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The effect of pancreatic duct ligation on the gastric inhibitory polypeptide (GIP), gastric acid secretion.. 1982

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THE EFFECT OF PANCREATIC DUCT LIGATION ON THE GASTRIC INHIBITORY POLYPEPTIDE (GIP), GASTRIC ACID SECRETION AND GLUCOSE METABOLISM IN DOGS BY Akira Nakayasu, M.D., F.A.C.S. University of B r i t i s h Columbia, 1982 A thesis submitted i n p a r t i a l f u l f i l m e n t of the requirements f o r the DEGREE OF MASTER OF SCIENCE. in THE DEPARTMENT OF SURGERY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 1982. © A k i r a Nakayasu, 1982. In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date 15th July, 1982 DE-6 (3/81) i i Supervisor: Dr. I. G. M. Cleator ABSTRACT (A) Gastric Secretion The present study was performed to investigate the canine post-pancreatic duct l i g a t i o n GIP secretion i n response to f a t ingestion using a meat meal mixed with unhydrolyzed or hydrolyzed whipping cream, and to determine whether GIP plays a role in the production of hyperacid secretion i n the pancreatic duct l i g a t e d dogs. Four mongrel female dogs were prepared with Heidenhain pouch (HP) and g a s t r i c f i s t u l a (GF), and d a i l y acid secretion from the HP was measured before and a f t e r pancreatic duct l i g a t i o n (PDL). HP acid output, serum immunoreactive ga s t r i n (IR-Ga) and serum immunoreactive g a s t r i c i n h i b i t o r y polypeptide (IR-GIP) concentrations during f i v e hours following oral ingestion of a meat meal alone, a meat meal mixed with 125g of unhydrolyzed cream and meat meal mixed with 125g of hydrolyzed cream were measured before and a f t e r PDL. Twenty four hour HP acid outputs increased s i g n i f i c a n t l y in each of the four dogs a f t e r PDL. Five hour HP acid outputs in response to a meat meal alone and a meat meal plus unhydrolyzed cream were modestly increased, while those i n response to a meat meal plus hydrolyzed cream were rather reduced a f t e r PDL. Serum IR-Ga responses to a l l stimulants were lowered a f t e r PDL and those to meat meal plus hydrolyzed cream lowered most markedly. i i i Serum IR-GIP responses to a meat meal a lone were s i g n i f i c a n t l y i n c r e a s e d , w h i l e those t o a meat meal p l us unhydrolyzed and hydro lyzed cream were reduced. The r e s u l t s of the p resen t study demonstrate serum IR-GIP i n response to a meat meal i s i nc reased by PDL i n dogs, suggest ing augmented a c i d j u i c e pass ing i n t o the i n t e s t i n a l lumen i s r e s p o n s i b l e f o r the i nc reased GIP response. I t i s i n d i c a t e d tha t hypo -sec re t i on of GIP i s not the cause of hype rsec re t i on of g a s t r i c a c i d i n the PDL dogs. (B) Glucose Metabo l ism. F u n c t i o n a l a l t e r a t i o n i n g lucose homeostasis e s p e c i a l l y concern ing the ea r l y onset of d iabe tes a f t e r PDL was s tud ied i n dogs. Intravenous ( i . v . ) and i n t r a g a s t r i c g lucose t o l e r a n c e t e s t s were performed at two to ten weeks and two weeks a f t e r PDL r e s p e c t i v e l y . Serum g lucose , IR I , and IR-GIP i n response to a meat meal w i th and w i thout unhydrolyzed or hydro lyzed f a t were est imated at s i x weeks a f t e r PDL. S i g n i f i c a n t l y impaired g lucose t o l e r a n c e and e a r l y phase IRI s e c r e t i o n a f t e r i . v . g lucose were shown a t two to ten weeks a f t e r PDL. I n t r a g a s t r i c g lucose load revea led delayed p a t t e r n of serum g lucose and IRI (no evidence of g lucose i n t o l e r a n c e or d im in i shed IRI s e c r e t i o n ) , i n d i c a t i n g decreased g a s t r i c m o t i l i t y a f t e r PDL. Serum IR-GIP response to i n t r a g a s t r i c g lucose load was not a t tenuated by the ope ra t i on but showed a s i m i l a r p a t t e r n to IRI response. Serum IRI responses to meat meals w i th and w i thout unhydrolyzed or hydro lyzed cream were impaired a f t e r PDL. i v I t i s i n d i c a t e d tha t * dogs a f t e r PDL show e a r l y onset (two to ten weeks) of d i a b e t e s , i . e . b lun ted e a r l y phase i n s u l i n s e c r e t i o n , 2 the mechanism of GIP s e c r e t i o n as an i n s u l i n o t r o p i c enterohormone remains i n t a c t a f t e r PDL i f s u f f i c i e n t s t imu lan ts are g i v e n . V TABLE OF CONTENTS 1. INTRODUCTION 1 2. PURPOSE OF STUDY 14 3. MATERIALS AND METHODS 15 1) Twenty four hour acid study. 2) Five hour acid, immunoreactive gastrin (IR-Ga) and immunoreactive gastric inhibitory polypeptide (IR-GIP), immunoreactive insulin (IRI), and glucose responses to a meat meal alone. 3) Effect of ingestion of fat (unhydrolyzed and hydrolyzed) on five hour acid, IR-Ga, IR-GIP, IRI, and glucose responses to a meat meal alone. 4) Serum glucose and IRI responses to i.v. glucose load and serum glucose, IRI, and IR-GIP responses to intragastric glucose load. 5) Assays. 4. RESULTS 21 1) Twenty four hour acid study. v i 2) Five hour, IR-Ga, IR-GIP, IRI, and glucose responses to a meat meal alone. 3) Five hour, IR-Ga, IR-GIP, IRI, and glucose responses to a meat meal plus unhydrolyzed cream. 4) Five hour, IR-Ga, IR-GIP, IRI, and glucose responses to a meat meal plus hydrolyzed cream. 5) Serum glucose, IRI and IR-GIP responses to intragastric glucose. 5. DISCUSSION 29 6. CLINICAL OBSERVATIONS AND PROJECTIONS FOR THE FUTURE 46 7. FIGURES 51-71 8 . PHOTOGRAPH .91 9. BIBLIOGRAPHY 72 10. APPENDIX 84 VI 1 LIST OF FIGURES Figure 1 Twenty four hour acid outputs from the Heidenhain pouch before and after pancreatic duct ligation (PDL). Figure 2 Acid response from the Heidenhain pouch to meat meal alone before and after PDL. Figure 3 Serum gastrin response to meat meal alone before and after PDL. Figure 4 Serum GIP response to meat meal alone before and after PDL. Figure 5 Serum IR response to meat meal alone before and after PDL. Figure 6 Serum glucose response to meat meal alone before and after PDL. Figure 7 Acid response from the Heidenhain pouch to meat meal plus unhydrolyzed cream before and after PDL. Figure 8 Serum gastrin response to meat meal plus unhydrolyzed cream before and after PDL. Figure 9 Serum GIP response to meat meal plus unhydrolyzed cream before and after PDL. v i i i F i g u r e 10 Serum IRI response to meat meal p lus unhydrolyzed cream before and a f t e r PDL. F i g u r e 11 Serum g lucose response to meat meal p lus unhydrolyzed cream before and a f t e r PDL. F i g u r e 12 A c i d response from the Heidenhain pouch to meat meal p lus hydro lyzed cream before and a f t e r PDL. F i g u r e 13 Serum g a s t r i n response to meat meal p lus hydro lyzed cream be fo re and a f t e r PDL. F i g u r e 14 Serum GIP response to meat meal p lus hydro lyzed cream before and a f t e r PDL. F i g u r e 15 Serum IRI response to meat meal p lus hydro lyzed cream before and a f t e r PDL. F i g u r e 16 Serum g lucose response to meat meal p lus hydro lyzed cream before and a f t e r PDL. F i g u r e 17 Serum g lucose response to i . v . g lucose load be fore and a f t e r PDL. F i g u r e 18 Serum IRI response to i . v . g lucose load before and a f t e r PDL. i x F i g u r e 19 Serum g lucose response to i n t r a g a s t r i c g lucose load before and a f t e r PDL. F i g u r e 20 Serum IRI response to i n t r a g a s t r i c g lucose load be fore and a f t e r PDL. F i g u r e 21 Serum 6IP response to i n t r a g a s t r i c g lucose load be fo re and a f t e r PDL. X PHOTOGRAPH Photo 1: Gross pathology of post-mortem pancreas. x i ACKNOWLEDGEMENT I wish to express my sincere gratitude to Iain G. M. Cleator, my teacher i n the M.Sc. thesi s , who gave me personal guidance, encouragement and advice. Without his interest and knowledge t h i s work would not have been completed. R. Cameron Harrison, Professor i n the Department of Surgery, U.B.C, to whom I am grateful for his i n t e l l i g e n t c r i t i c i s m , his advice and friendship. John C. Brown, Professor i n the Department of Physiology, U.B.C, who provided the GIP antisera. Anthony J . Dowel 1, my post-graduate course colleague f o r stimulating c o l l a b o r a t i o n with valuable c r i t i c i s m . Nicola O'Connor, f o r excellent technical assistance. My sincere thanks also go to: Takeo Yamagishi, Research Fellow in the Department of Surgery, U.B.C, for his valuable c r i t i c i s m . Raphael L u i , f o r helping me with the necessary arrangements. Jan van den Broek and a l l the s t a f f of the Animal Laboratory in the Department of Surgery, U.B.C, for t h e i r s k i l l e d laboratory assistance. 1 INTRODUCTION Canine g a s t r i c hype rsec re t i on f o l l o w i n g PDL i s a wel l -known phenomenon, 1»2,3,4 bUt, the mechanism(s) f o r t h i s phenomenon remains obscure. I t i s g e n e r a l l y accepted tha t the g a s t r i c hype rsec re t i on may be due i n p a r t to the absence of by-products of f a t d i g e s t i o n which normal ly s t imu la te r e l e a s e of g a s t r i c i n h i b i t o r y hormone(s) from the duodenum and smal l bowel.5 Feng e t al*> demonstrated tha t duodenal i r r i g a t i o n by f a t suppressed the a c i d s e c r e t i o n of t r ansp lan ted g a s t r i c pouches, i n d i c a t i n g t h a t the i n h i b i t i o n was humoral ly mediated, and Kosaka and L i m 7 proposed the name "en te rogas t rone" f o r the humoral i n h i b i t o r y agent. GIP has been found to s a t i s f y the c r i t e r i a as an enterogast rone i n dogs,8 but i n innerva ted stomach p repa ra t i ons of the dog9 and in normal man^O i n h i b i t i o n of p e n t a g a s t r i n s t i m u l a t e d a c i d s e c r e t i o n by GIP was found to be weak. I t has been specu la ted tha t a d i s t u r b e d GIP r e l e a s e may be r e s p o n s i b l e f o r the abnormal a c i d s e c r e t i o n i n duodenal u l c e r d i s e a s e . Cont ra ry to t h i s assumpt ion, an exaggerated GIP r e l e a s e f o l l o w i n g o ra l g lucose or t e s t meal was observed i n p a t i e n t s w i th duodenal u l c e r . H > 1 2 GIP i s known to p o t e n t i a t e g lucose induced i n s u l i n r e l e a s e , and the i nc rease i n b lood l e v e l s of g lucose and GIP i n the ma jo r i t y of duodenal u l c e r p a t i e n t s , l ead ing to an inc reased i n s u l i n response, might be exp la ined by an enhanced absorp t ion of g lucose by the smal l bowel mucosa, p o s s i b l y as a consequence of an abnormal ly r a p i d ra te of g a s t r i c emptying and/or inc reased i n t e s t i n a l m o t i l i t y ^ . 2 Eber t e t a l l ^ demonstrated in t raduodenal i n f u s i o n of h y d r o c h l o r i c ac i d (HCl) dose dependent ly p o t e n t i a t e s g lucose induced i n s u l i n r e l e a s e i n r a t s , w h i l e Brown et a U 5 f a i l e d to show IR-GIP r e l e a s e i n dogs by H C l . R e c e n t l y , LeRo i th et a l 1 6 showed tha t HCl by i t s e l f i s capab le of s t i m u l a t i n g GIP i n man, suggest ing p h y s i o l o g i c a l s i g n i f i c a n c e of a c i d induced GIP s e c r e t i o n . Func t i ona l a l t e r a t i o n i n g lucose metabol ism as we l l as g a s t r i c ac id s e c r e t i o n i s an important p h y s i o l o g i c a l problem i n human and animal performed PDL. I t i s we l l known tha t PDL r e s u l t s i n atrophy and f i b r o s i s o f the exoc r ine p a n c r e a t i c t i s s u e . D e t a i l e d morphologica l s t u d i e s 1 7 a t va r ious i n t e r v a l s a f t e r PDL i n r a t s have revea led tha t ac i na r c e l l s complete ly d isappear w i t h i n one week and never reappear, and PDL caused some i n i t i a l damage to the i s l e t w i th subsequent regenera t ion of the i s l e t parenchyma. Whether the endocr ine f u n c t i o n w i l l f i n a l l y d e t e r i o r a t e a f t e r PDL or not has so f a r been c o n t r o v e r s i a l . Heptner et a l 1 ^ observed tha t four to s i x months a f t e r PDL i n dogs both the i n t r a g a s t r i c and the i . v . g lucose t o l e r a n c e were impai red and the i nc rease i n serum IRI was d imin ished a f t e r i n t r a g a s t r i c and i . v . g lucose l o a d , i n d i c a t i n g the abnormal i ty i n g lucose t o l e rance as a consequence of i s l e t c e l l damage a f t e r PDL. 3 PURPOSE OF STUDY The purpose of the present study is to investigate the canine post-PDL GIP secretion in response to fat ingestion using a meat meal mixed with unhydrolyzed or hydrolzyed cream, and to determine whether GIP plays a role in the production of hyperacid secretion in the PDL dogs. The present study was also designed to obtain further information about earlier changes of glucose tolerance after PDL in dogs. 4 MATERIALS AND METHODS Four healthy mongrel dogs, initially weighing between 15 and 20 kg were used. They were prepared with Heidenhain pouch (HP) and gastric fistula (GF). The GF was made in the most dependent portion of the stomach. Stainless steel canulas were used for the HP and GF. After allowing three weeks for recovery, the first series of tests was started as control study. 