The pathogenesis of tumour hypoglycaemia: Blocks of hepatic glucose release and of adipose tissue lipolysis
The Pathogenesis of Tumour Hypoglycaemia: Blocks of Hepatic Glucose Release and of Adipose Tissue Lipolysis*
0 Metabolic Unit, Department of Medicine, University of Zurich and Department of Medicine , KantonsspitM St. Gallen
Summary. Earlier findings on the pathogenesis of tumour hypoglycaemia  were confirmed and extended in a second patient with this disease. -- A block of hepatic glucose release was found to be the main cause of hypoglycaemia in both patients suffering from large tumours of non-endocrine origin. The free f a t t y acid level failed to increase upon hypoglycaemia. Low free fatty acid levels correlated with an increased rate of glucose assimilation and glucose oxidation. -- Immunoreactive, suppressible and nonsuppressible I L A measured in vitro and in vivo were normal. -- However, the serum of patient Z.B. inhibited lipolysis o2 adipose tissue in vitro to a greater extent than serum of normal subjects. This difference was no longer present after dialysis of the sera and the antilipolytic activity was now found in the diffusate. -- The block of hepatic glucose release may be overcome by a pharmacological dose of intravenous glucagon. The block of hepatic glucose release is of paramount importance for the development of hypoglycaemia since the pharmacological blocking of lipolysis alone does not lead to hypoglycaemia, although it m a y increase glucose assimilation and glucose oxidation. -- An a t t e m p t is being made to characterize further the antilipolytic substance which is present in increased amounts in the serum of patients with tumour hypoglycaemia.
La pathogdn@se de t'hypoglycdraie par tumeurs:
Inhibition de la libgration du glucose clans le foie et de la lipolyse
dans le tissu adipeux
Rgsumd. Le mdtabolisme glucidique et lipidique a dt6
6tudid chez un patient avec un fibrosarcome
rdtrop6riton6al rdcidivant accompagnd de graves attaques
d'hypoglyc6mie. Les notions obtenues en 1963 chez un malade
montrant la m~me symptomatologie [
] out 6t6
confirmdes et approfondies. -- Dans les deux cas la
production de glucose par le foie 6taft presque compl@tement
bloqude. E n outre ces sujets @taient incapables
d'augmenter le t a u x des acides gras libres plasmatiques pendant
la chute prononcde de la glyc6mie. -- I1 existait une
corrdlation 6troite entre le t a u x eonstamment bas des
acides gras libres du plasma et une assimilation et
oxydatiou accdl6r@e du glucose sanguin. -- La libdration de
glucose par le foie pouvait @tre stimul@e par une dose
pharmacologique de glucagon. -- Les t a u x d'insuline
immunologique du sdrum ainsi que l'aetivit6 insulinique
supprimable et non-supprimable dtaient toujours
normaux. -- Auctme substance "insulino~de" n'a pu 6tre
d6montrde par des tests in vivo et in vitro. -- D ' a u t r e
part, le sdrum de la malade produisait une inhibition plus
* This work was supported by grants from the
Schweizerische l~ationalfonds (3336) and from the U.S.
Public Health Service (AM 5387).
Key-words: Hypoglycaemia, extrapancreatic tumour
hypoglycaemia, paraneoplastic syndrome, glucose turnover,
glucose assimilation, free fatty acids, lipolysis,
antilipolysis, hepatic glucose release, plasma insulin, insulin-like
activity, urinary catecholamines, plasma growth
M e s e n c h y m a l a n d e p i t h e l i a l t u m o u r s of n o n - e n d o
crine origin o c c a s i o n a l l y p r o d u c e h y p o g l y c a e m i a .
