The pathogenesis of tumour hypoglycaemia: Blocks of hepatic glucose release and of adipose tissue lipolysis

Diabetologia, Dec 1967

Summary Earlier findings on the pathogenesis of tumour hypoglycaemia [15] 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 fatty 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 ILA measuredin vitro andin vivo were normal. — However, the serum of patient Z.B. inhibited lipolysis of adipose tissuein 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 may increase glucose assimilation and glucose oxidation. — An attempt is being made to characterize further the antilipolytic substance which is present in increased amounts in the serum of patients with tumour hypoglycaemia.

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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* Diabetologia 0 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 [15] 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. - Switzerland 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 [ 15 ] 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 hormone. 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 [ 22 ], [ 19 ] a n d [26a].). 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~ [ 33 ]. 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 [ 15 ]. 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 [ 20 ]. Case report 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 hypoglycaemie attacks. 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 be established. Necropsy findings 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 . Methods B l o o d glucose was m e a s u r e d w i t h glucose oxidase [ 1 ]. 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 [ 35 ]. 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 [ 17 ]. 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 [ 2 ]. l~C-labelled 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 [11]. 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 glucose. 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 [ 16 ]. 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 [ 4, 14 ]. 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 [12]. 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 [ 9 ]. Results 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 hormones 9 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 no lherep# lingglucegoniv. diazoxide, 22s 0.8 0..6 0.4 0.2 I 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 1 l 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 glucose incorporation. \._/ I I I 2 I 3 ~ I 4 grOWh/IorzToneI%1O S , / ~ e - . uz'/nar# e....._ _ _ . . * ~~0-- / no,-,epine0p~hrin.f...-'~ ep/neOp_/iz_r_/h_e~.~- 27 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 [ 16 ]. 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 m#/700,'z/ 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 E too~e, /g/YOml~. ~7/,!/cogen of <//'ep/Tr',~#rn /o/e/ I/pi#$ of fafpa#s 4 5 " 7 1 0 2 S /nsu/~n m/2/I0@ re/ 1 in~serum pe/-ienf norms~ Z B. suhjec/ 0 2 6 insu//nmU/lOOg rat Iml s~rwrn #a/ion/ Icor'~o'/ 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 [ 8 ]. 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 in sulin: 22.2  3.5 #U/ml serum (mean ~: SEM) bloods u g a r rag/100 ml nonsuppressible suppressible ILA ILA /~U/ml /~U/ral 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. III 1:50 IV dialysed 1:10 ' . . . . . . . . ~ - - X , - , , , , / o " .....~ A. JA~:OB et al. : The Pathogenesis of Tumour Hypoglyeaemia cologieal doses [10]. The effects of glueagon on hepatic gluconeogenesis m a y be mimicked b y increasing the free f a t t y acid concentration [ 37 ]. 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 disorder. 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 [ 21 ]. These 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 protog 200 -100 50 25 150 100 5 0 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 [ 36, 32 ]. 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 [ 5 ]. 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 [ 13 ], never provoke hypoglycaemia b u t rather hyperglycaemia when administered over prolonged periods of time [ 24 ]. 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 [ 30 ]. 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 [ 31 ]. 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 [ 23 ]. 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 [ 21 ]. 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 [ 26 ]. 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 [ 33 ] 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 animals [ 29 ]. 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. Literature [1] BERG~EYER , H . U . , and E. BERNT, in: BERGMEYER, H.U. : Methoden der enzymatischen Analyse . Weinhelm, Germany, Verlag Chemic, S. 123 -- 130 , 1962 . [2] BERTLER , A. , A. CAI~LSSONand E. ROSENGEEN : A method for the fluorimetric determination of adrenalin and noradrenalin in tissues . Acta physiol. scand . 44 , 273 -- 292 ( 1958 ). [3] BosHELL , B.t~., J . J . KIRSCIt-ENFELD and P.S. SOTERES : Extrapancreatie insulin-secreting tumor . 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LABItART: Nonsuppressible insulin-like activity of h u m a n serum: 1)urification, physicochemical and biological properties and its relation to total serum ILA . Recent Progr. Hormone Res . 23 , 565 -- 616 ( 1967 ). [14] -- -- E.B. RAMSEIER , P. BAttY and A . LABHART: Antibody-suppressible and nonsuppressible insulinlike activities in h u m a n serum and their physiological significance. An insulin assay with adipose tissue of increased precision and specificity . J. clin. Invest . 42 , 1816 -- 1834 ( 1963 ). [15] -- -- W. ZmGLER , P. BAndY and A . LAB~ART: Zur Pathogenese der tumorbedingten Hypoglyk/~mie ohne Hyperinsulinismus . Schweiz. reed. Wschr . 93 , t250 -- 1255 ( 1963 ). [16] -- W .A. MUE~LER, H. BUERGI , M. WALDVOGELand A. LABHART : Nonsuppressible insulin-like activity of h u m a n serum. II. Biological properties of plasma extracts with nonsuppressible insulin-like activity . Biochim. biophys. Acta 121 , 360 -- 374 ( 1966 ). [17] GORDON, :R.S., J ~.: Unesterified fatty acids in hum a n blood plasma. II. The transport function of unesterified fatty acids . J. d i n . Invest . 36 , 810 -- 815 ( 1957 ). [18] HALES , E.N. , and P . J . RA ~ CDLE: Immunoassay of insulin with insulin-antibody precipitate . Bioehem. J . 88 , 137 -- 146 ( 1963 ). [19] HOBBS , C.B. , and A.L. MILLER : :Review of endocrine syndroms associated with tumors of nonendocrine origin . J. clin. Path . 19 , 119 -- 127 ( 1966 ). [20] JAKOB , A. , N. LA ~-PER, : R. FLUKY , A. LAB/~ARTand E.I~. FROESCH: Pathogenesis of tumor hypoglycemia . Diabetologia 2 , 202 -- 203 ( 1966 ). [21] K ~P~ELE~ , H.: Zur l~harmakologie tier Lipolysehemmung. I. Wirkungsweise adenosinhaltiger Nucleoside u n d Nucleotide auf die Lipolyse des Fettgewebes in vitro . Diabetologia 2 , 52 -- 61 ( 1966 ). [22] MARKS , V. , and E. SA ~o~s: Hypoglycemia of nonendocrine origin (non-islet cell tumors) . Proe. roy. Soc. Med . 59 , 338 -- 340 ( 1966 ). [23] MmsKY , I . 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A. Jakob, U. A. Meyer, R. Flury, W. H. Ziegler, A. Labhart, E. R. Froesch. The pathogenesis of tumour hypoglycaemia: Blocks of hepatic glucose release and of adipose tissue lipolysis, Diabetologia, 1967, 506-514, DOI: 10.1007/BF01213569