1. Twenty Four Hour Acid Study. Twenty four hour gastric secretion was collected daily in a glass bottle attached to the HP cannula for 14 to 24 days in which no other test was done. The daily standard meal consisted of l,000g of a dog kibble (Wayne Dog Food, Allied Miles Inc., Chicago). Ingredients: protein 25% (250g), fat 8% (80g), linoleic acid 2% (20g), calcium 2% (20g), etc.) The bottle was emptied each morning. Volume and acid output were measured daily. Acid concentration was determined by titration with 0.1 N NaOH to pH 7 on an automatic titrator (Radiometer, Copenhagen). The result of each day's acid production was expressed in milliequivalents. 2. Five Hour Acid, IR-Ga, IR-GIP, IRI and Glucose Responses To A Meat Meal Alone. Before each test the dog was fasted for at least 18 hours. For one hour before each test the GF was kept open to ensure that the dog's stomach was entirely empty. The dog was then allowed to stand in the dog 5 stand w i th a support under the dog 's abdomen to prevent the dog from s i t t i n g down. An i . v . i n f u s i o n l i n e was in t roduced i n to the l a r g e v e i n on the a n t e r i o r aspect o f the f o re l imb f o r b lood samples. I n fus ions of 154 mM NaCl were d e l i v e r e d through po lye thy lene tub ing i n to the leg v e i n . A p e r i s t a l t i c pump (Harvard Apparatus Company, Dover, Mass.) mainta ined the i n f u s i o n at 60 m l / h r . Each dog was tes ted e i t h e r tw ice or three t imes per week. There was always a t l e a s t 48 hours between each t e s t . A mod i f i ed washout techn ique was used to c o l l e c t a c c u r a t e l y the s e c r e t i o n of the HP: At the end of each 15 minute c o l l e c t i o n p e r i o d , 50 ml s y r i nge was connected to the s t a i n l e s s canu la and 20 ml of p h y s i o l o g i c a l s a l i n e was i n s t i l l e d i n t o the HP us ing the sy r i nge to i r r i g a t e gen t l y the HP t w i c e . The volume of each sample was measured to w i t h i n 0 .2 m l , and t o t a l ac id was determined as s t a t e d above. Basal s e c r e t i o n f rom HP was c o l l e c t e d f o r two 15 minute p e r i o d s . A measured 15 oz (425 g) meat meal (Dr. B a l l a r d ' s Dog Food, Standard Brands L t d . , Canada. I ng red ien t s : p r o t e i n 9% (38g) , f a t 5% (21g)) were g iven to each dog. Fo r f i v e hours f o l l o w i n g the s tandard meat meal , HP s e c r e t i o n was c o l l e c t e d at 15 minute i n t e r v a l s . The GF was kept c l osed dur ing the feed ing exper iments . Each dog had venous b lood drawn f o r serum IR-Ga, IR-GIP, IRI and g lucose de te rmina t ions at f a s t i n g , 15, 30, 45 , 60, 90, 120, 150, 180, 210, 270 and 300 minutes f o l l o w i n g the meal . B lood samples were c e n t r i f u g e d w i t h i n one hour, the serum separated and kept f r ozen u n t i l IR-Ga, IR-GIP , 6 IRI and g lucose de te rmina t ions were performed. The standard meal s t i m u l a t i o n s were performed tw ice i n each dog. 3 . E f f e c t of I nges t i on of Fa t (Unhydrolyzed and Hydro lyzed) on F i v e Hour A c i d , IR-Ga, IR-GIP, IRI and Glucose Responses to a Meat M e a l . 125g of cream (S i lverwood Sh ipp ing Cream, S i l verwood D a i r i e s , Toronto, Canada. I ng red ien t s : p r o t e i n 2 . 6 g ; f a t 3 8 . 2 g ; sa tu ra ted f a t t y ac ids 21 .4g ; o l e i c ac i d 1 3 . l g ; l i n o l e i c ac i d I g ; carbohydrate 4 . 2 g ; ca l c i um 0.1 g) was mixed w i th 15oz standard meat meal and inges ted w i t h i n th ree minutes. On another o c c a s i o n , the same amount of cream was incubated w i th th ree capsu les of Cotazymes (Organon C o . , Toronto, Canada: each capsu le con ta ins 800 u n i t s of panc rea t i c l i p a s e ) f o r th ree hours at 37°C (hydro lyzed f a t ) (see APPENDIX) and mixed w i th 15oz s tandard meat meal and ingested w i t h i n th ree minutes. F o r f i v e hours f o l l o w i n g the meat meal mixed w i th unhydrolyzed or hydro lyzed cream, HP s e c r e t i o n was c o l l e c t e d at 15 minute i n t e r v a l s . The volume of each sample was measured, and t o t a l ac i d was determined as desc r i bed above. Venous b lood was drawn f o r serum IR-Ga, IR-GIP, IRI and g lucose de te rmina t ions a t f a s t i n g , 15, 30, 45 , 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes f o l l o w i n g the meal . Those t e s t s were each performed tw ice i n each dog. 7 4 . Serum Glucose and IRI Responses to i . v . Glucose Load, and Serum Glucose , IRI and IR-GIP Responses to I n t r a g a s t r i c G lucose Load. P a n c r e a t i c endocr ine f u n c t i o n was examined by i . v . and i n t r a g a s t r i c g lucose t o l e r a n c e t e s t s w i th dext rose s o l u t i o n ( Ig /kg body weight) and P a l - a - d e x 100 ( J . T. Baker Chemical C o . , P h i l 1 i psbu rg , New J e r s e y ; 2g/kg body we igh t ) , r e s p e c t i v e l y . 50% dext rose s o l u t i o n w i th an equal volume of s a l i n e was in fused over a two to four minute p e r i o d . P a l - a - d e x was g iven i n t r a g a s t r i c a l l y by means of the GF. Under f a s t i n g c o n d i t i o n s f o r at l e a s t 18 hours , p e r i p h e r a l venous blood was sampled at p r e - i n j e c t i o n , 15, 30, 45 and 60 minutes a f t e r i . v . g lucose l o a d , and a t f a s t i n g , 15, 30, 60, 90, 120, 150, and 180 minutes a f t e r i n t r a g a s t r i c g lucose l o a d . The t e s t s were performed tw ice i n each dog. Blood samples were cen t r i f uged w i t h i n one hour, the serum separated and kept f rozen u n t i l g l ucose , IR I , and IR-GIP de termina t ions were per formed. A f t e r complet ing a l l the con t ro l s t u d i e s , PDL was performed on a l l dogs: under general i n t u b a t i o n anes thes ia , both the major and minor p a n c r e a t i c ducts were l i g a t e d , and the pancreas was separated from the duodenum by i n t e r p o s i t i o n of the omentum. F o l l o w i n g PDL, the f i r s t s e r i e s of t e s t s was repeated : 24 hour study was s t a r t e d one week a f t e r PDL and f i v e hour a c i d , IR-Ga, IR-GIP, IRI and g lucose i n response to meal i n g e s t i o n were es t imated at f ou r to e igh t weeks ( s i x weeks i n average) a f t e r PDL, w h i l e 1 serum g lucose and IRI i n response to i . v . g l ucose , and 2 serum g lucose , IRI and IR-GIP i n response to i n t r a g a s t r i c g lucose were 8 est imated at two and ten weeks, and two weeks a f t e r PDL, r e s p e c t i v e l y . L i v e r f u n c t i o n t e s t s were performed ten days and s i x weeks a f t e r PDL on a l l of f ou r dogs. Serum g lu tamic o x a l o a c e t i c t ransaminase was s l i g h t l y inc reased in th ree of four dogs, serum a l k a l i n e phosphatase s l i g h t l y to moderately inc reased i n a l l dogs, and serum albumin s l i g h t l y inc reased i n th ree of four dogs. Changes of serum amylase and ca l c ium were not c o n s i s t e n t . Body weight of the dogs was s t a t i o n a r y to s l i g h t l y inc reased except one dog i n which marked l o s s o f body weight was observed. Marked s tea to r rhea was not observed i n any dog. A f t e r comple t ing a l l t e s t s f o l l o w i n g PDL, autopsy was performed on a l l dogs. Marked atrophy of the pancreas and mi ld to moderate hemorrhagic gas t roduoden i t i s were observed i n a l l dogs s t u d i e d . 5 . Assays . Serum IR-Ga, IR-GIP and IRI concen t ra t i ons were measured i n d u p l i c a t e us ing the Schwarz/Mann G a s t r i n Radioimmunoassay K i t , the method of Kuz io et a l , 1 9 and the Amersham Radioimmunoassay K i t , r e s p e c t i v e l y ; and serum g lucose concen t ra t i ons us ing a Beckman g lucose a n a l y z e r . The c ross r e a c t i v i t y check of the GIP an t ibody , GP01 (purchased from Dr. J . C. Brown, U n i v e r s i t y of B r i t i s h Co lumbia) , i s as f o l l o w s : m o t i l i n , 0.1%; i n s u l i n , 0.02%, C - t e r GIP minus) , 135%; N- te r GIP minus) , 1.0%; 9 CCK, 1.1% VIP, 0.05%, secretin and glucagon, no cross reactivity. Integrated acid, IR-Ga, IR-GIP, IRI and glucose responses were calculated as previously described (20). Results are given as mean ± standard error of the mean (SEM). GP01 was a reliable antibody, but i t was discovered subsequent to the completion of this work, that i t recognized only one of the G.I.P. moieties and our levels are therefore lower than those using an antiserum that recognized both. Statistical comparisons between mean responses on the different stimulations and between pre and post PDL conditions were made using the multiple comparison method of Scheffe.21. Values of less than 0.05 were considered statistically significant. 10 RESULTS 1. Twenty Four Hour Study. Twenty four hour HP acid outputs increased significantly (p < 0.05) in each of the four dogs after PDL (Fig. 1). This rise occured one to two weeks postoperatively in all dogs studied. 2. Five Hour Acid, IR-Ga, IR-GIP, IRI and Glucose Responses to a Meat Meal Alone. The mean fasting HP acid outputs were not significantly different in the pre and post-pancreatic duct 1igated dogs (0.038 + 0.010 mEq/15 minutes before PDL vs. 0.061 + 0.030 mEq/15 minutes after PDL). The mean peak acid outputs from the HP before and after PDL were 0.664 + 0.174 mEq/15 minutes at 150 minutes and 0.719 + 0.124 mEq/15 minutes at 135 minutes, respectively. Following PDL, the HP acid was augmented, but there was no significant difference at each of the time points (Fig. 2). Integrated HP acid outputs during five hour period after the meat meal were greater than those prior to PDL (98 + 27 mEq/five hours before PDL vs. 113 ± 34 mEq/five hours after PDL), but with no significant difference. The mean fasting serum IR-Ga concentrations in the four dogs after PDL were lower than those before PDL but not statistically significant (103 + 12 pg/ml before PDL vs. 86 ± 13 pg/ml after PDL). The mean IR-Ga concentrations were lower in the PDL dogs than in the control dogs, but 11 the d i f f e r e n c e was not s t a s t i c a l l y s i g n i f i c a n t ( F i g . 3 ) . No s i g n i f i c a n t d i f f e r e n c e s i n basal IR-GIP concen t ra t i ons were found between the pre and post-PDL dogs. The mean peak IR-GIP concen t ra t i ons before and a f t e r PDL were 468 ± 52 pg/ml at 60 minutes and 610 ± 110 pg/ml a t 60 minutes a f t e r PDL, r e s p e c t i v e l y , and the d i f f e r e n c e was s t a t i s t i c a l l y s i g n i f i c a n t (p < 0.05) F i g . 4 ) . In tegra ted serum IR-GIP response dur ing the f i v e hour pe r i od f o l l o w i n g the meat meal a lone was s i g n i f i c a n t l y g r e a t e r than tha t p r i o r to PDL (28 ± 10 n g / m l / f i v e hours be fo re PDL v s . 63 ± 15 n g / m l / f i v e hours a f t e r PDL, p < 0 . 0 5 ) . M u l t i p l e comparison procedure revea led s i g n i f i c a n t decrease i n the IRI s e c r e t i o n a f t e r PDL (p < 0.05) ( F i g . 