is noticed, that
is to say hypogiyeaeaia is obtained. What is more striking, sp1
nephrlne , administered during such a state, no more exercises
its usual effect; it may even cause a slight fall In blood glu.
come level..
Similar results are obtained concerning inorgani e
phosphorus during conditioned insulin stimulation. A. shown in
fig 2., where the results are expressed as percentages of the
initial values,
FIG 2.
insulin causes a decrease in the amount of inorganic phospho..
rus in blood. Even a greater fall is noticed on the administra_
tion or the conditioned stimulus.
Subsequent administrations of the conditioned stimq
lus lead to the establishment of cortical inhibItien, during
which period a considerable rise of the amount of blood phos.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
phorus is obtained. Insulin, given under such conditions, eve..
kes almost no change in the level of blood phosphorus. Simihar
results have been obtained in respect to blood glucose level.
The sage thing is noticed in those experiments
where blood glucose and pyruvate are determined following the
administration of food rich in sugar conjugated With the ^oun.
ding of a buzzer. The rise. in blood.sugar and pyruvate, noticed
on the administrations of the unconditioned and conditioned sti.
mull, Is no more obtained after the third administration of the
conditioned stimulus. As shown in fig 3, during this and the fol.
lowing m three experiments the development of internal inhibition
causes a further lowering of blood pyruvate level. These data,
together with many others obtained during our experiments, India
Gate that oortical stimulation and inhibition have contrary ef.
foots on the metabolic of
prooessesleffeotor organs.
Pavlov pointed out the active nature of sorticall
inhibition and stated that it required much further study. The
results of our investigations show that during cortical inhibim
tion active processes are at work, the study of which gives us a
means for following the development of cortical inhibition be..
yond the zero offset, when the administrations of the ssmuiittened
stimulus induce no change. It is established that inhibitory
pbcooesses protect the nerve cells from complete exhaustion and
enable its recovery. As will be reported in greater detail in an=
other paper , studies at our laboratory have shown that during
cortical inhibition there is a reversal of metabolic processes
 Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
even in brain tissue itself.
Here the reversal of metabolic processes in of..
fector organs has been demonstrated. Thus inhibition embraces
the Whole of the organism. It undoubtedly serves the replenish?
sent of those substances that have been used up during the high..
toned activity of the organ in question, subsequent to cortical
exaltation*
Now what is the mechanism of the reversal of the
metabolic processes observed during cortical inhibition?
The results obtained in the Bourse of our investigations indi?
Oats that during the inhibition of certain cortical centres, the
activity of the reciprocal system is increased. This is obvious
from the facts obtained during the development of cortical In.
hibition in respect to conditioned epinephrine hyperglyeaesia
and conditioned insulin hypoglycaemia..
FIG 4.
As shown in fig 4, the conditioned stimulus pro.
duoes the same increase in blood glucose level as epinephrine.
On developing cortical inhibition, however, the same conditioned
stimulus brings about a lowering of blood glucose level.The few
subsequent administrations of epinephrine do not produce any
hyperglycaemia. This is indicative of a depression to adrenal
activity with a corresponding increase in insulin secretion.
A reversatil picture to noticed on the develop.
sent of cortical inhibition regarding conditioned insulispo~
glyoaemla. Here a depression of insular activity is accompanied
with an increase in adrenal activity, when becomes obvious from
the Increase in blood glucose level. These changes are illus.
trated in the second half of figure 4.Insulin and the condition.
ed stimulus produce a fall in blood glucose level. This effect
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
is reversed on the development of cortical inhibition, during
whioh ~biod the lypoglyoaemia effect of insulin In also abolish
ed.
Similar results have been obtained in expert..
cents where the amount of oateohol; ermined and histamine have be&
on determined in blood, during conditioned epinephrine reflexes
and the inhibition of this reflex. As is shown in FIG. 5, epi-
nephrine , as well as the conditioned stimulus following a num..
ber of administrations of epinephrine bring about an increase Sk
the amount of oatechol amines and a decrease in that of histaw
mine. A reversal of effects, that is to say, a fall in the amouai
! of cateohol amines and a rise in that of histamine is attained
on the development of internal inhibition.
