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

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THE EFFECT OF PANCREATIC DUCT LIGATION ON THE GASTRIC  INHIBITORY  POLYPEPTIDE (GIP), GASTRIC ACID SECRETION AND GLUCOSE METABOLISM  BY  A k i r a Nakayasu, M.D., University  o f B r i t i s h Columbia, 1982  A t h e s i s submitted i n p a r t i a l requirements  F.A.C.S.  f u l f i l m e n t of the  f o r the DEGREE OF MASTER OF SCIENCE.  i n THE DEPARTMENT OF SURGERY  We  accept t h i s t h e s i s as conforming  t o the  r e q u i r e d standard  THE UNIVERSITY OF BRITISH COLUMBIA JUNE,  ©Akira  1982.  Nakayasu, 1982.  IN DOGS  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of  requirements f o r an advanced degree a t the  the  University  of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make it  f r e e l y a v a i l a b l e f o r reference  and  study.  I further  agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may  be granted by the head of  department or by h i s or her  representatives.  my  It is  understood t h a t copying or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l gain  s h a l l not be  allowed without my  permission.  Department o f The U n i v e r s i t y of B r i t i s h 1956 Main Mall Vancouver, Canada V6T 1Y3 Date  DE-6  (3/81)  15th  July,  1982  Columbia  written  i i S u p e r v i s o r : Dr. I . G. M. C l e a t o r  ABSTRACT  (A)  Gastric Secretion  The  p r e s e n t study was  performed  p o s t - p a n c r e a t i c duct l i g a t i o n GIP  t o i n v e s t i g a t e the c a n i n e  s e c r e t i o n i n response t o f a t i n g e s t i o n  using a meat meal mixed with unhydrolyzed and to determine whether GIP  or h y d r o l y z e d whipping  p l a y s a r o l e i n the p r o d u c t i o n of h y p e r a c i d  s e c r e t i o n i n the p a n c r e a t i c duct l i g a t e d  dogs.  Four mongrel female dogs were prepared w i t h Heidenhain and g a s t r i c f i s t u l a  measured b e f o r e and a f t e r p a n c r e a t i c duct l i g a t i o n  inhibitory oral  pouch  (GF), and d a i l y a c i d s e c r e t i o n from the HP  serum immunoreactive  g a s t r i n (IR-Ga) and  (PDL).  HP  serum immunoreactive  acid  measured b e f o r e and  after  Twenty f o u r hour HP the f o u r dogs a f t e r PDL. meal alone and  output,  gastric  i n g e s t i o n o f a meat meal alone, a meat meal mixed w i t h 125g cream and meat meal mixed with 125g  (HP)  was  p o l y p e p t i d e (IR-GIP) c o n c e n t r a t i o n s d u r i n g f i v e hours  unhydrolyzed  cream,  following of  o f h y d r o l y z e d cream were  PDL.  a c i d outputs  increased s i g n i f i c a n t l y  F i v e hour HP  a c i d outputs i n response  a meat meal p l u s unhydrolyzed  cream were  i n each  to a meat  modestly  i n c r e a s e d , w h i l e those i n response t o a meat meal p l u s h y d r o l y z e d cream were r a t h e r reduced were lowered  a f t e r PDL.  a f t e r PDL  lowered most markedly.  of  Serum IR-Ga responses t o a l l s t i m u l a n t s  and those to meat meal plus h y d r o l y z e d cream  ii i  Serum IR-GIP responses t o a meat meal a l o n e were  significantly  i n c r e a s e d , w h i l e t h o s e t o a meat meal p l u s u n h y d r o l y z e d and h y d r o l y z e d cream were r e d u c e d .  The r e s u l t s of t h e p r e s e n t study demonstrate serum IR-GIP  in  response t o a meat meal i s i n c r e a s e d by PDL i n dogs, s u g g e s t i n g  augmented  a c i d j u i c e p a s s i n g i n t o the i n t e s t i n a l  the  i n c r e a s e d GIP r e s p o n s e .  It  lumen i s r e s p o n s i b l e f o r  i s i n d i c a t e d t h a t h y p o - s e c r e t i o n of GIP i s  not  the cause of h y p e r s e c r e t i o n of g a s t r i c a c i d i n the PDL dogs.  (B)  Glucose Metabolism.  