5 ) . The mean serum g lucose concen t ra t i ons at each of the subsequent t ime p o i n t s i n the dogs a f t e r PDL s i g n i f i c a n t l y exceeded those p r i o r to PDL ( F i g . 6 ) . 3 . F i v e Hour A c i d , IR-Ga, IR-GIP, IRI and G lucose Responses to a Meat Meal P l u s Unhydrolyzed Cream. A f t e r f eed ing a meat meal p lus cream the peak a c i d output from the HP p r i o r t o PDL occured at 150 minutes (0.0576 ± 0.227 mEq/15 minu tes ) , and remained almost a t the same l e v e l f o r the remainder of the two hour p e r i o d . A f t e r PDL ac id response e s s e n t i a l l y d id not change except f o r a smal l i n c r e a s e a f t e r 135 minutes ( F i g . 7 ) . In teg ra ted ac i d response dur ing the f i v e hour pe r iod f o l l o w i n g the meal a f t e r PDL was 12 i n s i g n i f i c a n t l y g rea te r than tha t p r i o r to PDL (121 + 45 mEq/ f i ve hours be fo re PDL v s . 137 ± 51 mEq/ f i ve hours a f t e r PDL) . The mean f i v e hour serum g a s t r i n concen t ra t i ons a f t e r PDL were lower than be fo re PDL ( F i g . 8) but i n teg ra ted f i v e hour serum IR-Ga response to the meal a f t e r PDL was g rea te r than tha t p r i o r to PDL v s . 8.6 + 3 .2 n g / m l / f i v e hours a f t e r PDL (5.4 ± 2 . 3 ng /ml / f i v e hours be fore PDL) , a l though there was no s i g n i f i c a n t d i f f e r e n c e . Fo l l ow ing the meal, the mean serum IR-GIP concen t ra t i ons were lower i n the dogs a f t e r PDL than before PDL. The peak IR-GIP response was s i g n i f i c a n t l y lower a f t e r PDL (844 ± 67 pg/ml be fore PDL v s . 655 + 129 pg/ml a f t e r PDL, p < 0.05) ( F i g . 9 ) . In teg ra ted serum IR-GIP response to the meal dur ing the f i v e hour pe r iod a f t e r PDL was s i g n i f i c a n t l y lower than tha t p r i o r to PDL (144 + 21 n g / m l / f i v e hours before PDL v s . 116 ± 23 ng/ml / f i v e hours a f t e r PDL, p < 0 . 0 5 ) . Be fo re PDL i n t eg ra ted serum IR-GIP response to a meal p lus unhydrolyzed cream dur ing the f i v e hour pe r iod was s i g n i f i c a n t l y h igher than tha t to a meat meal a lone (144 + 21 v s . 28 ± 10 n g / m l / f i v e hours, p < 0.01) and a f t e r PDL i n teg ra ted serum IR-GIP response to a meat meal p lus unhydro lyzed cream dur ing the f i v e hour pe r i od was a l s o h igher than tha t to a meat meal a lone but not s i g n i f i c a n t (116 ± 23 v s . 63 + 15 ng/ml / f i v e hou rs ) . F o l l o w i n g the meal the mean serum IRI concen t ra t i ons at each subsequent t ime po in t i n the dogs a f t e r PDL were lower than those p r i o r to 13 PDL. The t ime of the peak va lue of serum IRI concen t ra t i ons was almost i d e n t i c a l to tha t of serum IR-GIP concen t ra t i ons ( F i g . 9 and 10) . The mean serum g lucose concen t ra t i ons at each subsequent t ime po in t except a t 60 minutes f o l l o w i n g the meal i n the dogs a f t e r PDL were lower than those i n the same dogs p r i o r to PDL, and the d i f f e r e n c e was s i g n i f i c a n t a t 300 minutes (86 ± 3 v s . 98 mg /d l , p 0.05) ( F i g . 11) . 4 . F i v e Hour A c i d , IR-Ga, IR-GIP, IRI and Glucose Responses to a Meat Meal P l u s Hydro lyzed Cream. Fo r the 135 minute pe r iod f o l l o w i n g the meal the mean ac id response from the HP was lower than tha t p r i o r to PDL, but not s t a t i s t i c a l l y s i g n i f i c a n t . The peak a c i d outputs from the HP be fo re and a f t e r PDL were 0.990 ± 0.348 mEq/15 minutes a t 120 minutes and 0.991 ± 0.270 mEq/15 minutes at 195 minutes, r e s p e c t i v e l y ( F i g . 12 ) . In tegra ted HP a c i d output dur ing the f i v e hour pe r iod a f t e r PDL was sma l l e r than tha t p r i o r to PDL (198.39 mEq/ f i ve hours be fore PDL v s . 176.73 mEq/ f i ve hours a f t e r PDL) , but there was no s i g n i f i c a n t d i f f e r e n c e . In tegra ted serum IR-Ga response dur ing the f i v e hour pe r iod a f t e r PDL was sma l le r than tha t p r i o r to PDL (9.9 + 4 .0 n g / m l / f i v e hours be fore PDL v s . 4 .6 + 1.8 n g / m l / f i v e hours a f t e r PDL) , but there was no s i g n i f i c a n t d i f f e r e n c e . The mean serum IR-GIP concen t ra t i ons dur ing the 60 minute pe r iod f o l l o w i n g the meal a f t e r PDL were almost i d e n t i c a l to those p r i o r to PDL, 14 and they remained lower t h e r e a f t e r compared to those p r i o r to PDL ( F i g . 14) . In tegra ted serum IR-GIP response to the meal dur ing the f i v e hour pe r i od a f t e r PDL was i n s i g n i f i c a n t l y sma l l e r than tha t p r i o r to PDL (152 ± 18 n g / m l / f i v e hours be fo re PDL v s . 1 1 9 + 2 3 n g / m l / f i v e hours a f t e r PDL) . Serum IR-GIP response to meat meal p lus hydro lyzed cream a f t e r PDL was very s i m i l a r to t ha t of meat meal p lus unhydrolyzed cream a f t e r PDL. Be fo re PDL, i n t e g r a t e d serum IR-GIP response to meat meal p lus hydro lyzed cream dur ing the f i v e hour pe r i od was s i g n i f i c a n t l y h igher than tha t t o meat meal a lone (152 ± 18 v s . 28 ± 10 n g / m l / f i v e hours, p < 0101) , and almost i d e n t i c a l to t ha t of meat meal p lus unhydrolyzed cream (152 ± 18 v s . 144 + 21 n g / m l / f i v e hou rs ) . A f t e r PDL, i n t eg ra ted serum IR-GIP response to meat meal p lus hydro lyzed cream dur ing the f i v e hour pe r i od was i n s i g n i f i c a n t l y h igher than tha t t o meat meal a lone (119 + 23 v s . 63 ± 15 n g / m l / f i v e hou rs ) . The mean serum IRI concen t ra t i ons f o l l o w i n g the meal a f t e r PDL was almost i d e n t i c a l to those p r i o r to PDL ( F i g . 15) . F o r the 180 minute pe r iod f o l l o w i n g the meal a f t e r PDL, the mean serum g lucose response was g rea te r than p r i o r to PDL, but the d i f f e r e n c e was not s i g n i f i c a n t ( F i g . 16 ) . 5 . Serum Glucose and IRI Responses to i . v . G lucose Load . The mean serum g lucose concen t ra t i ons f o l l o w i n g i . v . g lucose were s i g n i f i c a n t l y h igher i n the post-PDL dogs than i n the same dogs p r i o r to 15 PDL at 15, 30, 45, and 60 minutes (326 + 12 vs. 205 ± 9 mg/dl at 15 minutes, two weeks after PDL, p < 0.01; 338 ± 30 vs. 205 + 9 mg/dl at 15 minutes, ten weeks after PDL, p < 0.01; 218 ± 13 vs. 100 ± 5 mg/dl at 30 minutes, two weeks after PDL, p < 0.001; 230 ± 6 vs. 100 + 5 mg/dl at 30 minutes, ten weeks after PDL, p < 0.001; 155 + 11 vs. 72 ± 3 mg/dl at 45 minutes, two weeks after PDL, p < 0.001; 170 ± 4 vs. 72 ± 3 mg/dl at 45 minutes, ten weeks after PDL, p < 0.001; 115 + 6 vs. 80 ± 4 mg/dl at 60 minutes, two weeks after PDL, p < 0.001; 140 ± 5 vs. 80 + 4 mg/dl at 60 minutes, ten weeks after PDL, p < 0.001) (Fig. 17). The mean serum IRI concentrations were significantly lowered after PDL (40.4 vs. 24.3 yU/ml at 15 minutes, two weeks after PDL, p < 0.05; 40.4 vs. 16.1 yU/ml at 15 minutes ten weeks after PDL, p < 0.05; 30.8 vs. 15.8 yU/ml at 30 minutes, two weeks after PDL, p < 0.05; 30.8 vs. 11.3 yU/ml at 30 minutes,ten weeks after PDL, p < 0.05; 18.4 vs. 10.4 yU/ml at 45 minutes, two weeks after PDL, p < 0.05; 18.4 vs. 9.6 yU/ml at 45 minutes, ten weeks after PDL, p < 0.5). In contrast, the mean serum IRI concentration at 60 minutes following i.v. glucose was significantly increased ten weeks after PDL (8.8 vs. 26.0 yU/ml, p < 0.05) (Fig. 18). 16 6 . Serum G lucose , IR I , and IR-GIP Responses to I n t r a g a s t r i c G lucose Load. The mean f a s t i n g serum g lucose va lues be fore and a f t e r PDL were 68 + 4 mg/dl and 79 ± 4 m g / d l , r e s p e c t i v e l y , and the d i f f e r e n c e was not s t a t i s t i c a l l y s i g n i f i c a n t . A f t e r PDL, the mean serum g lucose concen t ra t i ons were s i g n i f i c a n t l y lower a t 15 minutes (110 ±7 v s . 159 ± 15 mg /d l , p < 0 . 0 5 ) , at 30 minutes (122 + 10 v s . 183 ± 11 mg /d l , p < 0 . 0 1 ) , - and a t 45 minutes (138 ± 12 v s . 175 + 11 mg/d l , p < 0.05) f o l l o w i n g i n t r a g a s t r i c g lucose load and reached peak va lues at a l a t e r t ime (155 ± 10 mg/dl a t 90 minutes a f t e r PDL and 183 ± 11 mg/dl a t 30 minutes be fore PDL) , p e r s i s t i n g h igher l e v e l s than p r i o r to PDL (151 ± 12 v s . 87 ± 8 mg/dl at 120 minutes, p < 0 . 0 1 ; 116 ± 14 v s . 8 3 + 6 mg/dl at 150 minutes, p < 0.05) ( F i g . 19) . There was no s i g n i f i c a n t d i f f e r e n c e between the mean peak g lucose va lues be fore and a f t e r PDL, and thus only showing the de layed p a t t e r n a f t e r PDL. There was a l s o no s i g n i f i c a n t d i f f e r e n c e between the mean in teg ra ted g lucose response be fo re and a f t e r PDL (10211 + 1213 mg/dl /180 minutes be fo re PDL v s . 9180 ± 1184 mg/dl /180 minutes a f t e r PDL) . The mean serum IRI response was h igher at each t ime po in t a f t e r 60 minutes f o l l o w i n g g lucose load a f t e r PDL, and the d i f f e r e n c e was s i g n i f i c a n t at 120 minutes (11.8 yU/ml be fore PDL v s . 26.8 yU/ml a f t e r PDL, p < 0 . 0 5 ) . The mean i n teg ra ted IRI responses were 843 ± 192 yUml/180 minutes before PDL and 764 ± 164 yU/ml /180 minutes, and there was no s t a t i s t i c a l d i f f e r e n c e . 17 The mean serum IR-GIP response a f t e r PDL remained ra the r h igher f o r the l a t t e r 120 minute pe r i od than be fo re PDL. The p a t t e r n of serum IR-GIP response was very s i m i l a r to tha t of serum IRI response ( F i g . 2 1 ) . The mean i n teg ra ted serum IR-GIP response a f t e r PDL was g r e a t e r than t ha t be fo re PDL 37.3 ng/ml/180 minutes be fo re PDL v s . 51.5 ng/ml/180 minutes a f t e r PDL) , but was not s i g n i f i c a n t . 18 DISCUSSION (A) GASTRIC SECRETION G a s t r i c hype rsec re t i on i n the dog f o l l o w i n g panc rea t i c duct l i g a t i o n (PDL) i s a we l l recogn ized phenomenon. However, the mechanism behind i t has not y e t been d e f i n e d . The p o s s i b i l i t y t ha t the pancreas w i th obs t ruc ted ducts produce a g a s t r i c secretagogue, namely a g a s t r i n - l i k e substance, has been d isproved by b ioassay and immunoassay of the a t roph i c pancreas f o r g a s t r i n . Menguy a s c r i b e d g a s t r i c hype rsec re t i on f o l l o w i n g PDL to secondary l i v e r damage 2 2 . The m a l d i g e s t i o n of f a t and malabsorp t ion of e s s e n t i a l f a t t y ac ids was thought to be a cause of hepa t i c damage and g a s t r i c h y p e r s e c r e t i o n . I t has been suggested t ha t an augmented g a s t r i n response to feed ing i s a pr imary f a c t o r i n the p roduc t ion of g a s t r i c hype rsec re t i on occur ing when panc rea t i c enzymes are excluded from the d i g e s t i v e stream,1 whereas G r e e n l e e 4 cons idered g a s t r i n i s not a main f a c t o r as a f t e r antrectomy, PDL s t i l l produces an i nc rease i n g a s t r i c a c i d . A l though the i nc rease i n d a i l y ac i d s e c r e t i o n from the HP observed i n response to the i n g e s t i o n of an o rd inary meal a f t e r PDL conf i rms the p rev ious obse rva t i on of o t h e r s , 2 » 2 3 the re was only a modest i nc rease of HP a c i d and decrease of g a s t r i n response to a meat meal a f t e r PDL as compared to t ha t be fo re PDL. These f i n d i n g s d i f f e r from others who repor ted an augmented g a s t r i n response as we l l as an augmented HP a c i d response to feed ing i n dogs a f t e r PDL.1> 2 3 These d i s c r e p a n c i e s are hard to e x p l a i n , but may be due, at l e a s t i n p a r t , t o the d i f f e r e n t c o n d i t i o n s o f the exper iments ; i n the present experiment the dogs were fed w i th cream (unhydro lyzed and 19 hydrolyzed) mixed w i th o rd inary meals which might have r e s u l t e d i n the d i f f e r e n t sec re ta r y responses. Wormsley and Grossman 2 4 observed tha t c l o s i n g the GF produced marked i n h i b i t i o n of the response of the HP to s t i m u l a t i o n , suggest ing endogenous i n h i b i t i o n r e l a t e d to passage of ac i d from the main stomach i n t o the duodenum. The GF was kept c l osed dur