Alt h o u g h m o r e t h a n 200 such eases h a v e been r e p o r t e d ,
t h e p a t h o g e n e s i s of h y p o g l y e a e m i a a s s o c i a t e d w i t h
m a l i g n a n t t u m o u r s which do n o t o r i g i n a t e from t h e
p a n c r e a s is still u n k n o w n (reviewed in [
] a n d
S e v e r a l theories h a v e been p r o p o s e d to e x p l a i n
t u m o u r h y p o g l y c a e m i a a n d h a v e r e c e n t l y been
rev i e w e d b y U~-G~I~ [
]. I n c r e a s e d a m o u n t s of
circul a t i n g insulin a n d / or insulin-like substances, excessive
u t i l i z a t i o n of glucose b y t h e t u m o u r or a c o m b i n a t i o n
of t h e two were m o s t o f t e n i n c r i m i n a t e d as t h e cause
of this t y p e of h y p o g l y e a e m i a .
I n 1963, a p a t i e n t w i t h h y p o g l y c a e m i a a s s o c i a t e d
w i t h a m e t a s t a s i z i n g n e p h r o s a r e o m a was s t u d i e d in
our clinic [
]. The findings s u g g e s t e d t h a t h y p o g l y
c a e m i a in this p a t i e n t was due to several m e t a b o l i c
d i s t u r b a n c e s r a t h e r t h a n to one single cause. The
blocking of h e p a t i c glucose release a n d of a d i p o s e
tissue lipolysis in a s s o c i a t i o n w i t h a n e l e v a t e d glucose
c o n s u m p t i o n b y t h e t u m o u r was p r o v e d to be
responsible for t h e d e v e l o p m e n t of h y p o g l y c a e m i a in this
pat i e n t . A n t i b o d y suppressible a n d n o n s u p p r e s s i b l e I L A
were p r e s e n t in n o r m a l a m o u n t s in t h e b l o o d of this
p a t i e n t a n d no insulin-like m a t e r i a l could be e x t r a c t e d
from t h e t u m o u r . A careful r e v i e w of t h e l i t e r a t u r e
y i e l d e d p o o r evidence for i n c r e a s e d insulin-like
mat e r i a l in t h e b l o o d of these p a t i e n t s , a n d a n i n c r e a s e d
glucose u p t a k e b y p e r i p h e r a l tissues has n e v e r been
p r o v e d [
19, 15, 25
W e h a v e h a d t h e o p p o r t u n i t y to confirm a n d to
e x t e n d these d a t a in a s e c o n d p a t i e n t w i t h a r e t r o
p e r i t o n e a l s a r c o m a a n d w i t h severe h y p o g l y e a e m i a .
S e r u m of this p a t i e n t i n h i b i t e d lipolysis of a d i p o s e
tissue ir~ vitro t o a g r e a t e r e x t e n t t h a n d i d n o r m a l
serum. The s u b s t a n c e r e s p o n s i b l e for t h e i n h i b i t i o n of
lipolysis was d i a l y z a b l e a n d c o n s e q u e n t l y of s m a l l
m o l e c u l a r weight. I t has n o t y e t been i d e n t i f i e d a n d
i t is n o t c e r t a i n w h e t h e r it, or a r e l a t e d s u b s t a n c e m a y
be r e s p o n s i b l e for t h e b l o c k i n g of h e p a t i c glucose
release. The r e s u l t s of this s t u d y h a v e been p r e s e n t e d
elsewhere in p r e l i m i n a r y form [
I n this 52 year-old female patient, Z.B., J o u r n a l
N u m b e r 315/66, a retroperitoneal flbrosareoma was
t o t a l l y resected in J a n u a r y 1963. No metastases were
found at t h a t time. Till 1965 the p a t i e n t was without
complaints. I n September 1965 the p a t i e n t experienced
a t t a c k s of hypoglycaemia, which were at first slight, b u t
soon became severe. There was no evidence of
metastases or of ]oeM recurrence of the t u m o u r a t this time. I n
J a n u a r y 1966 the p a t i e n t was a d m i t t e d to the Metabolic
Unit of the D e p a r t m e n t of Medicine in Zurich for further
investigation of the hypoglycaemic attacks, which had
become extremely severe. The p a t i e n t avoided nocturnal
hypoglycaemia b y t a k i n g 20 g of sucrose every two hours.