Functional  alteration  i n g l u c o s e homeostasis e s p e c i a l l y  the e a r l y onset of d i a b e t e s a f t e r PDL was s t u d i e d i n dogs. (i.v.)  and i n t r a g a s t r i c  concerning Intravenous  g l u c o s e t o l e r a n c e t e s t s were performed at two  t e n weeks and two weeks a f t e r PDL r e s p e c t i v e l y .  Serum g l u c o s e , I R I ,  IR-GIP i n response t o a meat meal w i t h and w i t h o u t u n h y d r o l y z e d  to and  or  h y d r o l y z e d f a t were e s t i m a t e d at s i x weeks a f t e r PDL.  Significantly secretion after Intragastric IRI  i.v.  i m p a i r e d g l u c o s e t o l e r a n c e and e a r l y phase IRI g l u c o s e were shown a t two t o t e n weeks a f t e r PDL.  g l u c o s e l o a d r e v e a l e d d e l a y e d p a t t e r n o f serum g l u c o s e and  (no e v i d e n c e of g l u c o s e i n t o l e r a n c e or d i m i n i s h e d IRI  indicating  decreased g a s t r i c m o t i l i t y a f t e r PDL.  intragastric  g l u c o s e l o a d was not a t t e n u a t e d  s i m i l a r p a t t e r n to IRI  response.  Serum IRI  secretion),  Serum IR-GIP response t o  by the o p e r a t i o n but showed a responses t o meat meals w i t h  and w i t h o u t u n h y d r o l y z e d o r h y d r o l y z e d cream were impaired a f t e r PDL.  iv  It  i s i n d i c a t e d t h a t * dogs a f t e r PDL show e a r l y o n s e t (two t o  weeks) of d i a b e t e s , i . e .  b l u n t e d e a r l y phase i n s u l i n s e c r e t i o n ,  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 i n t a c t a f t e r PDL i f  sufficient  2  ten  the  enterohormone remains  s t i m u l a n t s 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)  4.  Assays.  RESULTS  1)  Twenty four hour acid study.  21  vi  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.  vi i i  F i g u r e 10  Serum IRI  response to meat meal p l u s u n h y d r o l y z e d cream b e f o r e  and a f t e r PDL.  F i g u r e 11  Serum g l u c o s e response t o meat meal p l u s unhydrolyzed  cream  b e f o r e and a f t e r PDL.  F i g u r e 12  A c i d response from the H e i d e n h a i n pouch t o meat meal  plus  h y d r o l y z e d cream b e f o r e 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 l u s h y d r o l y z e d cream b e f o r e and a f t e r PDL.  F i g u r e 14  Serum GIP response t o meat meal p l u s h y d r o l y z e d cream b e f o r e and a f t e r PDL.  F i g u r e 15  Serum IRI  response to meat meal p l u s h y d r o l y z e d cream b e f o r e  and a f t e r PDL.  F i g u r e 16  Serum g l u c o s e response t o meat meal p l u s h y d r o l y z e d cream b e f o r e and a f t e r PDL.  F i g u r e 17  Serum g l u c o s e response to i . v .  g l u c o s e l o a d b e f o r e and  after  PDL.  F i g u r e 18  Serum IRI  response to i . v .  g l u c o s e l o a d b e f o r e and a f t e r PDL.  ix  F i g u r e 19  Serum g l u c o s e response t o i n t r a g a s t r i c  glucose load before  a f t e r PDL.  F i g u r e 20  Serum IRI  response t o i n t r a g a s t r i c  glucose load before  and  a f t e r PDL.  F i g u r e 21  Serum 6IP r e s p o n s e t o i n t r a g a s t r i c a f t e r PDL.  g l u c o s e l o a d b e f o r e and  and  X  PHOTOGRAPH  Photo 1:  Gross pathology o f post-mortem  pancreas.  xi  ACKNOWLEDGEMENT  I wish t o express my s i n c e r e g r a t i t u d e t o I a i n G. M. C l e a t o r , my teacher and  i n the M.Sc. t h e s i s , who gave me personal  advice.  guidance,  encouragement  Without h i s i n t e r e s t and knowledge t h i s work would not have  been completed.  R. Cameron H a r r i s o n ,  Professor  i n t h e Department o f Surgery, U.B.C,  t o whom I am g r a t e f u l f o r h i s i n t e l l i g e n t c r i t i c i s m ,  h i s advice and  friendship.  John C. Brown, P r o f e s s o r who provided  i n the Department of P h y s i o l o g y ,  U.B.C,  t h e GIP a n t i s e r a .  