ing the present s tudy, and a l though a c i d i t y of the main stomach a f t e r meal i n g e s t i o n was not measured, p o s t c i b a l g a s t r i n r e l e a s e from the antrum and duodenum was probably suppressed by an t ra l and duodenal h y p e r a c i d i t y caused by an as y e t unknown mechanism f o l l o w i n g PDL. An t ra l a c i d i f i c a t i o n i s known to i n h i b i t g a s t r i n r e l e a s e , 2 5 but i t i s unknown whether a c i d d i r e c t l y suppresses the G c e l l s or whether i t r e l eases an i n h i b i t o r of g a s t r i n r e l e a s e from the an t ra l mucosa. I t has been shown tha t when innervated an t ra l pouches were per fused w i th a c i d or a l k a l i n e s o l u t i o n s i n dogs w i th a HP us ing chemical or vagal s t i m u l a t i o n of the antrum, g a s t r i n - l i k e immunoreact iv i ty appeared in a l l pe r fusa tes but was found to be seven t imes h igher i n the ac i d p e r f u s a t e s , i n d i c a t i n g the a c i d i f i c a t i o n of the antrum may not b lock r e l e a s e of g a s t r i n , but i t may change the d i r e c t i o n of r e l e a s e and d i v e r t g a s t r i n from the c i r c u l a t i o n to the an t ra l lumen 2**. Some workers have pos tu l a ted tha t ac i d i n the p y l o r i c g land area caused r e l e a s e of an an t ra l i n h i b i t o r y hormone " a n t r a l c h a l o n e " 2 7 , 2 8 tha t suppresses the a c t i v i t y of the o x y n t i c c e l l s , but i t s p h y s i o l o g i c a l s i g n i f i c a n c e , i f any, i s s t i l l to be s t u d i e d . A p o s s i b l e exp lana t i on of some of the f i n d i n g s cou ld be tha t new dogs were d e b i l i t a t e d by p a n c r e a t i t i s o r o ther o p e r a t i v e trauma. I f e e l however tha t t h i s does not match w i th our o b s e r v a t i o n s . Only one of the four dogs l o s t we ight , the o thers were a l l hea l thy and a te w e l l . Autopsy, too , d i s c l o s e d no s i g n i f i c a n t abnorma l i t i es apar t from some adhesions and very m i l d 20 i n f lammat ion . (Photo 1) G a s t r i c and duodenal a c i d i f i c a t i o n r e s u l t s i n a marked r i s e i n the plasma l e v e l of somatos ta t in .29 Somatos ta t in may be invo lved i n the an t ra l and duodenal i n h i b i t o r y mechanisms but f u r t h e r s t u d i e s are needed to determine the p h y s i o l o g i c a l r o l e of t h i s pep t ide i n an t ra l and duodenal feedback i n h i b i t i o n of g a s t r i c s e c r e t i o n . The name bu lbogast rone has been g iven to a hypo the t i ca l humoral f a c t o r 3 0 sec re ted from the duodenal bu lb where pH dependent g a s t r i c ac i d i n h i b i t i o n opera tes . The mechanism seems to suppress ac i d s e c r e t i o n by i n t e r f e r i n g w i t h the s t imu la to r y a c t i o n of g a s t r i n at the oxyn t i c glands and whether bu lbogast rone i n h i b i t s g a s t r i n r e l e a s e i s unknown. The p r i n c i p a l humoral mechanism of g a s t r i c ac i d i n h i b i t i o n by duodenal a c i d i f i c a t i o n i s the r e l e a s e of s e c r e t i n from the endocr ine S c e l l s i n the duodenal mucosa, and i t has been demonstrated tha t the i n h i b i t i o n of g a s t r i c a c i d s e c r e t i o n by endogenous or exogenous s e c r e t i o n i s brought about by b l o c k i n g the a c t i o n of g a s t r i n at the p a r i e t a l c e l l l e v e l through a non-compet i t i ve mechanism.31 Tasse et al32 showed tha t the serum g a s t r i n l e v e l s i n dogs having undergone the Exa l to -Mann-Wi l l i amson procedure remains unchanged, whereas the plasma s e c r e t i n concen t ra t i ons i n these animals are i nc reased , i n d i c a t i n g a l t e r a t i o n s i n c i r c u l a t o r y s e c r e t i n or g a s t r i n are not r e s p o n s i b l e f o r the g a s t r i c ac i d hype rsec re t i on f o l l o w i n g the procedure, and p o s t o p e r a t i v e hypersecre t inemia would be caused by s t i m u l a t i o n of s e c r e t i n r e l e a s e from the gut mucosa secondary to enhanced s e c r e t i o n of g a s t r i c a c i d . S e c r e t i n 21 was shown to suppress the r e l e a s e of g a s t r i n i n response to food i n dogs.33 There have been no s tud ies of s e c r e t i n s e c r e t i o n a f t e r PDL, but i t has been shown t ha t e x c l u s i o n of p a n c r e a t i c j u i c e i n dogs w i th p a n c r e a t i c f i s t u l a r e s u l t e d i n augmented plasma s e c r e t i n response to meal ingestion.34 I t seems reasonable to assume tha t marked a c i d i f i c a t i o n of the post bu lba r duodenum wel l below 4.5 ( the t h resho ld f o r s e c r e t i n r e l e a s e i n the dog) r e l eases enough s e c r e t i n to i n h i b i t g a s t r i n r e l e a s e and subsequent ly suppress the HP ac id s e c r e t i o n a f t e r PDL. I t has been shown tha t c h o l e c y s t o k i n i n (CCK) i s predominant ly the i n h i b i t o r y hormone re leased by s t rong a c i d i f i c a t i o n of the duodenum. Kakaj ima and Magee showed tha t duodenal a c i d i f i c a t i o n over a pH range of seven to th ree re leased mainly s e c r e t i n and, at a lower pH, mainly CCK.35 Suppress ion of g a s t r i n r e l e a s e i s brought about by a l l members o f s e c r e t i n f am i l y of hormones (g lucagon, v a s o a c t i v e i n t e s t i n a l po l ypep t i de (V IP) , and GIP) and by one chemica l l y un re la ted pep t i de , c a l c i t o n i n . A l l these hormones a l s o exe r t a d i r e c t i n h i b i t o r y a c t i o n on the p e r i e t a l c e l l s . The ques t ion o f .whether these humoral f a c t o r s i n h i b i t r e l e a s e of g a s t r i n under p h y s i o l o g i c a l c o n d i t i o n s i s not s e t t l e d . P o s s i b l e r o l e of GIP i n r e g u l a t i n g g a s t r i c a c i d and g a s t r i n w i l l be d i scussed l a t e r i n t h i s p a r t of the communicat ion. Thus the suppressed g a s t r i n response caused by the p o s s i b l e mechanisms as mentioned above was probab ly , a t l e a s t p a r t l y , r e s p o n s i b l e f o r the only modest i nc rease i n the f i v e hour HP s e c r e t i o n . A l s o these f i n d i n g s i n d i c a t e tha t the i n t e s t i n a l phase of g a s t r i c s e c r e t i o n may have 22 been more markedly augmented a f t e r PDL than g a s t r i c phase of a c i d s e c r e t i o n by the mechanism tha t the p e r s i s t e n c e of undigested and unabsorbed food products i n the small i n t e s t i n e r e s u l t s i n i n a p p r o p r i a t e l y pro longed s t i m u l a t i o n of g a s t r i c s e c r e t i o n . Chey at a l 2 showed the most s t r i k i n g i nc rease of HP ac id outputs dur ing the twelve to 24 hour pe r iod of d a i l y meal study i n PDL dogs, suggest ing tha t both g a s t r i c and i n t e s t i n a l phase of g a s t r i c s e c r e t i o n p a r t i c i p a t e d i n the response. The mechanism of i n t e s t i n a l s t i m u l a t i o n of g a s t r i c s e c r e t i o n has not y e t been d e f i n e d . U n t i l r e c e n t l y , " i n t e s t i n a l g a s t r i n " was the name g e n e r a l l y used when r e f e r r i n g to the mediator of the i n t e s t i n a l phase. Th is term i s u n s a t i s f a c t o r y s i n c e severa l d i f f e r e n t substances may be i nvo l ved i n the i n t e s t i n a l phase of g a s t r i c s e c r e t i o n , namely " e n t e r o - o x y n t i n " , an a n t r a l type of g a s t r i n , CCK, and h i s tam ine . Exper imenta l s t ud ies suggest t ha t the main i n t e s t i n a l phase s t imu lan t i s an as ye t u n i d e n t i f i e d hormone from the i n t e s t i n a l mucosa, f o r which the name " e n t e r o - o x y n t i n " has been proposed.24 " E n t e r o - o x y n t i n " i s the p r i n c i p a l hormone r e s p o n s i b l e f o r the i n t e s t i n a l phase of g a s t r i c s e c r e t i o n , having unique pa t t e rn of g a s t r i c s t i m u l a t i o n tha t cannot be accounted f o r by g a s t r i n , CCK, or h i s tamine . To da te , no s tud ies have been performed to determine the p o s s i b l e r o l e of CCK and h is tamine i n the i n t e s t i n a l phase of g a s t r i c s e c r e t i o n . Konturek e t al36 noted a marked r i s e i n serum g a s t r i n l e v e l and a potent s t i m u l a t i o n of g a s t r i c s e c r e t i o n dur ing i n t e s t i n a l p e r f u s i o n of l i v e r e x t r a c t meal , and suggested the i n t e s t i n a l meal s t imu la tes g a s t r i c s e c r e t i o n by a mechanism i n v o l v i n g the re l ease of an t ra l hormone. 23 Thompson et a\'if specu la ted tha t l i v e r e x t r a c t meal i n the i n t e s t i n e may r e l e a s e a bombes in-1 ike substance (entero-bombesin) t ha t , i n t u r n , r e l e a s e s an t ra l g a s t r i n . O r l o f f et al38 have r e c e n t l y i s o l a t e d the i n t e s t i n a l phase hormone (IPH) from hog i n t e s t i n a l mucosa. IPH i s not g a s t r i n and augments the maximum g a s t r i c sec re to r y response to g a s t r i n . I t i s we l l documented tha t f a t added to the meal i n the duodenum suppressed the a c i d s e c r e t i o n of t r ansp lan ted pouches^ i n d i c a t i n g t ha t the i n h i b i t i o n was humoral ly mediated and Kosaka and L i m 7 proposed the name "en te rogas t rone" f o r the humoral i n h i b i t o r agent. Qu ig ley and Meschan39 showed t h a t the products o f l i p o l y s i s were more potent i n h i b i t o r s o f g a s t r i c m o t i l i t y than cor respond ing neut ra l f a t , and the obse rva t i on of S i r cus^O i n d i c a t e s t ha t f a t s exer ts t h e i r e f f e c t only i f panc rea t i c j u i c e i s p resen t . I t i s we l l known t ha t p a n c r e a t i c l i p a s e p lays a dominant r o l e i n f a t abso rp t i on , and t r i g l y c e r i d e i s hydro lyzed by l i p a s e to f a t t y ac ids and g l u c e r o l . GIP obta ined from an e x t r a c t of duodenal mucosa has been i s o l a t e d , p u r i f i e d , and chem ica l l y c h a r a c t e r i z e d . 1 5 Th i s substance i n h i b i t s g a s t r i c ac i d and peps in s e c r e t i o n s t imu la ted by p e n t a g a s t r i n , h i s tam ine , and by i n s u l i n - h y p o g l y c e m i a i n d o g s , 8 and a l s o i n h i b i t s spontaneous motor a c t i v i t y of denervated fund ic and an t ra l pouches, q u a l i f y i n g as an en te rogas t rone . I t has been specu la ted tha t a d i s t u rbed GIP r e l e a s e may be r e s p o n s i b l e f o r the abnormal ac i d r e l e a s e i n duodenal u l c e r d i s e a s e . Cont ra ry to t h i s assumpt ion, an exaggerated GIP r e l e a s e f o l l o w i n g ora l g lucose or the t e s t meal was observed i n p a t i e n t s w i th duodenal u l c e r . 1 1 . 1 2 i t was suggested tha t r a p i d g a s t r i c emptying or inc reased 24 i n t e s t i n a l m o t i l i t y i s r e s p o n s i b l e f o r the inc reased GIP s e c r e t i o n . H Ca ta land et a U 2 c la imed tha t the p o s s i b i l i t y t ha t p a t i e n t s w i th duodenal u l c e r may r e l e a s e a form of GIP w i th weak g a s t r i c a c i d i n h i b i t o r y p r o p e r t i e s . The prime r o l e of GIP i s to p o t e n t i a t e g lucose- induced i n s u l i n r e l e a s e , ^ a n d there i s s t i l l some con t roversy as to whether GIP has the e n t e r o g a s t r o n e - l i k e e f f e c t . In innerva ted stomach p repa ra t i ons of the dog9 and i n normal manlO i n h i b i t i o n o f p e n t a g a s t r i n - s t i m u l a t e d a c i d s e c r e t i o n by GIP was found to be weak. The p o s s i b l e involvement of a c h o l i n e r g i c mechanism a n t a g o n i s t i c to the a c t i o n of GIP on the stomach has been suggested by the obse rva t i on tha t the a c i d i n h i b i t o r y e f f e c t o f t h i s hormone i n the denervated g a s t r i c pouch of the dog can be b locked by the i . v . i n f u s i o n of u r e c h o l i n e . 