The liver was grossly enlarged, firm, its edge uneven and
it r a p i d l y increased in size. During the stay a t the hospital
the need for glucose varied considerably. During episodes
])iabetologia, Vol. 3
of two to three days up to 600 g of glucose had to be
administered over 24 hours to m a i n t a i n the blood sugar
between 40 and 70 mg %. Diazoxide was given
therapeutically over a period of two to three months in a
dosage of 150 to 225 mg per day. W h e t h e r or not it h a d
any effect on glucose metabolism cannot be stated with
certainty since the spontaneous fluctuations of glucose
assimilation were considerable. Diazoxide did not
prevent hypoglycaemia, b u t appeared to delay its
development. The p a t i e n t was t r e a t e d with Endoxan, 100--150
mg per d a y over a period of several months without a n y
clear-cut effects on t u m o u r growth or hypoglycaemia. A t
home, the daily intake of glucose varied from 200 to
600 g. The cessation of diazoxide t h e r a p y enforced b y
gastrointestinal side effects did not appreciably alter the
need for glucose. The p a t i e n t ' s blood sugar 45 rain. after
breakfast was 46.1-t- 3.5 m g % (mean :t: SEM, n ----16).
The slightest work in the house i m m e d i a t e l y led to
I n J u l y 1966, the p a t i e n t had, for the first time, signs
of obstructive jaundice t h a t r a p i d l y became more severe.
She died in August 1966 at home after a coma of several
hours duration. The nature of the lethal coma could n o t
T u m o u r cachexia was n o t s t r i k i n g (length: 151 cm,
w e i g h t : 51 kg). I n t h e r e t r o p e r i t o n e a l region a local
r e c u r r e n c e of t h e t u m o r was found. The t u m o r h a d
i n v a d e d a n d c o m p r e s s e d t h e s u r r o u n d i n g loops of t h e
i l e u m a n d t h e left u r e t e r a n d h a d led to a h y d r o n e
phrosis of t h e left k i d n e y . H i s t o l o g i c a l l y t h e t u m o u r
was d e s c r i b e d as a well d i f f e r e n t i a t e d fibrosarcoma.
The liver was d e f o r m e d b y large m e t a s t a s e s a n d showed
a cholostasis w i t h ieterus. S m a l l e r m e t a s t a s e s were
f o u n d along t h e p a r a a o r t i c l y m p h a t i c ducts, on t h e
d i a p h r a g m , on t h e m e s o s i g m o i d a n d in b o t h k i d n e y s .
I n t h e t h y r o i d g l a n d a n d t h e r i g h t a d r e n a l g l a n d
m i n u t e m e t a s t a t i c n o d u l e s were f o u n d . T h e p a n c r e a s
a n d t h e islets l o o k e d normal. A differential s t a i n for
A- a n d B-islet cells was n o t p e r f o r m e d .
B l o o d glucose was m e a s u r e d w i t h glucose oxidase
]. Glycerol a n d l a c t a t e were e n z y m a t i c a l l y
determ i n e d [
P l a s m a free f a t t y acids were e x t r a c t e d a n d t i t r a t e d
a c c o r d i n g to GOI~DON [
]. E p i n e p h r i n e a n d
norepinep h r i n e were e s t i m a t e d f l u o r i m e t r i c a l l y [
glucose was i s o l a t e d from t h e b l o o d in t h e f o r m of
osazone 1. The t o t a l lipids of t h e r a t f a t p a d s were
e x t r a c t e d b y t h e m e t h o d of FoLctt, L ~ s a n d STA~I,Eu
. Glycogen was p r e c i p i t a t e d w i t h cold e t h a n o l
a f t e r h y d r o l y s i s of t h e tissue in boiling 30 % K O H .