Anthony J . Dowel 1, my p o s t - g r a d u a t e course c o l l e a g u e c o l l a b o r a t i o n with v a l u a b l e  f o r stimulating  criticism.  N i c o l a O'Connor, f o r e x c e l l e n t t e c h n i c a l  a s s i s t a n c e . My s i n c e r e  thanks a l s o go t o :  Takeo Yamagishi, Research F e l l o w U.B.C, f o r h i s v a l u a b l e  i n t h e Department of Surgery,  criticism.  Raphael L u i , f o r h e l p i n g me with t h e necessary  Jan  arrangements.  van den Broek and a l l t h e s t a f f o f t h e Animal L a b o r a t o r y  Department o f Surgery, U.B.C, f o r t h e i r s k i l l e d  laboratory  i n the  assistance.  1  INTRODUCTION  C a n i n e g a s t r i c h y p e r s e c r e t i o n f o l l o w i n g PDL i s a w e l l - k n o w n phenomenon, 1 » 2 , 3 , 4 b t, the mechanism(s) f o r t h i s phenomenon remains U  obscure.  It  i s g e n e r a l l y accepted t h a t t h e g a s t r i c h y p e r s e c r e t i o n may be  due i n p a r t t o the absence of b y - p r o d u c t s of f a t d i g e s t i o n w h i c h normally s t i m u l a t e 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 small bowel.5  hormone(s)  from t h e duodenum and  Feng e t al*> demonstrated t h a t duodenal i r r i g a t i o n by  suppressed the a c i d s e c r e t i o n of t r a n s p l a n t e d g a s t r i c pouches, t h a t t h e i n h i b i t i o n was humorally m e d i a t e d , and Kosaka and L i m the name " e n t e r o g a s t r o n e " f o r the humoral  inhibitory  agent.  fat  indicating 7  proposed  GIP has been  found t o s a t i s f y the c r i t e r i a as an e n t e r o g a s t r o n e i n dogs,8 b u t i n n e r v a t e d stomach p r e p a r a t i o n s of the dog9 and i n normal man^O  in inhibition  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 t o be weak.  It  has been s p e c u l a t e d t h a 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 t h e 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 . C o n t r a r y t o t h i s a s s u m p t i o n , an exaggerated GIP r e l e a s e f o l l o w i n g g l u c o s e o r t e s t meal was observed i n p a t i e n t s w i t h duodenal  oral  ulcer.H>12  GIP i s known to p o t e n t i a t e g l u c o s e induced i n s u l i n r e l e a s e , and the i n c r e a s e i n b l o o d l e v e l s of g l u c o s e and GIP i n the m a j o r i t y of duodenal ulcer patients,  l e a d i n g t o an i n c r e a s e d i n s u l i n r e s p o n s e , might be  e x p l a i n e d by an enhanced a b s o r p t i o n of g l u c o s e by the small bowel mucosa, p o s s i b l y as a consequence of an abnormally r a p i d r a t e of g a s t r i c and/or increased i n t e s t i n a l  motility^.  emptying  2  E b e r t e t a l l ^ demonstrated i n t r a d u o d e n a l a c i d (HCl) dose dependently p o t e n t i a t e s r a t s , w h i l e Brown e t a U R e c e n t l y , LeRoith et a l  5  1 6  i n f u s i o n of  hydrochloric  g l u c o s e induced i n s u l i n r e l e a s e  in  f a i l e d t o show IR-GIP r e l e a s e i n dogs by H C l . showed t h a t HCl by i t s e l f  s t i m u l a t i n g GIP i n man, s u g g e s t i n g p h y s i o l o g i c a l  i s c a p a b l e of  s i g n i f i c a n c e of  acid  induced GIP s e c r e t i o n .  Functional  alteration  i n g l u c o s e metabolism as w e l l  as g a s t r i c  acid  s e c r e t i o n i s an i m p o r t a n t p h y s i o l o g i c a l problem i n human and animal performed PDL.  It  is well  known t h a t PDL r e s u l t s  o f the e x o c r i n e p a n c r e a t i c t i s s u e . various intervals  i n atrophy  D e t a i l e d morphological  and f i b r o s i s  studies  1 7  at  a f t e r PDL i n r a t s have r e v e a l e d t h a t a c i n a r c e l l s  c o m p l e t e l y d i s a p p e a r w i t h i n one week and never r e a p p e a r , and PDL caused some i n i t i a l  damage t o the i s l e t w i t h subsequent r e g e n e r a t i o n of the  islet  parenchyma.  