These investigations, together with many o.
there carried out in our laboratory, indicate that there is wee"r_
#rooal activity between the antagonistic systems regulating blood
glucose level. This reciprocal activity was very outstanding
in a number of animals not with during our experiments , carried
out with the purpose of developing conditioned epinephrine hypes
glyeaemia. In such animals the usual hyperglysaemie Kiemi resm
ponse to epinephrine was obtained only during its first few In-*
'Jevtionss Subsequent administrations at first failed to induce
any change, and then produced a fall in blood sugar level. In
this connection , I should like to mention the results of expert
Rents carried out on one dog only. A. shown in fig 6,
FIG be
the first three intravenous administrations of 200 micrograms of
epinephrine bring about a noticeable rise in blood glucose level
(of about 2 0vot%). During the fourth and fifth a8minletratlons,
Approved For Release 2009/06/30: CIA-RDP80T00246A010200100001-6
 the amount of glucose remains unchanged . Further on, during the
6th, 7th and 8th applications, epinephrine produces a substanm
sial decrease in blood glucose level which falls down to 45 mg%.
Thus a picture similar to that obtained during cortical inhibi.e
tion of conditioned epinephrine hyperglycaemia was observed.
On the basis of these-and many other similar
results , we come to the conclusion that during a certain stage
of epinephrine excitation, a depression takes plane in the actim
vity of the systems concerned with the increase of blood glucose
level, of which the most important are the adrenal glands.A simsl_
attaneous activation of the antagonistic system=, of which the
most important is the insular, accounts for the fall in the blood
sugar level observed. This suggestion is further confirmed by
the following experiments, where the systematic administrations
of epinephrine lead to the cancelling of No its effect or even
to its reversal and in such cases, subthreshold doses of .pin p
rine, which during control experiments had had no effect on
blood glucose level, now cause an appreciable hyperglycaemia.
This is illustrated in fig 7, where 10 age of spinepkIne are
Of lei jbg
given cancelling the effect of 200 mg.,
FIG 7,
attained through its repeated' injections. As shown in the figure
a noticeable increase in blood glucose level is reached. Sere we
some across one of the characteristic phenomenon of the inhibim
tory process, called the paradoxical phase, Introduced by Veden;_
Oki and confirmed by many others. This states that during inhibd_
tbry.processes small doses ot~tiimulus cause a greater effect
than larger ones.
 Simultaneously with the inhibition of the cortical centres re.
gulating the secretion and action of epinephrine, those concern-
ed with the secretion and action of insulin are reciprocally aso
tivated. This is illustrated by the experiments shown in fig 7,w~erQ
0.5 units or insulin , whioh during prelinknary experiments had
AO --
narked)no change, given upon four administrations of 200 4 "4 , of
epinephrine after a reversal of its effect , caused a consider.
able fall during the three consequent administrations. On the
fourth and fifth infections, 0.5 units of insulin had no effect
on.- blood glucose level. These results were confirmed by many om
ther experiments.
The reciprocal interrelationship in the aetivie
ty of the antagonistic systemsdeseribed above plays a signifi.
cant role in the finer correlation of the meehanisas0 partisi.
pating in the homeostatic functions of the organism, including
the stability of the blood glucose level. Numerous investigations,
pit. carried in different laboratories, have shown that during
byypoglyoaemia, the secretion of epinephrine is enhanced and that
of insulin depressed# while quite the contrary is observed o ~1C
However, a more perfect regulation of-the floe,
tional interrelationship between the adrenal and insular systems
is realized by the cerebral cortex. This is confirmed by the in.
vestigationa of Hasratian and Coworkers, and Zakharov, carried
out on decortioated dogs. On 4esortisation the organism beeomea
more sensitive to epinephrine and insulin administrations. Here
the changes in blood glucose level last longer than in nonopers}.,
dogs. Similar data. have been obtained by a number of other in.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
IO .
of's
vestigatie a as well as by us in experiments carried out aesai+
seals where co#sal activity had been presluasa through narooti-
"OC sation. This effeeti is most probably due( he fact that OR remo?
4-,us
wing the tortes reluding its activity, the finer oortelation
of the compensatory mechanism is abolished. As a result of th*s
the action of the antagonistic mechanism for the removal of the
abnormal effect, In postponed and sometimes does not even tare
place.
To illustrate this I will present the results
of a few experiments. As I have already demonstrated In some
dogs, after repeated administrations, epinephrine no more inorea?
sex blood glucose level la, Now.- if the same amount is given to
a dog under aaldal or neabutal narcosis, it produces its usual
hyperglyoae.io effect. The results of some one such experiment
are shown in fig 8 . Acre the repeated intravenous infections of
FIG 8.
epinephrine produce no change in blood glucose level. The same
amount, administered under narsotisation produces its usual by
perglyeaeaie effect. Data available from the literature , had
the results of our experiments,. $ &. allow us to conclude that
decortieation and narootization produce a state of central "dw&
nervation". if it may be so called , as a result of whist recapo
rosal compensatory mechanisms suffer appreciably and the organism
becomes more sensitive to humoral agents. Cannon's law about the
increased sensitivity of denervated organs to humeral agents Is
explained by a number of investigathos through the depression,
in such organs, of these processes-which ses&tee lead to the In.
 activation of the humoral agent. For example, according to Burn
and Robinson, the increased sensitivity of the denervated nietie
tating membrane to epinephrine is due to the decrease in mono..
aminoxidase activity. Armin and Grant ascribe the increased sea.
sitivity of the denervated central artery of the rabbits ear to
acetylcholine to the fall in cholinesterase activity. Went finds
that in denervated structures, the formation of antimetabolites
neutralizing the offset of neurohumors, is reduced.
