Letter to the editor

Diabetologia, Dec 1965

E. F. Pfeiffer, M. Telib, J. Ammon, F. Melani, H. Ditschuneit

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Letter to the editor

Received September Letter to the Editor I n comparison to i.v. glucose loading oral, glucose causes a more rapid fall in blood sugar from maxim u m value 1G.This finding is supported b y insulin determinations carried out in dogs and humans. I n spite of identical maximum values for blood sugar, the significantly higher blood insulin levels were evoked b y oral glucose loading as compared with i.v. administration 1,9. These findings raised the question of the participation of hepatic and intestinal factors in the mechanism of insulin secretion. Injection of secretin during parenteral administration of glucose accelerates the fall of blood glucose to such an extent t h a t half-life values are reduced by 50% 5. We therefore tried to prove a possibly direct acting, glucose-independent, stimulation of insulin secretion by secretin, utilizing isolated pancreatic tissue. Pancreatic tissues from dogs and rabbits with a maximal thickness of 1 m m and a weight of 150 to 200 mg were used. After a pre-ineubation period of 30 min in Krebs-Ringer bicarbonate buffer the tissue segments were incubated for 21~ hrs. in 4 ml of KrebsRinger bicarbonate buffer, saturated with oxygen, containing 0.16 M of fumarate, lactate and pyruvate. Secretin (Vitrum, Stockholm) containing no intrinsic insulin activity or immuno-insulin was used in concentrations of 0.01 and 0.I U/ml. Determinations of insulin-like activity (ILA) and of immunologically measurable insulin (IMI) were carried out according to the standard methods of our laboratory 4,11 based on Table. Secretion of insulin in vitro from pieces of dog and rabbit pancreatic tissue following incubation in Krebs-Ringer bicarbonate buffer, buffer and 200 rag% glucose, buffer and 0.01 U secretin/ml and 0.1 U secretin/ml - results described it m a y be reasonably concluded that the intestinal local hormone secretin per se stimulates insulin secretion independent of the blood glucose coneentration. Clinical implications might be found in a better understanding of the theoretical basis of the measuring of glucose assimilation (the k-value) following i.v. administration of small amounts of glucose2,3, the minor role of release of pancreatic insulin, the shorter halflife of glucose given i.v. following primary oral glucose administration 6, the smaller increase in blood glucose and the gTeater increase in insulin, following the second of the two glucose loads in the oral glucose tolerance test according to STAuB-TRAuGOTT14. Furthermore, in slightly older diabetics satisfactorily controlled b y diet alone as well as in pre-diabetics, oral glucose administration often leads to a definite increase in insulin 18,v, whereas i.v. administered glucose remains ineffective, with regard to the increase of plasma insulin 12. All of these observations might be explained b y the action of secretin on insulin liberation, which always takes place upon entrance of glucose into the body. Eventually, spontaneous hypoglycemia observed following oral carbohydrate in post-gastrectomized cases (Dumping-Syndrome) can also be attributed to the rapid secretion of secretin, effected by glucose, reaching the duodenal and jejunal cavity directly. As is generally known, the clinical picture of the Dumping-Syndrome can be reproduced in normal sub I%ABBIT DOG Controls Glucose200mg% 0 . 0 1 U / m l S e c r e t i n 0.1U/mlSecretin X am n X am n ILA IMI 4 ILA IMI 4 ILA IMI ILA IMI X = #U insulin (ILA = insulin-like activity and IMI = immunological measurable insulin), am = standard error of the mean, n = number of experiments. the original procedures of MARTIN et al. s and u et al.lL The results obtained are given in the table. First we examined the release of insulin into the incubation medium with glucose concentration. Maximal insulin release ( I L A + I M I ) was obtained at 200 mg%, up to 6fold of the release without glucose. This effect was also elicited b y both seeretin dilutions (0.01 and 0.1 U/ml) in the absence of glucose, the values being slightly higher after the administration of 0.1 U/ml. F r o m the jects b y intrajejunal administration of glucose15. B y this procedure the discrepancy between low blood glucose and high insulin levels is further enhanced l~ Addendum: Similar observations concerning direct stimulation of insulin secretion in vitro by sccretin were made b y MCINTY~E et al. l~ Unfortunately, the secretin preparations used b y lV[cINwY~E et al. (Boots, Nottingham) showed both immuno-insulinl~ and insulimlike activity (own unpublished observation). However, the