9 An exp lana t i on f o r these observa t ions tha t GIP does not exe r t i t s i n h i b i t o r y e f f e c t d i r e c t l y on the p a r i e t a l c e l l but ra the r i n d i r e c t l y v i a the r e l e a s e of an i n h i b i t o r , from the corpus of the stomach which i s a l s o under c h o l i n e r g i c c o n t r o l . Mc in tosh et a l ^ l proposed tha t the a c i d i n h i b i t o r y a c t i v i t y of GIP i s probably mediated v i a r e l e a s e of g a s t r i c somatos ta t in -1 i ke immunoreac t i v i t y . E b e r t et a l ^ demonstrated tha t in t raduodenal i n f u s i o n of HCl dose-dependent ly re l eased GIP i n humans and r a t s , w h i l e Brown et a l 1 5 f a i l e d to show IR-GIP r e l e a s e i n dogs by H C l . LeRo i t h e t a l 1 6 showed t h a t HCl by i t s e l f i s capab le of s t i m u l a t i n g GIP, sugges t ing p h y s i o l o g i c a l s i g n i f i c a n c e of a c i d induced GIP s e c r e t i o n . I t has been shown by S p i t z et a l42 t h a t when HCl i s added to an ora l g lucose l o a d , the b lood l e v e l s of g lucose , GIP and i n s u l i n were h igher than a f t e r g lucose a lone. Augmented GIP r e l e a s e a f t e r in t ra -duodena l a d m i n i s t r a t i o n of g lucose was observed when exogenous g a s t r i n , p e n t a g a s t r i n , and CCK were g iven.43 F la ten44 0 n 25 the o ther hand, s tud ied the e f f e c t of duodenal a c i d i f i c a t i o n on the g l u c o s e - s t i m u l a t e d GIP or i n s u l i n r e l e a s e i n man and showed no augmentation of GIP or i n s u l i n by duodenal a c i d i f i c a t i o n . The c o n f l i c t i n g r e s u l t s from prev ious s tud ies seem to i n d i c a t e the importance of g a s t r i c emptying as w e l l as spec ies d i f f e r e n c e i n GIP s e c r e t i o n a f t e r duodenal a c i d i f i c a t i o n . A reason f o r the augmented GIP s e c r e t i o n , which i s the most important f i n d i n g of the present s tudy, i n the dogs a f t e r PDL admin is te red meat meal a lone cou ld be inc reased ac i d s e c r e t i o n coming i n t o the duodenum and the upper i n t e s t i n e . Another exp lana t i on f o r the i n c r e a s e of IR-GIP response to a meat meal a lone a f t e r PDL i s a change of g a s t r o i n t e s t i n a l m o t i l i t y . I t has been shown by Fau ley and Ivy tha t the emptying t ime of the stomach i s decreased by PDL i n dogs and the authors suggested tha t hunger, or po lyphag ia , i s the f a c t o r p r i n c i p a l l y concerned i n the causa t i on of the d e c r e a s e , 4 5 and Y e s c o 4 6 desc r ibed a s i m i l a r r e s u l t . Long et a l 4 7 desc r ibed abnormal ly r a p i d g a s t r i c emptying of l i q u i d f a t t y meals i n p a n c r e a t i c i n s u f f i c i e n c y and asc r i bed i t to m a l d i g e s t i o n , w h i l e Regan et a l 4 8 showed no pr imary g a s t r i c motor de fec t i n p a t i e n t s w i th exoc r ine panc rea t i c i n s u f f i c i e n c y . The d i sc repan t f i n d i n g of these s tud ies seems to be due to d i f f e r e n c e s of the technique used f o r the measurement of g a s t r i c emptying. CCK and s e c r e t i n have been shown to i n h i b i t g a s t r i c m o t i l i t y i n d o g s . 4 9 CCK was found to be inc reased i n p a n c r e a t i c i n s u f f i c i e n c y . 5 0 In the present s tudy , a l though CCK and s e c r e t i n concen t ra t i ons were not measured, both hormones might have been inc reased i n the dogs a f t e r PDL as above d i s c u s s e d . 26 I t seems to be an i n t r i g u i n g hypo thes is , t h e r e f o r e , t ha t g a s t r i c m o t i l i t y was decreased a f t e r PDL by augmented s e c r e t i o n of some gut pep t ide such as CCK and s e c r e t i n . In the present s tudy, g a s t r i c emptying was not measured, but as shown in F i g . 19, g a s t r i c empyting was probably delayed a f t e r PDL. Oral g lucose t o l e r a n c e t e s t has been suggested f o r the assessment of g a s t r i c e m p t y i n g . 5 1 I f so, t h i s i s noteworthy, as the r e s u l t s of the present study do i n d i c a t e t ha t marked lower ing of pH of duodenal contents due to augmented ac i d s e c r e t i o n together w i t h lack of a l k a l i n e (panc rea t i c ) j u i c e a f t e r PDL i s r e s p o n s i b l e f o r the augmented GIP r e l e a s e from the i n t e s t i n a l mucosa. P a t i e n t s w i t h ch ron i c p a n c r e a t i t i s were shown to have a s i g n i f i c a n t l y h igher GIP response to a t e s t m e a l . 5 2 The authors suggested tha t the e leva ted IR-GIP l e v e l s seen i n p a t i e n t s w i th ch ron i c p a n c r e a t i t i s cou ld be due to lack of i n h i b i t i o n of IR-GIP r e l e a s e by i n s u l i n , and concluded tha t perhaps IR-GIP r e l e a s e to a t e s t meal was dependent upon the ra te of abso rp t i on of n u t r i e n t ( f a t ) and the c a p a c i t y of the @-ce l l to sec re te i n s u l i n . The most important f i n d i n g of the present study tha t the g r e a t l y inc reased GIP a f t e r PDL i n response to meat meal a lone but somewhat decreased f o r f a t (unhydrolyzed and hydro lyzed) cannot be exp la ined by a lack of negat ive feedback i n h i b i t i o n of IR-GIP by i n s u l i n , because serum IRI response a f t e r PDL was more lowered i n response to the cream-added meal than to the meat meal a lone . GIP i s r e l e a s e d a f t e r i n g e s t i o n o f g l ucose , f a t , and amino a c i d , and f a t i s a most powerful s t imu lus f o r GIP r e l e a s e . 1 5 Fa t has to be hydro lyzed be fore GIP r e l e a s e i s i n i t i a t e d . I t has been shown t ha t long 27 cha in f a t t y a c i d s , r a t h e r than g l y c e r o l , s t imu la tes GIP r e l e a s e . * 5 F a t t y ac ids must be absorbed and metabo l ized by the GIP producing c e l l . The exac t mechanism whereby the absorp t ion caused r e l e a s e i s not known. Ross e t a l 5 3 observed tha t c h i l d r e n w i th c y s t i c f i b r o s i s had th ree f o l d i nc rease i n IR-GIP s e c r e t i o n i f g iven panc rea t i c enzymes w h i l e i n g e s t i n g the t r i g l y c e r i d e , w h i l e they had no IR-GIP response to t r i g l y c e r i d e on l y , and suggested tha t h y d r o l y s i s of t r i g l y c e r i d e i s requ i red be fo re GIP r e l e a s e can normal ly occur a f t e r f a t i n g e s t i o n . IR-GIP response to a meat meal was markedly augmented by mix ing unhydro lyzed cream: the peak IR-GIP concen t ra t i ons and the i n teg ra ted IR-GIP response to an unhydrolyzed cream-added meal was s i g n i f i c a n t l y g r e a t e r than those to a meat meal a lone i n d i c a t i n g g rea te r amount of GIP was re leased by adding f a t . A f t e r PDL, IR-GIP response to a meat meal p lus unhydrolyzed cream was s i g n i f i c a n t l y reduced, and t h i s i n d i c a t e s tha t GIP was not p rope r l y re l eased by f a t due to f a i l e d h y d r o l y s i s to f a t t y a c i d by lack of p a n c r e a t i c l i p a s e . I t can of course not be excluded tha t GIP s e c r e t i o n was suppressed by other y e t u n i d e n t i f i e d gut pept ides or neural mechanisms which were re leased or augmented by c l o c k i n g p a n c r e a t i c ex terna l s e c r e t i o n . Aga in , presumably augmented ac i d s e c r e t i o n may have occurred in the main stomach f o l l o w i n g the fa t -added meal i n g e s t i o n a f t e r PDL, and GIP s e c r e t i o n was augmented by passage of a c i d i n t o the i n t e s t i n a l lumen. Th is i nc rease i n GIP re leased by augmented passage of ac i d i n t o the i n t e s t i n a l lumen was probably masked by the f a t - i n d u c e d GIP. 28 Another impor tant f i n d i n g of the present study i s tha t the re was no d i f f e r e n c e i n the GIP response between the unhydrolyzed and hydro lyzed cream a f t e r PDL. A p o s s i b l e exp lana t i on f o r these unexpected f i n d i n g s i s tha t GIP response i s not determined by a s i n g l e f a c t o r , but i s a net r e s u l t of s t i m u l a t o r y and i n h i b i t o r y mechanisms. GIP response might be i n f l uenced by many f a c t o r s , which i nc l ude many k inds of r egu la to r y p e p t i d e s , i d e n t i f i e d or u n i d e n t i f i e d , i n t e s t i n a l m o t i l i t y , vagal c o n t r o l , e t c . Some p o s s i b l e change o f i n t e s t i n a l mucosal a b s o r b a b i l i t y f o r f a t should a l s o be cons ide red : even hydro lyzed f a t might have been unable to be absorbed due to an as y e t unknown mechanism a f t e r PDL, r e s u l t i n g i n much reduced GIP response to the hydro lyzed f a t mixed w i th the meat meal . The HP a c i d response to meat meal p lus unhydrolyzed cream was pro longed, a l though the t ime and the peak concen t ra t i ons were s i m i l a r to the case s t imu la ted by meat meal a lone . Th is i s probably due to inc reased osmo la r i t y of the inges ted meal by adding f a t . Cook showed i n h i b i t i o n of g a s t r i c emptying was r e l a t e d to the molar (and osmolar) concen t ra t i on of amino a c i d : the g r e a t e r the c o n c e n t r a t i o n , the g rea te r the d e l a y . 5 4 The exp lana t i on f o r the g r e a t e r HP ac id s e c r e t i o n s t imu la ted by i n g e s t i o n of meat meal p lus hydro lyzed cream than by i n g e s t i o n of meat meal p lus unhydrolyzed cream i s not c l e a r . Serum IR-Ga responses to both s t i m u l a t i o n s were s i m i l a r except a t a l a t e r p e r i o d , i n d i c a t i n g g a s t r i n i s not s o l e l y r e s p o n s i b l e f o r the g rea te r HP s e c r e t i o n . The at tenuated HP s e c r e t i o n ( e s p e c i a l l y i n the ea r l y phase) s t imu la ted by meat meal p lus hydro lyzed cream a f t e r PDL i s a l s o d i f f i c u l t 29 to e x p l a i n . A l though serum IR-Ga response was most markedly decreased a f t e r PDL compared to o ther two s t i m u l a n t s , aga in g a s t r i n i s not s o l e l y r e s p o n s i b l e f o r the decrease in the HP s e c r e t i o n . The p o s s i b i l i t y t ha t some g a s t r i c i n h i b i t o r y hormone(s) was re leased by the d iges ted f a t even i n the absence of panc rea t i c exocr ine f u n c t i o n can not be exc luded . Fa t induced GIP was shown to suppress meal s t imu la ted g a s t r i n , 4 3 but the p o s s i b i l i t y tha t GIP p layed any enterogast rone e f f e c t on the HP ac id s e c r e t i o n i n the present study i s debatab le , as there i s no apparent c o r r e l a t i o n among the IR-GIP, IR-Ga and HP s e c r e t i o n . A " g a s t r i n - G I P " a x i s i s not apparent i n the present s tudy. A p o s s i b l e d e f i c i e n c y in the p ro toco l i s the measurement of GIP us ing the GP01 an t i se rum. Th is has been shown to measure a 5000 MW moiety on e l e c t r o p h o r e s i s by Dr . John Brown. The measurement of t h i s t h e r e f o r e r e s u l t s i n lower amounts than i n other s tud ies us ing d i f f e r e n t a n t i s e r a recogn i z ing both (o r more) m o i e t i e s . Do these po lypep t ides of d i f f e r e n t mo lecu la r weights have d i f f e r e n t ac t ions or are they re leased i n va ry ing amounts i n response to d i f f e r e n t s t i m u l i ? Others w i l l have to look i n to these ques t i ons . In defence, I contend tha t t h i s i s a purer ant iserum than the o thers and r e f l e c t s the r e s u l t s f o r the lower mo lecu la r we ight GIP. Thus the present study c l e a r l y i n d i c a t e s tha t d e f e c t i v e s e c r e t i o n of GIP due to f a i l e d f a t d i g e s t i o n i s not r e s p o n s i b l e f o r the g a s t r i c hype rsec re t i on a f t e r PDL, and another mechanism must be c o n s i d e r e d . A number of s tud ies suggest tha t PDL causes h y p e r a c i d i t y by i n t e r f e r i n g w i th the i n h i b i t o r y e f f e c t normal ly exer ted by f a t and i t s by -p roduc ts . Many 30 s t u d i e s have been performed to i d e n t i f y the hormones re leased by f a t i n the gut . I t has been shown tha t f a t r e l eases CCK from the i n t e s t i n a l mucosa but there i s l i t t l e doubt t ha t t h i s hormone cannot be s o l e l y r e s p o n s i b l e f o r the i n h i b i t i o n , s i n c e f a t induces suppress ion of h i s tam ine -s t imu l ated ac i d s e c r e t i o n tha t cannot be reproduced by CCK or s e c r e t i n r ega rd less o f the dose used.55 VIP i s another cand ida te f o r en te rogas t rone , and i n h i b i t s g a s t r i c ac i d s e c r e t i o n i n dogs.56 However, recen t study of Holm-Benzen et a l 5 7 showed tha t exogenously admin is te red VIP i s metabo l ized r a p i d l y and has no e f f e c t on submaximally p e n t a g a s t r i n - s t i m u l a t e d a c i d s e c r e t i o n , i n d i c a t i n g tha t VIP probably does not exer t any hormonal e f f e c t on ac i d s e c r e t i o n i n man. Al though GIP appears to s a t i s f y most complete ly the c r i t e r i a f o r being the enterogast rone desc r i bed by Kosaka and L im, f u r t h e r s tud ies are needed be fo re a hormonal s ta tus can be asc r i bed to GIP and before i t s p h y s i o l o g i c a l r o l e as the enterogast rone re leased by f a t i s proved. 