Carrier g l y c o g e n was used as a p r e c i p i t a t i n g aid. The
g l y c o g e n was twice r e d i s s o l v e d a n d r e p r e c i p i t a t e d a n d
t h e n d e p o s i t e d on a filter p a p e r b y s u c t i o n t h r o u g h a
1 The specific a c t i v i t y of the serum glucose was
obtained b y dividing the counts in the osazones b y the serum
sintered glass filter for counting. All radioactive
samples were counted in a low background flow counter and
a correction for self-absorption was applied. Details
of the isolation and counting procedures used in our
laboratory m a y be found elsewhere [
]. I L A was
measured in vitro b y the fat p a d technique using
antiinsulin serum from guinea-pigs for differentiation
between suppressible and nonsuppressible I L A [
Insulin-like or insulin-potentiating substances in the
blood of this patient were also searched for b y
injecting serum together with glucose-6-14C
intravenously into rats and b y measuring the incorporation
of carbon 14 into glycogen of the diaphragm and into
total lipids of the epididymal fat pads [t6]. I m m u n e
reactive insulin and growth hormone were determined
b y double a n t i b o d y immunoassays [t8, 38] I. The
antilipolytic activity of serum was estimated in vitro b y
the inhibition of basal glycerol release of adipose tissue
from fasted-refed rats . Visking tubing (8/100 FT),
rinsed overnight in tap water, was used for dialysis of
serum. The glucose assimilation coefficient (KG) was
determined b y the intravenous glucose tolerance test
according to CONiRD [
1. Glucose assimilation
Glucose assimilation was repeatedly estimated in
patient Z.B. b y intravenous glucose tolerance tests.
levels one hour after stopping the administration of
glucose were significantly higher on diazoxide t h e r a p y
t h a n without it.
I n an a t t e m p t to determine the locus of increased
glucose uptake the differences of the glucose
concentration between the brachial a r t e r y and the femoral
vein on the one hand, and the vena cava on the other
were measured. I t was assumed at the time of the
experiment t h a t the vena cava was draining not only
the legs but also p a r t of the turnout metastases in the
pelvis, an assumption which was proved to be correct
a t autopsy. The difference in the glucose
concentration between a r t e r y and vena cava represents the sum
fo the glucose uptake b y peripheral tissues plus
turecur tissue. The tip of the catheter in the vena cava
was placed just below the diaphragm. Hence, hepatic
handling of glucose did not influence our
measurements. The blood sugar was maintained constant at
two different levels b y constant infusions of glucose.
The results of this study are presented in Table 2. A t
the lower level of blood sugar of 128 m g ~o the glucose
difference between artery and vena eava was
significantly greater t h a n the peripheral arteriovenous
difference, indicating t h a t the glucose consumption b y
the t u m o u r was relatively greater t h a n t h a t of the
tissues of the legs. Lactic acid levels were within the
normal range, independently of the sampling site
(brachial artery: 0.57 =k 0.04 mg ~o ; vena cava: 0.54
0.01 r a g % ; femoral vein: 0 . 5 8 m g % ) .
Infusions of glucose were stopped one hour prior to
the beginning of the tests. The glycaemia at this time
and glucose assimilation coefficients are shown in
Table 1. The K s varied from normal to m a r k e d l y
increased values. When the patient was treated with
diazoxide (150--225 mg per day) the m e a n K a was
somewhat lower t h a n without t h e r a p y but the
difference was statistically not significant. Blood glucose
1 We are grateful to Dr. G. ZA~ZCD,Geneva, for his
most valuable help in the determination of peptide
2. Hepatic glucose release, free fatty acid metabolism
and rate of glucose oxidation
On two occasions 100 #C of glucose-U-lac were
given intravenously together with 16 g of unlabelled
glucose. The blood sugar, the total and the specific
a c t i v i t y of serum glucose, the specific activity of the
expired C02 and the free f a t t y acids were followed
over a period of 2 ~ h. On one occasion the patient
received no drugs, whereas she was on diazoxide
ther a p y during the other test. As m a y be seen on the left
of figure 1 the glucose assimilation was v e r y rapid. The
A. 3A~:OB et al. : The Pathogenesis of Tumour Hypoglycaemia
K e was 3.15 10-~ corresponding to a half-life of
blood glucose of only 22 rain. I n t r a v e n o u s
administration of glucagon (1 mg) led to a sudden rise in
blood sugar and it relieved hypoglycaemic symptoms.