The cortical regulation of metabolic processes
may be considered a more developed stage of that same fundamen..
tai rule governing the regulation of enzymatic processes. It is
well known thal,Q a certain stage of the enzymatic process, the
activity of the enzyme is suppressed the reaction being often
stimulated in the opposite direction.
In connection with the cortical regulation of
metabolic processes the results of some other experiments of ours
are of interest. Section of the right vague nerve, which stimuft
laces insulin secretion, increases the sensitivity of the orgam
nism to epinephrine and lovers its sensitivity to insulin. In
such an animal the effect oven small doses of epinephrine is cam.
celled during its third or fourth administrations.
This indicates; that when insulin secretion is
deprived of its nervous control, the suppression of the metaw
bolic effect of epinephrine occurs more quickly. In this rase
peat , the cerebral cortex plays undoubtedly an important part
in the regulation of the compensatory mechanisms governing the
homeostatic state of the organism.
 This may be illustreted by the results obtained on
dogs where the right vagus nerve baa been ineisad. In such anim
pals 25 m& of epinephrine and I unit of insulin given in the
course of control experiments had no offset on blood glucose is..
vel . Then followed the injections of I00 i of epinephrine. A
noticeable hyperglyeaesia was observed only omits first two ad.
ministrations. The third brought no change in blood sugar level,
while the fourth and fifth produced a hypoglycaemia. 25 0160 of
epinephrine given during this stage induced an appreciable by...
perglyoaemia. This indicates the establishment of a sktate, eha.
racteristio of the inhibitory process, known ask the paradoxi.
cal phase.
At the ease tome the administrations of I unit of
insulin produced an appreciable lowering of blood glucose levels.
Thus together with the inhibition of the mechanisms taking part
in producing hyperglyeaemia, there was a reeiprosai activation
of tae hypoglyeaealo effect of insulin. ALL of this nowever was
not observed during narsotiaatione.
The above+nentioned facts indicate that the offset
of epinephrine and insulin on blood glucose level depends on
the reciprocal activity of the antagonistic systems, which are
subordinated to Cortical mechanisms* When one of these systems
gets the upper hang the hyperglyeaemic erreot of epinephrine and
the hypoglyoaemio effect of insulin , may dissappear. During our
investigations we have frequently net with the elimination of
the effects of epinephrine and insulin on blood glucose level,
 13 ..
when they were used in easesf lnhibitbd conditioned adrenalin
and conditioned insulin hypoglyoaeala. On the other hand, after
repeated administrations of epinephrine, when it was replaced by
insulin, during the first and sometimes even the second injeetions
ps hyperglyoaemia was obtained instead of the hypoglycaemia ex.
peoted. Similarly, after repeated administrations of insulin,
when* it was replaced by epinephrine , a rise of blood glucose
level was not to be seen. The hyperglyoaemia characteristic of
epinephrine, was noticed only on the 2nd and 3rd days of its ad..
ministrations. To illustrate these fasts a few examples are quo&
ted from our investigations.
FIG 9, 109
Fig 9 and 10 demonstrate that insulin, administered after re..
peatea injections or epinephrine , continues to raise blood glu.
rose level. Similarly epinephrine given after repeated daily ad*
ministrations of Insulin brings about hypoglycaemia.
A number of authors have failed to develop con-
ditioned epinephrine hyp.rglyoaemia and conditioned insulin hypo..
glyoaemia. In the case of some animals, our repeated trials for
establishing conditioned reflexes in respect to epinephrine and
insulin have also been unsuccessful. On the basis of a number of
facts obtained.during the study of this problem, it nay be come
oluded that the failure to develop conditioned epinephrine by.
perglyoaeala may be due to the depression of adrenal function
with the simultaneous activation of the insular system. In some
animals this condition seems to develop more quickly than in ow
there, which probably depends on the correlative activity of the
above mentioned systems and the doses of epinephrine and insulin,
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
..