31 (B) GLUCOSE METABOLISM PDL was the model f i r s t u t i l i z e d by Bant ing and Best 5 ** to e x t r a c t i n s u l i n from the p e r s i s t e n t i s l e t , but the p r e s e r v a t i o n of the i s l e t t i s s u e was f o r at l e a s t a shor t pe r iod of t ime. D r a g s t e d t 5 ^ repor ted tha t ex tens ive degenerat ion of the pancreas a f t e r o c c l u s i o n of the panc rea t i c duct cou ld o f ten lead to d iabe tes i n dogs. Whether the endocr ine f u n c t i o n w i l l f i n a l l y d e t e r i o r a t e a f t e r PDL or not has so f a r been c o n t r o v e r s i a l . Heptner et a l!8 observed impai red g lucose t o l e r a n c e f o l l o w i n g the i n t r a g a s t r i c and i . v . g lucose load four to s i x months a f t e r PDL i n dogs. They s t r essed an i n s u f f i c i e n t reserve of i n s u l i n as a cause of development of d i a b e t e s . L i t t l e i s known about f u n c t i o n a l a l t e r a t i o n s f o l l o w i n g PDL e s p e c i a l l y concern ing the e a r l y onset of d i a b e t e s . In the present experiment, i n t r a g a s t r i c g lucose t o l e r a n c e t e s t performed two weeks a f t e r PDL showed delayed serum g lucose and IRI response, i n d i c a t i n g g a s t r i c m o t i l i t y was decreased a f t e r PDL. The serum IRI response to i . v . g lucose was c l e a r l y d im in ished i n the PDL dogs (two and ten weeks) i n d i c a t i n g f a i l u r e of the i n i t i a l phase of i n s u l i n r e l e a s e . Th is f i n d i n g i s i n accordance w i th the obse rva t i on of Ka lk e t a l 6 0 t ha t i n p a t i e n t s w i th severe p a n c r e a t i c i n s u f f i c i e n c y IRI response to o ra l g lucose was not s i g n i f i c a n t l y lower than i n the c o n t r o l s w h i l e t ha t to i . v . g lucose was s i g n i f i c a n t l y l e s s than i n the c o n t r o l s . They suggested tha t the g l u c o s e - s t i m u l a t e d " e n t e r o - i n s u l a r a x i s " i s probably i n t a c t i n these p a t i e n t s , but i n the d i a b e t i c p a t i e n t s there i s c l e a r l y l o s s of p a n c r e a t i c be ta c e l l s e n s i t i v i t y to g lucose which may be due to damage to " g l u c o r e c e p t o r s " on the be ta c e l l membrane or a l t e r n a t i v e l y r e l f e c t a d i s o r d e r beyond the membrane l e v e l . They a l s o suggested tha t t h i s probably represents a d i s o r d e r of the pos tu la ted g l u c o s e - s t i m u l a t e d acute 32 r e l e a s e i n s u l i n pool as the one to ten minute response was impa i red . F u r t h e r , Pupo e t a l 6 1 showed tha t the a l l o x a n - d i a b e t i c dogs had s i g n i f i c a n t l y decreased ea r l y -phase i n s u l i n response to g lucose pu lses and s lower plasma g lucose d isappearance r a t e s , w h i l e these m i l d l y d i a b e t i c dogs achieved comparable i n s u l i n l e v e l s and h igher g lucose l e v e l s dur ing a pro longed g lucose i n f u s i o n than p r e - a l l o x a n con t ro l v a l u e s , i n d i c a t i n g the pa t t e rn of b lun ted e a r l y phase i n s u l i n s e c r e t i o n and cont inued l a t e phase i n s u l i n s e c r e t i o n i s not n e c e s s a r i l y dependent on gene t i c de te rmina t ion and may be induced i n m i ld a l l o x a n d i a b e t e s , a model i n which there i s an acqu i red b e t a - c e l l i n s u l i n d e f i c i e n c y . The f i n d i n g tha t serum IR-GIP response to i n t r a g a s t r i c g lucose load was very s i m i l a r to t ha t of serum g lucose and IRI when performed at two weeks f o l l o w i n g PDL i n d i c a t e s tha t the GIP s e c r e t i n g mechanism as one of the " e n t e r o - i n s u l a r a x i s " remains i n t a c t i n t h i s pe r iod a f t e r PDL. Thus i t has been shown tha t the PDL dogs had ea r l y onset (two to ten weeks) of d i a b e t e s , i . e . , b lun ted e a r l y phase i n s u l i n s e c r e t i o n , i n d i c a t i n g an acqu i red b e t a - c e l l i n s u l i n d e f i c i e n c y . D iabe tes i s a f requent c o m p l i c a t i o n of ch ron i c p a n c r e a t i t i s , being present i n o n e - t h i r d or more of the p a t i e n t s w i t h more advanced stage o f p a n c r e a t i c f i b r o s i s and a t rophy. A l though J o f f e e t al62 have pos tu la ted tha t the d i a b e t i c syndrome of ch ron i c p a n c r e a t i t i s represen ts an example of acqu i red i n s u l i n o p e n i a , recent observa t ions suggest a s e l e c t i v e or q u a l i t a t i v e impairment of the response of the beta c e l l s to g lucose a d m i n i s t r a t i o n but maintenance of the i n s u l i n response to va r i ous 33 enterohormones.60 The a b i l i t y of the remaining beta c e l l s to sec re te i n s u l i n i n response to i n t r a g a s t r i c g lucose was r e ta i ned in a l l dogs s tud ied d e s p i t e d e s t r u c t i o n of the exoc r ine pancreas, as evidenced by the comple te ly a t roph ied pancreas a f t e r PDL, i n disagreement w i th the hypothes is t ha t beta c e l l f u n c t i o n i s dependent on the i n t e g r i t y of the e x o c r i n e t i s s u e . 6 3 A l s o the f i n d i n g tha t serum IR-GIP response to i n t r a g a s t r i c g lucose was re ta ined i n s p i t e of b lun ted ea r l y -phase i n s u l i n response to i . v . g lucose suppor ts the idea of Ka lk e t al^O mentioned above. Serum IRI response to meat meals w i th and w i thou t unhydrolyzed or hydro lyzed cream examined at s i x weeks a f t e r PDL were apparent ly impaired compared to those examined before PDL. An i n t e r e s t i n g f i n d i n g i s t ha t meal s t imu la ted IRI responses seem to be (a t l e a s t p a r t l y ) dependent on serum GIP s e c r e t i o n s t imu la ted by the meal, q u a l i f y i n g GIP as an i n s u l i n o t r o p i c enterohormone, al though i t i s known tha t GIP i s i n s u l i n o t r o p i c only i n the presence of hyperg lycemia^ 4 and the peak g lucose concen t ra t i ons f o l l o w i n g the meat meal i n the present study were w i t h i n 100 mg/dl (eug lycemia ) . The exp lana t i on f o r the GIP dependent i n s u l i n response to the meals i n s p i t e of euglycemic background i s not c l e a r from the p resent s tudy . The serum g lucose response to meat meal a lone was s i g n i f i c a n t l y inc reased a f t e r PDL, w h i l e decreased and unchanged serum g lucose concen t ra t i ons were seen i n response to meat meal p lus unhydrolyzed cream and meat meal p lus hydro lyzed c r e x s , r e s p e c t i v e l y . The p o s s i b i l i t y of the i n f l u e n c e of GIP induced glucagon cannot be excluded al though 34 controversial.15,65 35 CLINICAL OBSERVATIONS AND PROJECTIONS FOR THE FUTURE P a n c r e a t i c ducta l l i g a t i o n i s c u r r e n t l y a p p l i e d i n c l i n i c a l t r a n s p l a n t a t i o n of the p a n c r e a s 6 6 and s u r g i c a l procedure as an a l t e r n a t i v e t o pancreatoje junostomy a f t e r pancreatoduodenectomy. 6 7 p 0 w i s et a l 6 7 c la imed the mod i f ied procedure i s s a f e r and l e s s prone to exoc r ine and endocr ine d i s t u r b a n c e s , p a n c r e a t i c f i s t u l a s and stomal u l c e r a t i o n s than the convent iona l pancreatoduodenectomy, w h i l e Papach r i s tou e t a l 6 8 showed d i s t a l pancreatectomy w i th duct l i g a t i o n i s a r e l a t i v e l y sa fe procedure but a f t e r pancreatoduodenectomy the morb id i t y i s reduced by a pancreato je junostomy. The major o b j e c t i o n s to the rou t i ne use of the panc rea t i c duct l i g a t i o n procedure are t ha t i t abo l i shes exoc r ine a c t i v i t y and tha t i t may impai r panc rea t i c endocr ine f unc t i on .59 These f unc t i ona l abno rma l i t i es a r i s e i n another p a t h o l o g i c a l c o n d i t i o n s of the pancreas bes ides i n p a t i e n t s w i t h p a n c r e a t i c duct l i g a t i o n . They i n c l u d e p a t i e n t s w i th d i s t a l pancreatectomy, pancreatoduodenectomy and t o t a l pancreatectomy f o r trauma, ch ron i c p a n c r e a t i t i s , endocr ine adenomas, and cancer . P a t i e n t s whose pancreatoje junostomy have become stenosed or i n whom the main p a n c r e a t i c duct i s obs t ruc ted by cancerous l e s i o n and are born w i th atrophy of the pancreas are a l s o i n c l u d e d . The p a t h o l o g i c a l outcomes i n common w i th these c o n d i t i o n s are l o s t or decreased exoc r ine and endocr ine f u n c t i o n of the pancreas. These p a t i e n t s may have mal abso rp t i ve phenomena and d i a b e t e s . Ma labsorp t ion and s tea to r rhea do not develop u n t i l 90 per cent of 36 p a n c r e a t i c exoc r ine f u n c t i o n i s l o s t . With l e s s than two per cent of normal f u n c t i o n s tea to r rhea i s severe and energy malabsorp t ion w i l l deve lop . Marked s tea to r rhea was not observed i n the dogs s tud ied i n the present exper iment, and t h i s i s probably due to f requent a d m i n i s t r a t i o n o f p a n c r e a t i c enzyme mixed w i th the meat meal f o r assessment of the sec re to ry eva lua t i on a f t e r PDL. Thus replacement of panc rea t i c enzyme tha t i s d i s t r i b u t e d w i t h meals i s u s u a l l y e f f e c t i v e f o r ma labsorp t ion phenomena of the p a n c r e a t i c d i s e a s e s . Dragstedt59 has repor ted tha t d iabe tes occurs only a f t e r r e s e c t i o n o f 80 per cent or more of the e n t i r e pancreas. F u r t h e r , Drags ted t et al69 have repor ted t ha t the amounts of i n s u l i n requ i red to con t ro l g l y c o s u r i a a f t e r p a r t i a l pancreatectomy i s much g rea te r than tha t needed a f t e r t o t a l r e s e c t i o n of the pancreas. In d iabe tes m e l l i t u s , i n s u l i n s e c r e t i o n i s decreased and the a n t i - i n s u l i n system such as g lucagon s e c r e t i o n i s s t i m u l a t e d . The a n t i - i n s u l i n system a f t e r t o t a l pancreatectomy has been shown to be depressed and i t has been suggested tha t d iabe tes a f t e r t o t a l r e s e c t i o n of the pancreas would not r e q u i r e as much exogenous i n s u l i n . 7 0 I t has a l s o been repor ted tha t g lucagon response to a r g i n i n e i n f u s i o n decreased a f t e r pancreatoduodenectomy i n p a t i e n t s w i th per iampurary c a n c e r , 7 * and N ish iwak i et al have shown tha t plasma glucagon response to a r g i n i n e i n f u s i o n was low i n dogs s i x months a f t e r P D L . 