On another occasion 2 mg of glueagon administered
intravenously lead to an increase of the blood sugar
from 46 to 129 m g % within 20 min. 15 mg of
zinc glucagon injected i.m. enabled the patient to
and the blood sugar tended to level off at 30 mg %.
The block of hepatic glucose release was almost
complete. The free f a t t y acid level was 1.2 #eq/ml at the
beginning of the test. I t fell to 0.4 #eq/ml during the
test. On this occasion hypoglycaemia provoked a clear
cut rise to a level of 0.7 #eq/ml. 20 % of the expired
CO2 was derived from glucose, i.e. m u c h less t h a n in
the first experiment.
I I I I I I f |
0 20 40 60 80 IO0 120 140 IGO m/nu/es
0 20 40 GO 80 /00 720 /40 160 m/~ules
fast during 9 h. before witnessing hypoglycaemic
symptoms. These consisted of sweating, dizziness and
a disturbing apathy, and t h e y became severe when the
blood sugar fell below 20 mg %. Despite severe
hypog]ycaemia the a m o u n t of glucose released from the
liver was small as indicated b y the curve of the specific
activity of serum glucose. The calculated hepatic
release was a p p r o x i m a t e l y 30 mg of glucose per
minute during the sharp fall of the blood sugar, and it
did not increase when the blood sugar levelled off at
10 r a g % . The labelled glucose administered at the
beginning of the test was rapidly oxidized as shown
b y the sharp increase in the specific activity of the
expired COS. A p p r o x i m a t e l y 60 % of the total expired
CO2 was derived from glucose. The concentration of
free f a t t y acids remained low during the whole
experim e n t and did not rise in spite of the v e r y severe
hypoglycaemia. During the second test, carried out in the
same m a n n e r but this time on diazoxide t h e r a p y
(right of Fig. 1), glucose assimilation was less rapid
3. Endocrine counterregulation against hypoglycaemia
Since hormonal counterregulation normally
prevents a sustained fall of the blood sugar, the levels of
epinephrine, norepinephrine and growth hormone
were measured during a fall of blood glucose from
I20 mg % to 10 mg %. When hypoglycaemia
developed, a rise was observed in the level of b o t h
epinephrine and growth hormone (Fig. 2).
4. Immunoreactive and biological insulin-like
activities of the serum
I m m u n o r e a c t i v e and suppressible I L A were
measured at different levels of blood sugar, varying from
26 to 115 r a g % and t h e y were found to be well within
the normal range (Table 3). There was no correlation
between immunoreaetive and suppressible I L A with
the blood sugar, indicating t h a t regulation of insulin
secretion b y the blood sugar was disturbed b y the
v e r y frequent hypoglycaemic attacks. Nonsuppressible
I L A was in the normal range. Serum was injected
intravenously into rats together w-ith glucose-6-14C and
incorporation of radioactive carbon into glycogen of
the diaphragm and into total lipids of the epididymal
fat pads was determined (Fig. 3). Whereas serum of
the patient and of a normal subject had no effect,
2 m U of crystalline insulin significantly stimulated
grOWh/IorzToneI%1O S , / ~ e - .