insulin concentrations and activities Diabetologia m e a s u r e d in these preparations w e r e far b e l o w the insulin quantities released f r o m pancreatic pieces following addition of secretin 1~ ( o w n u n p u b l i s h e d observation), a n d in n o w a y invalidates the finding of a n insulin-stimulatory action of secretin. W i t h support of Deutsche Forsch~mgsgemeinschaft, B a d Godesberg, Germany. The authors wish to express their gratitude to Dr. MCINTu and Dr. TURNEa for m u t u a l exchange of ideas and sending the British Secretin preparation (Boots, Nottingham). A m o r e detailed report will be given elsewhere. R e f e r e n c e s i A R N O U L D , Y., R. BELLEI ~S, J. R. I ~. FRANCI~SON, a n d V. C O N A R D : Insulin response a n d glucose-C it disappearance rate during the glucose tolerance test in the unanesthetized dog . M e t a b o l i s m 12 , 1122 ( 1963 ). 2 B A S T E N I E , P. A. , a n d V. CONAI~D: Essai d'interpr~tation des dpreuves d'hyperglycdmie provoqude . Rev. Franc. Et. Clin. Biol . 2 , 223 ( 1957 ). 3 C O N A a D , V. : M e s u r e de l'assimilation d u glucose. A c t a gastro-enterolog . Belgiea 18 , 803 ( 1955 ). 4 I)ITSCHUN ]~IT,H., J . ~ ). FAULItABERund E. F. PFEIFFER Verbesserung der Methode zur B e s t i m m u n g yon Insulin im Blur m i t ttilfe r a d i o a k t i v e r 1-1~C-Glukose und d e m epididymalen l~attenfettgewebe. A t o m p r a - xis 8 , 172 ( 1962 ). 5 DuPR~, J . : An intestinal hormone affecting glucose disposal in man. L a n c e t I I No . 7361 , 672 ( 1964 ). 6 FRA:NOKSO1E, J . R . M . , P. A. BASTENIE , and V. CONtAin : Analyse de faeteurs i n t e r v e n a n t dans les modifications de l'assimilation glucidique apr~s ingestion de glucose . :Rev. Franc. Et. Clin. Biol . 5 , 702 ( 1960 ). 7 Gt~onsI4Y, G . M . , J . H. KARAI~ , F. Ctt . PAVLATOS,and P. H. FORS~AM : Serum-insulin response to glucose in prediabetic subjects. L a n c e t I I No . 7380 , 290 ( 1965 ). 8 MARTIN, D. B. , A. E. I= ~ENOLD,and Y. M. DAGENAIS: An assay for insulin-like-activity using r a t adipose tissue . Lancet I I , 76 ( 1958 ). 9 M C I N ~ Y R E , i~ ., C.D. H O L D S W O a T H , a n d D. S. T U R N E R : N e w interpretation of oral glucose tolerance . Lancet II No. 7349 , 20 ( 1964 ). Io -- , D. S. TUI ~NER, a n d C. D. H O L D S W O R T H : Intestinal factors a n d insulin secretion. a) First A n n u a l Meeting, Europ. Ass. for the S t u d y of Diabetes , 20 .-- 22 . 4. 1965 , Montecatini T e r m e , Diabetologia I , 73 . b) Verbal Version of 10a. llMELANI , F. , H. DITSCttU1WEIT , K.M. BARTELT , H. F~IEDRICH a n d E . F . PFEIFFER: U b e r die radioimmunologische B e s t i m m u n g yon Insulin im Blur . Klin. Wschr . 43 , 1000 ( 1965 ). 12 PFEIFFER , E . F . : Recognized diabetogenic hormones and diabetes in man. I n : On the nature and treatm e n t of diabetes mellitus. (Proc V. Congr. I n t e r n a t . Federation, J u l i 1964 , Toronto). E x c e r p t a Medica, A m s t e r d a m (in press) . Chapt. 26 , p. 36 ..8, 1965 . 13 - - , I-I. DITSCHUNEIT und R. ZIEGLE~: U b e r die Bes t i m m u n g yon Insulin im Blur a m epididymalen F e t t a n h a n g der 1Ratte m i t Hilfe markierter Glukose. IV. Die D y n a m i k der InsulinsekretJon des Stoffwechselgesunden a n d des Altersdiabetikers nach wiederholter Belastung m i t Glukose, Sulfonylharnstoffen a n d menschlichem Wachstumshormon, ein Beitrag zur Pathogenese des menschlichen Altersdiabetes . Klin. Wsehr . 39 , 415 ( 1961 ). i4 -- , M. PFEIFFER , H. D I T S C H U N E I T a n d C H A N ~ - S U A ~ N : 1~ber die B e s t i m m u n g y o n Insulin i m Blut a m epid i d y m a l e n F e t t a n h a n g der Ratte mit Hilfe markierter Glukose. II. Experimentelle a n d klinische Erfahrungen . Kiln. ~r 37 , 1239 ( 1959 ). 15 S C H R A D E , W . : N a c h k r a n k h e i t e n n a e h Magenoperationen. Dtsch. M e d . Wsehr . 77 , 1087 ( 1952 ). i6 S c o w , 1 %. P., a n d J . CO]~NFIEL]) : Quantitative relations b e t w e e n the oral a n d intravenous glucose tolerance curves. A m . J. Physiol . 179 , 435 ( 1954 ). iT Y A L O W , R . S., a n d S. A. B E R S O N : I m m u n o a s s a y of p l a s m a insulin concentrations in n o r m a l a n d diabetic m a n : Insulin secretory response to glucose a n d other agents . J. Clin. Invest . 39 , 1041 ( 1960 ). 2. F. PFEII ~FER, M . TELIB , J. AIVIIKON , F. MELAl~I a n d H. DITSCHUIVEIT Abteilung ffir ]{linische Endokrinologie, I. Medizinisehe 141inik der JohannWolfgang-Goethe-Universitt a n d der Stadt Frankfurt a m Main.

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E. F. Pfeiffer, M. Telib, J. Ammon, F. Melani, H. Ditschuneit. Letter to the editor, Diabetologia, 1965, 131-132, DOI: 10.1007/BF00421489