7 2 37 As s ta ted i n the DISCUSSION of the present paper, g lucagon response may have been inc reased a f t e r PDL due to augmented GIP s e c r e t i o n which probably s t imu la tes glucagon s e c r e t i o n . In any case , from these observa t ions i t can be recommended t h a t p a n c r e a t i c d iabe tes should be t r ea ted sepa ra te l y depending upon e t i o l o g y or background of the d i s e a s e . There has been con t roversy about whether or not inc reased g a s t r i c s e c r e t i o n or p e p t i c u l c e r occur i n ch ron i c p a n c r e a t i t i s . I t seems probable t ha t much of the con t roversy concern ing the c a p a c i t y of the p a t i e n t s w i th panc rea t i c d i sease to sec re te ac i d r e f l e c t s d i f f e r e n c e s i n the nature and degree of the p a n c r e a t i t i s . In s u r g i c a l s e r i e s which i n c l u d e most ly p a t i e n t s w i th ch ron i c p a n c r e a t i t i s s u f f i c i e n t l y severe to r e q u i r e ope ra t i on , an i nc reased i nc idence of u l c e r has been repo r ted . On the other hand, Hashida e t a l 7 3 have r e c e n t l y repor ted the Kyoto U n i v e r s i t y exper ience w i th complete ducta l o b s t r u c t i o n due to pancreas head cancer as evidenced by ERCP o r resec ted specimen: 33 cases were measured g a s t r i c s e c r e t i o n us ing P e n t a g a s t r i n , and i t was revea led tha t 21 p a t i e n t s were anac id , 11 p a t i e n t s had normal ac id l e v e l s , and only one p a t i e n t showed marked h y p e r s e c r e t i o n . They a l so showed tha t pe r i phe ra l c i r c u l a t i o n of the g a s t r i c antrum was d i s tu rbed i n dogs a f t e r PDL, suggest ing impairment of mucosal defence i s at l e a s t p a r t l y r e s p o n s i b l e f o r the fo rmat ion of u l c e r i n the p a t i e n t s w i t h panc rea t i c in f lammat ion . As shown i n the present s tudy, complete duc ta l o b s t r u c t i o n induces g a s t r i c hype rsec re t i on and even tua l l y causes u l c e r . There seems to be no 38 r e l a t i o n s h i p between g a s t r i c hype rsec re t i on and ma labsorp t ion phenomena as evidenced by no marked s tea to r rhea i n any dog s t u d i e d . However, Saunders e t a l 7 4 have repor ted tha t the presence of ove r t ma ld i ges t i on i s r e l a t e d to g a s t r i c hype rsec re t i on i n t h e i r p a t i e n t s w i th ch ron i c p a n c r e a t i t i s . They specu la ted when there i s much g a s t r i c j u i c e i n the duodenum and there i s any r e s i d u a l s e c r e t i o n of p a n c r e a t i c enzymes by p a t i e n t s w i t h c h r o n i c p a n c r e a t i t i s , g a s t r i c j u i c e causes rap id and i r r e v e r s i b l e dena tu ra t i on of panc rea t i c enzymes, and the ma ld iges t i on of p a t i e n t s w i th ch ron i c p a n c r e a t i t i s may be worsened. I t seems wise to admin is te r o ra l enzymes to a l l p a t i e n t s w i th ex tens i ve panc rea t i c d i sease or r e s e c t i o n , be fo re s tea to r rhea and g a s t r i c hype rsec re t i on become man i fes t , as i t i s d i f f i c u l t to d iagnose enzyme d e f i c i e n c y i n the e a r l y p o s t o p e r a t i v e p e r i o d . C l i n i c a l r e c o g n i t i o n of e a r l y panc rea t i c i n s u f f i c i e n c y i s thus d i f f i c u l t , but may be p o s s i b l e by per forming i . v . g lucose t o l e r a n c e t e s t . As shown i n the p resent s tudy, g lucose i n t o l e r a n c e and decreased e a r l y phase i n s u l i n response cou ld be a s i g n of e a r l y onset of p a n c r e a t i c i n s u f f i c i e n c y . C l i n i c a l i m p l i c a t i o n of the r e s u l t i n the present study tha t serum IR-GIP response to the meat meal a lone i s s i g n i f i c a n t l y augmented a f t e r PDL i s complex but of g rea t importance. There have been only a few i s o l a t e d case repo r t s of marginal u l c e r a t i o n as a c o m p l i c a t i o n o f pancreatoduodenectomy, w h i l e Grant et a l 7 5 have r e c e n t l y repor ted tha t the o v e r a l l i nc i dence of stomal u l c e r i n p a t i e n t s submit ted to a Whipple procedure or t o t a l pancreatoduodenectomy was s i x per cen t . 39 Al though these s u r g i c a l procedures are g e n e r a l l y known as u l c e r o g e n i c , why do so few p a t i e n t s get u l c e r s ? Any study of GIP s e c r e t i o n a f t e r these s u r g i c a l procedures has not so f a r been repo r ted . The p o s s i b i l i t y t ha t augmented GIP s e c r e t i o n p lays some p r o t e c t i v e r o l e aga ins t u l c e r fo rmat ion i n these p a t i e n t s i n c o - o p e r a t i o n w i t h o ther as ye t u n i d e n t i f i e d neural and hormonal f a c t o r s cannot be exc luded . The p resent study has not s u f f i c i e n t l y v e r i f i e d the r o l e of GIP i n i n h i b i t i n g g a s t r i c hype rsec re t i on a f t e r PDL. Fu tu re work w i l l e l u c i d a t e the t r ue r o l e of GIP i n the pathogenesis of g a s t r i c hype rsec re t i on and u l c e r fo rmat ion i n dogs a f t e r PDL and lead to p r a c t i c a l a p p l i c a t i o n . 40 40- CT ill E 30- | | before op. IHI after op. IS 20- 10- r1! a 1 »2 *3 *4 Individual dogs with Heidenhain pouches F i g . l . 24-hour acid outputs from the Heidenhain pouch , before and after pancreatic duct l i g a t i o n . Each bar represents the mean and standard error of values for 4 dogs. Number of experiments before and after pancreatic duct l i g a t i o n for each dog i s : 18 and 29 for #1 dog; 15 and 19 for §2 dog; 21 and 25 for #3 dog; 26 and 12 for #4 dog3 respectively. *=p<0.05 i'significant change compared with the control period). 41 1.5- "c • before op. E Minutes Fig. 2. Acid response from the Heidenhain pouch to meat meal alone before and after pancreatic duct l i g a t i o n . The g a s t r i c f i s t u l a was closed during the experiment. Each point represents the mean and standard error of values for 4 dogs(8 experiments). 42 30 60 90 j 120 150 180-210 240 270 300 Minutes Fig.3. Serum gastrin response to meat meal alone before and after pancreatic duct ligation. Each point represents the mean and standard error of values for 4 dogs(8 experiments). \ 43 2 0 0 - ¥ 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0 2 4 0 2 7 0 3 0 0 Fig. 4 Serum GIP response to meat meal alone before and after 'pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs(8 experiments). *=p<0. OS ( s i g n i f i c a n t change compared with the control period) 44 30 60 9 'o , 2 0 ,50 ,80 2 \ 0 240 ' 270 300 Minutes Fig. 5 Serum IRI response to meat meal alone before and after pancreatic duct ligation. Each point represents the mean and standard error of values for 4 dogs(8 experimetns). 45 . before op. 100- 60 E - J - o— — — — o after op. -J—L— . 1 i 1 O 50- 30 60 90 120 150 180 210 240 270 300 Minutes Fig. 6 Serum glucose response to 'meat meal alone before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs (8 experimetns). *=p<0. 05. ( s i g n i f i c a n t change compared with the control period). 46 1.5- » • before op. ° c after op. Minutes Fig. 7 Acid response from the Heidenhain pouch to meat meal plus unhydrolyzed cream before and after pancreatic duct l i g a t i o n . The g a s t r i c f i s t u l a was closed during the experiments.' Each point represents the mean and standard error of values for 4 dogs(8 experiments). 47 150- =• 100- 50- M e a t • • before op. o o .af ter op. 30 60 90 120 150 180 210 240 270 300 Minutes Fig. s Serum gastrin response to meat meal plus unhydrolyzed cream before and after pancreatic duct l i g a t i o n . Each point represents the mean and error of values for 4 dogs(8 experiments) 4 48 ^ 1 I I i i i i i i 30 60 90 120 150 180 210 240 270 300 Fig. 9 Serum GIP response to meat meal plus unhydrolyzed cream before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs (8experiments). *=p<0. 0 5 ( s i g n i f i c a n t change compared with the control period). 49 30- T • • before op. T T o — —o after bp. 60 90 120 150 180 210 240 270 300 Minutes Fig. 1 0 Serum IRI response to meat meal plus unhydrolyzed cream before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs (8 experiments). *=p<0.05} * *=p<0. 01.(signif icant change compared with the control period). 50 100- E O 50- O 30 60 90 120 150 180 210 240 270 300 Minutes Fig,11. Serum glucose response to meat meal plus unhydrolyz cream before and. after pancreatic duct ligation. Each point represents the mean and standard error of values for 4 dogs (8 experiments). *=p<0.05.(significant change compared with the control period). 51 1.5" • • before op. 'c ° o after op. Minutes Fig X{1 Acid response from the Heidenhain pouch to meat meal pius hydrolyzed cream before and after pancreatic duct l i g a t i o n . The g a s t r i c f i s t u l a was closed during the experiments. Each point represents the mean and standard error of, values for 4 dogs(8 experimetns). 52 150- hydrolyzed cream 30, 60 90 120 150 180 210 240 270 300 Minutes i ^ f 7 - Serum gastrin response to meat meal plus hydrolyzed cream before and after pancreatic duct ligation. Each point represents the mean and standard error of values for 4 dogs (8 experimetns). 53 "I ' 1 1 I 1 | | 1 T — 30 60 90 120 150 180 210 240 270 300 Minutes Fig. 14 Serum GIP response to meat meal plus hydrolyzed cream bofore and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs (8 experiments). 54 3 0 - Minutes Fig. 1 5 Serum IRI response to meat meal plus hydrolyzed cream before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs (8 experiments). / 55 150- 30. 60 90 120 150 180 210 240 270 300 Minutes Fig. Serum glucose response cream before and after pancreatic represents the mean and standard (8 experiments). to meat meal plus hydrolyzed duct l i g a t i o n . Each point error of values for 4 dogs \ 56 i i 0 30 M i n u t e s Fig. 1' Serum glucose response to i.v.glucose load before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs(8 experimetns). *=p<0.05, **=p<0.01s ***=p<0.005 ( s i g n i f i c a n t change compared with the control period). 57 5 0 - 0 3 0 6 0 m i n u t e s Fig. Serum IRI response to i.v. glucose load before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs(8 experimetns). *=p<0. 0 5 ( s i g n i f i c a n t change compared with the control period). 58 300- „ 200- no 0) in o u _2 O 100- 80- 60- 40- 20- 0 G l u c o s e — • b e f o r e o p . " ° a f t e r o p . (2wks) 30 60 90 120 150 180 Minutes Fig. 9 Serum^glucose response to i n t r a g a s t r i c glucose load before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs(8 experiments), *=p<0.053 **=p<0. 01 ( s i g n i f i c a n t change compared with the control period). 59 Fig. d 0 Serum IRI response to i n t r a g a s t r i c glucose load before and after pancreatic duct l i g a t i o n . Each point represents the mean and standard error of values for 4 dogs(8 experimetns). 60 before op. I 60 30 90 120 Minutes Fia 2 1 Serum GIP response to i n t r a g a s t r i c glucose load before and after pancreatic duct l i g a t i o n . 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G . : Acute and l a t e - p h a s e i n s u l i n s e c r e t i o n and g lucose t o l e r a n c e in m i ld a l l o x a n d iabe tes i n dogs. D i a b e t o l o g i a 25:161-166, 1976. 62 . J o f f e B . I . , Banks S . , Jackson W . P . U . , K e l l e r P . , O ' R e i l l y I .G. and V i n i k A . I . : I n s u l i n reserve i n p a t i e n t s w i th ch ron i c p a n c r e a t i t i s . Lance t I I : 890-892, 1968. 6 3 . Hinz M . , Ka ts i lambos N . , Schwe i t ze r B . , Rap t i s S. and P f e i f f e r E . F . : The r o l e of the exoc r ine pancreas i n the s t i m u l a t i o n of i n s u l i n s e c r e t i o n by i n t e s t i n a l hormones. I. The e f f e c t of pancreozyn in , s e c r e t i n , g a s t r i n pentapept ide and of glucagon upon i n s u l i n s e c r e t i o n of i s o l a t e d i s l e t s of r a t pancreas. D i a b e t o l o g i a 7 : 1 - 5 , 1971. 64. C r e u t z f e l d t W.: The i n c r e t i n concept today. D i a b e t o l o g i a 16:75-85, 1979. 