14
The failure to develop a conditioned insulin by
poglyoaemia is most probably due t- the early activation of andb
ti.insular aeohanisas. With the purpose of confirming this eona
cept of ours we have studied these effects on dogs with one adsenai
17O e
removed and the other denervated. In this way we We tried to
reduce the activity of the most important of the anti.insular
aeohanisms,
During experiments carried out prior to the a.
bone mentioned operation, it was noticed that the conditioned
stimulus, given after Iu?II administrations of insulin aid not
induce a fall of blood gluoose level.
FIG II
The resahlta of one such experimental are illus.
trated in fig II.
Upon the removal of one adrenal and the denere
nation of another, the sensitivity towards insulin as expected,
was found to be increased, while., that towards epinephrine had
decreased. Than followed the systematic administrations of the
usual doses of insulin which was four time* greater than*its
threshold doses(O.4 units). After the tenth injection of insulin
the administration of the conditioned stimulus induced a pronoun.
unpsed hypoglycaemia. A lowering of blood glucose level was also
noticed on the second, third and fourth administrations of the
conditioned stimulus, after which it produced no effect on blood
glucose level. Thus, the above mentioned operation by weakening
one of the most powerful of the anti.insular systems, the adrew
nal glands, and the removal of their central nervous control led
to the earlier and sore permanent establishment of conditioned
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
15
Insulin hypoglyoa.mia.
It was interesting to follow the changes in
blood glucose level during the development of Cortical inhibi.
e
tion in the abovno1perated animals. It was observed that in these
as dogs, during cortical inhibition, there was no appersiable
change in blood glucose level. The development of cortical In.
hibitionsthrough the extinction of the conditioned insulin by.
poglyeaemia lad, as was the case with nonoperated arils a to
an increase in blood glucose level. This phenomenon had been
explained through the reciprocal enhancement of anti.insular
activity, especially that of the adrenal glands. In these .Z.
periments, the failure to obtain such an increase must, most
probably, be explained by the weakening of the matn anti.iaa
solar system' Preliminary experiments indicate that in such
animals during the development of cortical inhibition no rise
is noticed in blood cat.ohol amines.
Numerous provious investigations had shown
that insulin, epinephrine or any other stimulus, when given
during the first few days fallowing the development of cortie
cal inhibition , does not manifest its characteristic effect.
The same thing was observed in experiments carried out on ope
erwted animals. The results obtained on one such operated anio
mal during the development and extinction of Conditioned insu.
11n hypoglyoaemla, are given in table I..
Table I.
As shown in the tables the conditioned stain a
from its fourth adminlatration onwards, falls to produoe a bypQ?
 glycaeaia. the subsequent administrations of the conditioned stio
mulus lead to the development of cortical inhibition.
On the establishment of vortical inhibition,
insulin given in the same amounts as before, rails to produce as
any aignifiolant decrease in blood glucose level during its fir-40t
pt , second , third and fourth administrations. Only on its
fifth injection it produsea a fall in blood glucose level equal
to that obaersed in experiments proceeding oortioal inhibition
? a decrease of about 30 mg.%.
What is the reason of the absence or consim
derable weakening of the hypoglycaemic effect of insulin given
during cortical inhibition?
One of the main mechanisms underlying the
hypoglyoaemis effect of insulin is its enhancement of membrane
permeability to glucose, especially in muscle and fai tissue.
Probably during pertain functional states of the cerebral cortex
especially the inhibition or conditioned insulin hypoglycaemia,
membrane permeability is so changed through nervous impulses, as
to produce a reversal in the effect of insulin on glucose trans.
port. Many inveatigatprs have shown that in muscular tissue, tom.
Anrough the action of nervous impulses, the transport of a number
of substances, including the sugars, can be changed. Of partiou-
lar interest are the changes in the metabolic processes of mus-
cular tissue following its denervation. According to Axelson
and Thesleft, the sensitivity of reohptor sites, in the deaerva-
vated muscular membrane, is increased towards acetylcholine and
other agents. Such a membrane is free from oholinesterase actin
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
17-
vity and its selective permeability towards sodium and potasium
is changed. Koshdoyantz and Manson have shown that in deserve..
ted muscle the structure and properties of muscular glycogen
are changed..Gerritsen has established that during the first
period following denervation the glucokinase activity of musettw
lar tissue is increased. According to Takashi, phosphorylase ac..
tivity is also enhanced and 1s no more affected by epinephrine..
A lowering in aldolase activity has also been reported.
It was interesting tb study the permeability
of musetlar tissue to glucose following its denervation. This
was studied on the gastroenemeus muscle of frogs three days af-w
ter its denervation. The results given in table 2, are the mean:
values of 25 testa. The uptake of
Table 2,
glucose by muscular tissue is expressed in ago % for I gro of
fresh tissue. Incubation was carried out at 37Q for 30 minutes,
in Ringer's solution.