e....._ _ _ . . * ~~0-- /
I I I I
5. Antilipolytic effect of the patient's serum on rat
adipose tissue in vitro
Crystalline insulin, suppressible and
nonsuppressible I L A inhibit the glycerol release of adipose tissue
]. The experiments represented in Table 4 were
carried out in order to investigate whether or not the
serum of patient Z.B. contained antilipolytic
activities out of proportion to its content of insulin-like
A. JAI(o~ et al. : The Pathogenesis of Tumour Hypoglycaemia
d e m o n s t r a t e s t h e two m e t a b o l i c blocks which were
c o m p l e t e in this p a r t i c u l a r p a t i e n t w i t h t u m o u r h y p o
g l y c a e m i a . A t t h e low level of free f a t t y acids, a r o u n d
0.4 # e q l m l , t h e p e r c e n t a g e of e x p i r e d C02 d e r i v e d
from glucose was 60.
glucose t u r n o v e r a n d b l o c k e d lipolysis t h e s e s u b j e c t s
d i d n o t become h y p o g l y e a e m i e , p r e s u m a b l y because
t h e liver was still c a p a b l e of i n c r e a s i n g glucose release.
Therefore, a b l o c k of h e p a t i c glucose release m u s t
a c c o m p a n y t h e i n h i b i t i o n of lipolysis to cause severe
.~ zlo/es/g/.~O rn<>z
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/o/e/ I/pi#$ of fafpa#s
0 2 S
/nsu/~n m/2/I0@ re/
Z B. suhjec/
0 2 6
Z B. subfec/
A p h a r m a c o l o g i c a l b l o c k of lipolysis alone does
n o t l e a d to p r o n o u n c e d h y p o g l y c a e m i a . CARLSO~ et
al. i n h i b i t e d lipolysis in exercising m e n b y t h e
adm i n i s t r a t i o n of nicotinic a c i d [
]. The b l o o d s u g a r was
lower t h a n in c o n t r o l subjects, b u t d e s p i t e i n c r e a s e d
h y p o g l y c a e m i a . The K c in our p a t i e n t Z . B . v a r i e d
from n o r m a l to e l e v a t e d values. A l t h o u g h t h e a p p a
r e n t correlation of low free fatty acids with a rapid
glucose turnover might speak in favour of glucose
uptake b y muscle, this could n o t be s u b s t a n t i a t e d b y
a r t e r i o - v e n o u s glucose differences. A c c o r d i n g to t h e
results p r e s e n t e d in T a b l e 2 t h e t u m o u r a p p e a r e d to
utilize glucose in a n u n c o n t r o l l e d fashion. Thus, t h e
v a r i a b l e glucose c o n s u m p t i o n b y t h e t u m o u r seems
to a g g r a v a t e h y p o g l y c a e m i a , t h e p r i n c i p l e cause of
w h i c h is t h e i n v a r i a b l e i n a b i l i t y of t h e liver t o release
glucose in sufficient q u a n t i t i e s .
Since t h e m e c h a n i s m s u n d e r l y i n g these two m e t a
bolic d i s t u r b a n c e s are still u n k n o w n a few
speculations m a y suggest new lines of i n v e s t i g a t i o n in f u r t h e r
cases of t u m o u r h y p o g l y c a e m i a .
TaMe 3. I n s u l i n - l i k e activities a n d i m m u n o r e a c t i v e i n s u l i n
at different blood sugar levels i n p a t i e n t Z . B .
Normal fasting values of nonsuppressible I L A : 168 ~: 32;
of suppressible I L A : 13 4-8; and of immunoreactive
sulin: 22.2 3.5 #U/ml serum (mean ~: SEM)
bloods u g a r
T h e r e are s e v e r a l possible correlations b e t w e e n
s e r u m free f a t t y acids a n d h e p a t i c glucose p r o d u c t i o n .
EZDINLI a n d SOKAL h a v e shown t h a t g l u c a g o n s t i m u
lates h e p a t i c glucose release m u c h m o r e efficiently
t h a n epinephrine, which is a c t i v e only in p h a r m a
P* = difference between the effects of the two sera.