65 . Fu j imoto W.Y . , W i l l i a m s R.H. and Ens inck J . W . : G a s t r i c i n h i b i t o r y po l ypep t i de , c h o l e c y s t o k i n i n , and s e c r e t i n e f f e c t s on i n s u l i n and g lucagon s e c r e t i o n by i s l e t c u l t u r e s . P r o c . Soc . Exp. B i o l . Med. 160:349-353, 1979. 71 66 . Hodge H.H. and Young H . B . : P a n c r e a t i c a u t o t r a n s p l a n t a t i o n f o l l o w i n g r e s e c t i o n . Surgery 83:359-360, 1978. 67 . Powis S . J . A . and Young H . B . : A mod i f i ed pancreatoduodenectomy. Surg . Gyneco l . Obs te t . 137:259-262, 1973. 68 . Papach r i s t ou D . N . , D 'Agos t ino H. and F o r t n e r J . G . : L i g a t i o n of the p a n c r e a t i c duct i n pancreatectomy. B r . J . Surg . 67 :260-262, 1980. 69 . Drags ted t L . R . , A l l e n J . G . and Smith E . M . : Ex tens i ve i n s u l i n t o l e r a n c e i n d i a b e t i c dogs. P r o c . Soc. Exp. B i o l . Med. 54 :292, 1943. 70. Yasugi H . , Mizumoto R.., Sakura i H. and Honjo I.: Changes i n carbohydrate metabol ism and endocr ine f u n c t i o n of remnant pancreas a f t e r major p a n c r e a t i c r e s e c t i o n . Am. J . Su rg . 132:577-580, 1976. 71 . M iya ta M. , Hamaji M . , Yamamoto T . , Nakao K . , Sakaguchi H. and Sakamoto T . : An app ra i sa l of r a d i c a l pancreatoduodenectomy based on glucagon s e c r e t i o n . Ann. Surg . 191:282-286, 1980. 72 . N i sh iwak i H . , Sakazak i S . , Sh in K . , Satake K. and Umeyama K . : Exper imental s t u d i e s on p a n c r e a t i c endocr ine f u n c t i o n of dogs a f t e r p a n c r e a t i c duct l i g a t i o n . J a p . J . G a s t r o e n t e r o l . 76 :104-111, 1979. 72 73 . Hashida S . , Suzuki T. and Tobe: G a s t r i c r e s e c t i o n i n p a t i e n t s w i th p a n c r e a t i c d i s e a s e . P r o c . J a p . Soc. G a s t r i c Sec . Res. 14 :43-44, 1982. 74 . Saunders J . H . B . , C a r g i l l J . M . and Wormsley K . G . : G a s t r i c s e c r e t i o n of ac i d i n p a t i e n t s w i th p a n c r e a t i c d i s e a s e . D i g e s t i o n 17:365-369, 1978. 75 . Grant C . S . , van Heerden J . A . : Anastomot ic u l c e r a t i o n f o l l o w i n g sub to ta l and t o t a l pancreatectomy. Ann. Surg . 190 :1 -5 , 1979. 73 APPENDIX In order to a s c e r t a i n the complete h y d r o l y s i s of cream by i ncuba t i on w i th the d i g e s t i v e agent, gas chromatographic a n a l y s i s was per formed. One hundred and t w e n t y - f i v e g of whipping cream (S i lverwood Whipping Cream, S i l ve rwood D a i r i e s , Toronto , Canada. I ng red ien t s : Fa t 38.2 g , sa tu ra ted f a t t y ac ids 21.4 g, o l e i c ac i d 1 g, p r o t e i n 2.6 g, carbohydrate 4.2 g, c a l c i u m 0.1 g) was incubated w i th th ree capsu les of Cotazymes (Organon C o . , Toron to , Canada. Each capsu le con ta ins 800 u n i t s of p a n c r e a t i c l i p a s e ) f o r th ree hours a t 37° C. A f t e r the i n c u b a t i o n , re leased f a t t y ac i ds were ex t rac ted w i th e the r , c r y s t a l i z e d as C a - s a l t , and r e s o l u b i l i z e d as f r e e f a t t y a c i d w i t h concent ra ted HCl h y d r o l y s i s . Boron t r i f l u o r i d e (BF3) methanol complex was used f o r the p repa ra t i on of f a t t y a c i d methyl es te rs us ing the method of Me t ca l f e et a l (Me tca l f e L .D . and Schmitz A . A . : The rap id p r e p a r a t i o n of f a t t y a c i d es te r s f o r gas chromatographic a n a l y s i s . A n a l y t i c a l Chem. 33: 363-364, 1961). The hydro lyzed sample was put i n t o the 50 ml of myer - f l ask coo led in an i c e ba th , added 7 ml of BF3 reagent , and b o i l e d f o r two minutes; 5 ml o f heptane was added and b o i l e d f o r one munte; Heptane l a y e r was r a i s e d up to the neck of the myer - f l ask w i th sa tu ra ted aquous sodium c h l o r i d e s o l u t i o n . A l i q u o t of heptane l a y e r was taken i n t o the sample b o t t l e and 74 d r i e d w i t h disodium s u l f a t e anhydr ide . Gas chromatographic a n a l y s i s was done us ing H i t a c h i 663 gas chromatograph ( H i t a c h i C o . , Tokyo) . F igu res 1 t o 5 show the chromatographic pa t te rns and opera t ing c o n d i t i o n s . F i g u r e 1 shows the pa t t e rn a f t e r 3-hour i ncuba t i on w i thout the d i g e s t i v e agent. Any f a t t y a c i d methyl e s t e r peak cannot be seen. F i g u r e s 2, 3 and 4 i l l u s t r a t e s i n g l e chromatographic pa t te rns of methyl l a u r a t e , methyl p a l m i t a t e and methyl s t e a r a t e r e s p e c t i v e l y as c o n t r o l s . F i g u r e 5 shows the p a t t e r n o f sample of 3-hour i ncuba t i on w i th the d i g e s t i v e agent, and many peaks of f a t t y a c i d methyl es te r s which w i l l correspond to the c o n t r o l s can be seen. 75 3 nr. Incubation non enzyme DEGS Chromosorfa WAW DMCS 80/100 Glass I.D. 3*X2m 160-200'C 4"C/min Nj 20ml/min O 5 tO 15 Retention time (min) Fig.1(forAPPENDIX)• The chromatographic pattern of cream after 3-hr incubation at 37 °C without the digestive agent. 76 OEGS Chromosorb WAW DMCS 80/100 Glass I.D. 3*X2m 160-200'C 4*C/min N2 20 ml/min Methyl Laurate C12 5 10 » 5 r R e t e n t i o n time (min) Fig. 2(for APPENDIX)• The chromatographic pattern of methyl laurate. 77 Methyl Palmitate C16 DEGS Chromosorb WAW DMCS eo/ioo Glass I.D. 3 * X 2 m 160-200'C 4'C/min N; 20ml/min 5 10 15 » Retention time (min) Fig. ' 3 ( f o r APPENDIX ) methyl -palmitate. The chromatographic pattern of 78 DEGS Chromosorb WAW DMCS 60/100 Glass I.D. 3*X2m 160-200"C 4*C/min N2 20ml/min Fig. 4 (for APPENDIX ) . methyl stearate. The chromatographic pattern of 79 3 nr. Incubation with enzyme DEGS Chromosorb WAW DMCS 80/100 Glass I.D. 3*X2m 160-200'C 4'C/min Ni 20ml/min C12 C16 C14 cie:o cis:i O s 10 , 15 Retention time (min) Fig. 5 (for APPENDIX ) . The chromatographic pattern of fatty acid methyl esters after 3-hr incubation at 37°C with the digestive agent. 80 PHOTOGRAPH I Dog #4 pos t mortem specimen. Duodenum and panc rea t i c ducts showing a t rophy o f pancreas , but no in f lammat ion . 82 PAPERS WRITTEN: 1. S t a m ' s h e f f s ope ra t i on f o r nephrop tos is . Opera t ion (Japan) 25 :661 , 1971. 2 . A case of hydrops of the g a l l b l a d d e r due to non-ca lcu lous c y s t i c duct o b s t r u c t i o n . Surgery (Japan) 38 :427, 1976. 3 . S e l e c t i v e angiography i n cancer of the pancreas a t a r e s e c t a b l e s tage . Am. J . Surg . 122:402, 1971. 4 . S u r g i c a l s i g n i f i c a n c e of anatomic v a r i a t i o n s o f the hepa t i c a r t e r y . Am. J . Surg . 122:505, 1971. 5 . Z o l l i n g e r - E l l i s o n syndrome assoc i a ted w i th pa ra thy ro i d adenoma and ec top i c g a s t r i c t i s s u e i n the lower esophageal mucosa. Can. J . Su rg . 6 . P e p t i c u l c e r and g lucose homeostasis : I. I n s u l i n , g a s t r i n and glucagon responses to o ra l g lucose and in t ravenous a r g i n i n e i n p e p t i c u l c e r p a t i e n t s . A r c h . J a p . C h i r . 48 :517, 1979. 7. R e l a t i o n s h i p between GIP and i n s u l i n . Surg . Ther . (Japan) 41 :447 , 1979. 8 . Negat i ve feedback e f f e c t of i n s u l i n on the s e c r e t i o n of GIP. J a p . J . G a s t r o e n t e r o l . 76:2432, 1979. 83 9 . A case of long term combined use of N e o c a r c i n o s t a t i n and humanimmunoglobulin f o r co lon cancer . K i s o - t o - R i n s h o 14:138, 1980. 10. The i n h i b i t o r y e f f e c t of s u l p i r i d e i n a r g i n i n e - s t i m u l a t e d serum g a s t r i n and growth hormone i n normal sub jec t s and p e p t i c u l c e r p a t i e n t s . J a p . J . G a s t r o e n t e r o l . 78:1363, 1981. 11. P e p t i c u l c e r and g lucose homeostasis: I I . I n s u l i n , g a s t r i n and glucagon responses to ora l and i . v . L - a r g i n i e n i n two groups of duodenal u l c e r p a t i e n t s . Submitted to G a s t r o e n t e r o l . J a p . 84 PAPERS PRESENTED: 1. S u r g i c a l s i g n i f i c a n c e of l i v e r angiography ( e s p e c i a l l y f o r l i v e r c a n c e r ) . The 8 th Meet ing of Japanese Soc ie t y of Ang io logy . 1967. 2 . S i m u l a t i o n of s p l e n i c c i r c u l a t o r y dynamics. The 7 th Meet ing of Japanese Soc ie t y of Medical E l e c t r o n i c s and B i o l o g i c a l E n g i n e e r i n g . 1968. 3 . C o r r e l a t i o n of l i v e r cancer and i t s b lood supp ly . The 3rd Meet ing of Japanese Soc ie t y of Hepato logy. 1967. 4 . A n a l y s i s of s p l e n i c and po r ta l c i r c u l a t o r y dynamics. The 9 th Meeting of Japanese Soc ie t y of Ang io logy . 1968. 5 . A n a l y s i s of s p l e n i c and po r ta l c i r c u l a t i o n us ing s u p e r s e l e c t i v e r a d i o i s o t o p e i n j e c t i o n to s p l e n i c a r t e r y . The 9th Meet ing of Japanese S o c i e t y of Nuc lear Med i c i ne . 1969. 6 . Angioscanography of l i v e r cancer . Kyoto S u r g i c a l Congress . 1969. 7. Hepatoma of i n f a n t . Kyoto S u r g i c a l Congress . 1969. 8 . Exper ience of mod i f ied S t a n i s c h e f f s ope ra t i on f o r nephrop tos i s . Okayama S u r g i c a l A s s o c i a t i o n . 1970. 85 9 . A case of hydrops of the g a l l b l a d d e r due to nonca lcu lous c y s t i c duct o b s t r u c t i o n . K i n k i Su rg i ca l A s s o c i a t i o n . 1972. 10. I n t r a o p e r a t i v e e x p l o r a t i o n of the g a s t r i c mucosal change. K i n k i S u r g i c a l A s s o c i a t i o n . 1973. 11 . Traumat ic urachal c y s t of the k idney . K i n k i S u r g i c a l A s s o c i a t i o n . 1977. 12. A m y l a s e - c r e a t i n i n e c l ea rance r a t i o f o l l o w i n g in t ravenous i n j e c t i o n of pancreozymin in ch ron i c p a n c r e a t i t i s . K i n k i S u r g i c a l A s s o c i a t i o n . 1977. 13 . P e p t i c u l c e r and g lucose homeostas is . K i n k i S u r g i c a l A s s o c i a t i o n . 1979. 14. H ia tus he rn ia assoc i a t ed w i th pep t i c u l c e r . K i n k i S u r g i c a l A s s o c i a t i o n . 1979. 15. Rad ica l ope ra t i on f o r i n t r a h e p a t i c s tones . K i n k i S u r g i c a l A s s o c i a t i o n . 1978. 16. The negat i ve feedback con t ro l o f GIP by i n s u l i n . The 20th Meet ing of Japanese Gas t roen te ro logy A s s o c i a t i o n . 1978. 17. GIP f o l l o w i n g l i g a t i o n of the panc rea t i c duct i n dogs. The 14th Meeting of Japanese G a s t r o e n t e r o l o g i c a l Surgery A s s o c i a t i o n . 1979. 86 18. In t ravenous a r g i n i n e , and o ra l g lucose s t imu la ted i n s u l i n , g a s t r i n and g lucagon i n p e p t i c u l c e r p a t i e n t s . The 22nd Spr ing Meet ing of Japanese Gas t roen te ro logy A s s o c i a t i o n . 1979. 19. Post -sp lenectomy thrombocythemia. Japan C l i n i c a l Hematology A s s o c i a t i o n . 1979. 20 . Serum CEA l e v e l s a f t e r mumps v i r u s vacc ine i n j e c t i o n f o r co lon cancer . K i n k i S u r g i c a l A s s o c i a t i o n . 1979. 2 1 . P e r f o r a t e d smal l i n t e s t i n a l u l c e r . Kyoto Emergency Treatment A s s o c i a t i o n . 1979. 22 . Serum g a s t r i n , i n s u l i n and glucagon in response to in t ravenous a r g i n i n e i n p e p t i c u l c e r p a t i e n t s . The 15th Meet ing of Japanese G a s t r o e n t e r o l o g i c a l Surgery A s s o c i a t i o n . 1980. 23 . The suppress i ve e f f e c t of s u l p i r i d e on a r g i n i n e - s t i m u l a t e d g a s t r i n and growth hormone. The 66th Meet ing of Japanese G a s t r o e n t e r o l o g i c a l A s s o c i a t i o n . 1980. 24. D isseminated i n t r a v a s c u l a r coagu la t i on a s s o c i a t e d w i t h acute o b s t r u c t i v e supp ra t i ve c h o l a n g i t i s . K i n k i S u r g i c a l A s s o c i a t i o n . 1980. 87 25 . Treatment of c o l o n cancer w i t h N e o c a r c i n o s t a t i n and human immunoglobul in. Kyoto Cancer Research A s s o c i a t i o n . 1980. 26 . Abdominal trauma. Kyoto Medica l A s s o c i a t i o n . 1980. 27. Treatment of p e p t i c u l c e r . Kyoto Medical A s s o c i a t i o n . 1980.

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