As seen from the table , the uptak^ of glu.
cose by muscular tissue is about 13.5 ag. %. On the addition of
insulin, this amount increases to 20 ag %. A similar rate of
glucose uptake is noticed after denervation, where the addition
of insulin causes a further increase, in its quantity. Intercom
ting results have been obtained on the stimulation of muscle.
Here an increase in uptake of I6.3 mg % is observed. This obe
servation is compatible with those found inthe literature. Insuo
ling added to stimulated muscle raises glucose uptake to a level
of 31.8 ag %. A reversed effect is obtained on the stimulation d
of denervated muscle.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
In this case, the uptake of glucose is appreciably
redused by about I0.3mg %, and what is more interesting, the addi
tion of insulin, does not An t Ms s increase
glucose uptake,
which remains at 8.8 mg.%. These results indicate that the nor..
vous factor has an essential role in the regulation of glucose
transport brought about by Insulin..
These findings are compatible with our sup.
position regarding the failure of obtaining a hypoglyoaemio ofa
feat of insulin during the inhibition of the conditioned insulin
hypoglycaemia. As will be remembered , we had already proposed, ;.,;
that one o[' the mechanisms underlying this fact may be a ohanft
gad membrane permeability towards glucose , under the influence
of oortioal impulses. This concept was supported by other stuw
dies carried out on dogs where the utilization of glucose by
skeletal muscle was determined. This was done by taking blood
samples from the carotid artery and the corresponding vein in
the hind limb.
Present studies emphasise the signifielant
role or gaamoamdno butyric acid (BABA) in inhibitory processes.
This substance has a certain effect on membrane permeability
also. In this respect we have studied the effect of &i3& on the
the penetration or giuooss in muscular tissue.
The results or experiments carried out on
the 13olated rat diaphragm have shown that in muscle tissue GAB&
in amounts of I AS %,causes an appreciable increase In the trans.
port of the glucose and the subsequent syathosis of glycogen.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
In the abolishment of the hyperglycaemic effect of
insulin on its administration in certain functional states of
the brain, other anti..insular mechanisms seem to take part.
Among these glucose, insulinase activity of certain tissues
and the conjugation and inactivation of insulin by certain
proteins of blood seem to be of some importance. These prob_
lama are being studied in our laboratory
It has been shown that during the cortical inhibition
of conditioned insulin hypoglycaemia, the elimination of the
hypoglycaemic effect of insulin is accompanied by a noticeable
rise in glucagen activity. Thus, for instance , 0p5 mg* of
glucagon, which in control experiments had had no effect,'under
such conditions evokes a rise in blood glucose level of about
25 mgi. This promotion in glucagon activity is noticed also on
the 2nd and 5rd days following cortical inhibition, after
which it fades away. This is another fact pointing to the reoi.,
prooal activation of antagonistic mechanisms during cortical
inhibition.
In thin respect it is Interesting to mention the re.
sults of another series of experiments , where the inactivation
of a known amount of insulin following its incubation with blood
was studied. It was shown that in control experiments insulin
activity was halved following its incubation with blood for I
0
at 37 Q. On incubating insulin with blood samples taken during
the state of cortical inhibition, when the hypoglycaemic effect
of insulin was no more obtained, it was noticed that insulin
activity was decreased much more, than when incubated with sam.
ples of blood taken during control experiments.
 Approved For Release 2009/06/30 : CIA-RDP80T00246A010200100001-6
49
Facts , such as the abolishment of the hypogly..
oaemic effect of insulin during the inhibition of the condi-
tioned insulin hypoglycaemia as well as the reversal of Insulin
action following the systematic administrations of epinephrine
and in certain neurotic states of the organism obtained in
the course of our experiments, confirm the significance of
the nervous factor in the aetiology and course of diabetes.
There are many instances in the literature where the origin
of diabetes is connected with a nervous stress. Mirsky believes
that v4ey comparatively few case or diabetes can be ascribed
to structural lesions of the pancreas . He cites data from
Bell who finds that in about 40 % of oases of diabetes no deo-
rease in beta..granulation is observed. Some decrease is noticed
in 35 %, while a complete loss of beta-granulation is observed
only in 25 ;$ of the cases. It has been reported that for the
initiation of experimental diabete more than 85 % of the
pancreas must be removed. These results indicate that diabetes
cannot always be ascribed to pancreatic lesions, it may be
or non-pncreatic aetiology, due to a?deorease in the effect
of insulin on tissues or to its more rapid inactivation. These
processes are undoubtedly regulated by thm central nervous
system.