P** = difference between the effects of the same serum before and after dialysis.
' . . . . . . . . ~ - - X ,
- , , , , /
A. JA~:OB et al. : The Pathogenesis of Tumour Hypoglyeaemia
cologieal doses . The effects of glueagon on hepatic
gluconeogenesis m a y be mimicked b y increasing the
free f a t t y acid concentration [
]. Therefore, it is
the block of hepatic glucose release, and it also led to
a rise of the free f a t t y acid level. However, a
normalization of the free f a t t y acid level in patient Z.B. did
not prevent hypoglycaemia but retarded its
developm e n t b y lowering the glucose assimilation. Therefore,
a direct link between the two blocks of lipolysis and
of hepatic glucose release through the level of the free
f a t t y acids is not apparent. I t would be of interest to
know whether the level of glueagon in these patients
is normal, and whether it rises during hypoglyeaemia
as in normal subjects. Two other hormones which
take p a r t in the endocrine eounterregulation of
hypoglycaemia, growth hormone and epinephrine, rose
during hypoglyeaemia i n patient Z.B.
Thus, the deficiencies of glucose release b y the
liver and of free f a t t y acid release b y adipose tissue do
not appear to be linked together b y an endocrine
A link between the two blocks m a y be construed
b y postulating t h a t both reactions, glycogenolysis and
lipolysis, might be subject to common inhibitors.
Serum of normal subjects inhibited spontaneous
lipolysis of adipose tissue of fasted-refed rats more
m a r k e d l y t h a n ean be attributed to its content of
suppressible and nonsuppressible ILA. After dialysis
the antilipolytie effects of serum corresponded to its
insulin-like effects on glucose u p t a k e of adipose tissue.
The serum of patient Z.B. inhibited lipolysis more
m a r k e d l y t h a n serum of normal subjects, and this
additional antilipolytic activity was dialyzable and
therefore exerted b y a substance of small moleeular
weight. Several groups of small molecular compounds
have been shown to inhibit spontaneous as well as
hormonally activated lipolysis of adipose tissue. ATP,
ADP, adenosine and other nucleosides and nueleotides
are active in concentrations down to 10-5 M [
substances are usually present in blood in minute
coneentrations and it is hardly conceivable t h a t
neerotizing t u m o u r tissues might release such compounds in
amounts large enough to inhibit lipolysis.
Furthermore, these compounds cause flushing, whieh these
patients do not exhibit. Another group of naturally
occuring antilipolytic compounds is t h a t of the
I I F 1 T I
0 10 30 50 70 901U4 C_ _ 110 130
min after injection of glucose
~'ig. 4. 1V[etabolism of gluoose-U-140 during the
development of spontaneous hypoglyeaemia in patient L.H. lO0
#C of glueose-lJ-ltC was administered together with 44 g
of unlabelled glucose
o - - o blood glucose (rag/100 ml);
. - - . specific activity of the blood glucose (cpm/Fmole) ;
9 9 specific activity of expired CO~ (epm/6 #moles);
A - - / k lactic acid (mg/100 ml 9 10-1);
A--A plasma free fatty acids (/~eq/ml 9 10-~)
conceivable t h a t glucagon acts on hepatic
glueoneogenesis b y first stimulating lipolysis in the liver, and
thereby increasing the free f a t t y acid level [
I n b o t h patients, a pharmacological dose of glucagon
1 mg administered intravenously rapidly overcame
A. JAKOB et al. : The Pathogenesis of Tumour Hypoglycaemia
staglandins. We are not aware of a n y data on the
content of prostaglandins in the blood and t u m o u r
tissue of these patients.
I t has been claimed t h a t lipolysis like hepatic
glycogenolysis is activated b y cyclic AMP, and t h a t
insulin and m a y be other substances inhibit lipolysis
b y decreasing the level of cyclic AMP in adipose tissue
]. However, even the m o s t p o t e n t antilipolytic drugs,
nicotinic acid and 5-methylpyrazole-3-carboxylic acid
which m a y occasionally lead to a transient depression
of the blood sugar through increased glucose u p t a k e
b y adipose tissue [
], never provoke hypoglycaemia
b u t rather hyperglycaemia when administered over
prolonged periods of time [
]. There is no evidence
to date t h a t antilipolytic substances m a y also decrease
hepatic glucose release.
We propose a more complex link between the two
well documented metabolic disturbances. SmVERSTEI~,
WAKr~ and BAH~ found t h a t mice inoculated with
tissue from a l y m p h a t i c leukaemic neoplasm exhibited
hypoglycaemia. A substance released b y the t u m o u r
was thought to be responsible for hypoglycaemia [
Later, the same authors extended this observation to
two patients with t u m o u r hypoglyeaemia. Since t h e y
observed elevated concentrations of 1-tryptophan and
its metabolites in the serum of these patients, t h e y
postulated t h a t t r y p t o p h a n might p l a y an i m p o r t a n t
role in the pathogenesis of t u m o u r hypoglycaemia
Many years ago, MII~SKu demonstrated t h a t
1t r y p t o p h a n m a y induce hypoglycaemia in rats [
l~ecently, RAY, FOSTE~ and LARDY observed t h a t
hepatic gluconeogenesis from p y r u v a t e was blocked in
rats treated with 1-tryptophan [
]. T h e y suggested
t h a t the enzyme phosphoenol-pyruvate-carboxy-kin.
ase, which was found to be activated in the liver
homogenate of rats pretreated with l-tryptophan, was
"non-functionM" in vivo.
Thus, an increased production of t r y p t o p h a n b y
the t u m o u r could explain the block of hepatic glucose
production. I n addition, t r y p t o p h a n is metabolized to
nicotinamide and nicotinic acid a m o n g other
compounds. Nicotinic acid is a v e r y potent inhibitor of
Hpolysis. An increased production of t r y p t o p h a n b y
the t u m o u r would, therefore, explain b o t h the block
of hepatic glucose release as well as the inhibition of
lipolysis b y its metabolites.
Increased levels of biological I L A in the blood or
in the t u m o u r were reported in several cases [
3, 34, 7
The meaning of such findings is questionable if the
assay systems were set up for the occasion, since a
considerable a m o u n t of experience with these
techniques is needed. Of the cases discussed in the literature,
only one showed a high value of immunoreactive I L A
on a single occasion [
]. I n our two patients
immunoreactive, suppressible and nonsuppressible I L A were
normal. I f anything, immunoreactive I L A was low,
and the B-cells appeared to have lost their ability to
respond to glucose with increased insulin secretion.
An "insulinoid" or insulin potentiating substance,
suggested b y UNGEa [
] Was searched for b y injecting
serum of patient Z.B. intravenously into rats
together with glucose-6-14C, and b y determining the
incorporation of carbon 14 into the diaphragm and the
fat pad of the rats. If the serum of patient Z.B. did
contain such a substance it should have increased
glucose incorporation, which it did not.
Diazoxide did not prevent hypoglycaemia b u t it
clearly delayed its onset. This clear cut amelioration
of glucose metabolism was not due to an effect on
hepatic glycogenolysis, but rather on lipolysis and
glucose consumption. Glyeogenolysis was not
improved on diazoxide, although this drug has been
suggested to affect the rate of glycogenolysis in
E n d o x a n was well tolerated b y the patient.
However, t u m o u r growth progressed steadily. I t is
notew o r t h y t h a t neither of our two patients showed the
typical picture of t u m o u r cachexia. Both patients had
an ample a m o u n t of subcutaneous adipose tissue. This
substantiates our chemical finding of blocked lipolysis,
which m a y have led to an accumulation of fat stores.
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