Whether the e n d o c r i n e f u n c t i o n w i l l  after  PDL o r not has so f a r been c o n t r o v e r s i a l .  finally  deteriorate  Heptner et a l ^ observed t h a t 1  f o u r t o 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 l u c o s e t o l e r a n c e were i m p a i r e d and the i n c r e a s e i n serum IRI was diminished a f t e r abnormality a f t e r PDL.  intragastric  and i . v .  glucose load,  indicating  the  i n g l u c o s e t o l e r a n c e as a consequence of i s l e t c e l l damage  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, i n i t i a l l y 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 f i r s t 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. daily.  Volume and acid output were measured  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  s t a n d w i t h a s u p p o r t under the d o g ' s abdomen to p r e v e n t 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 i n t r o d u c e d i n t o the l a r g e v e i n on the  a n t e r i o r a s p e c t o f t h e f o r e limb f o r blood samples. NaCl were d e l i v e r e d through p o l y e t h y l e n e t u b i n g  I n f u s i o n s of 154 mM  i n t o the l e g v e i n .  A  p e r i s t a l t i c pump (Harvard Apparatus Company, Dover, Mass.) m a i n t a i n e d i n f u s i o n a t 60 m l / h r . week.  the  Each dog was t e s t e d e i t h e r t w i c e o r t h r e e times per  There was always a t l e a s t 48 hours between each t e s t .  A modified  washout t e c h n i q u e 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: A t 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 n g e was connected to the s t a i n l e s s c a n u l a and 20 ml of p h y s i o l o g i c a l s a l i n e was instilled  i n t o t h e HP u s i n g t h e s y r i n g e t o i r r i g a t e g e n 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 was determined as s t a t e d above.  acid  B a s a l s e c r e t i o n f r o m 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 ( D r . B a l l a r d ' s Dog Food, S t a n d a r d Brands L t d . , Canada. g i v e n to each dog.  Ingredients:  p r o t e i n 9% ( 3 8 g ) ,  f a t 5% (21g)) were  F o r f i v e hours f o l l o w i n g the s t a n d a r d meat m e a l , HP  s e c r e t i o n was c o l l e c t e d a t 15 minute i n t e r v a l s .  The GF was kept c l o s e d  d u r i n g the f e e d i n g e x p e r i m e n t s .  Each dog had venous b l o o d drawn f o r serum I R - G a , I R - G I P , IRI  and  g l u c o s e d e t e r m i n a t i o n s a t f a s t i n g , 15, 30, 4 5 , 6 0 , 9 0 , 120, 150, 180, 210, 270 and 300 minutes f o l l o w i n g the m e a l .  B l o o d samples were c e n t r i f u g e d  w i t h i n one hour, the serum s e p a r a t e d and kept f r o z e n u n t i l  IR-Ga,  IR-GIP,  6  IRI  and g l u c o s e d e t e r m i n a t i o n s were p e r f o r m e d .  The s t a n d a r d meal  s t i m u l a t i o n s were performed t w i c e i n each dog.  3.  E f f e c t of I n g e s t i o n of F a t ( U n h y d r o l y z e d and H y d r o l y z e d ) on F i v e Hour A c i d ,  I R - G a , I R - G I P , IRI  and G l u c o s e Responses t o a Meat M e a l .  125g of cream ( S i l v e r w o o d S h i p p i n g Cream, S i l v e r w o o d D a i r i e s , T o r o n t o , Canada.  Ingredients:  protein 2.6g; fat 38.2g; saturated  fatty  acids 21.4g; o l e i c acid 1 3 . l g ; l i n o l e i c acid Ig; carbohydrate 4 . 2 g ; c a l c i u m 0.1 g) was mixed w i t h 15oz s t a n d a r d meat meal and i n g e s t e d w i t h i n three minutes.  On another o c c a s i o n , the same amount of cream was i n c u b a t e d w i t h t h r e e c a p s u l e s of Cotazymes (Organon C o . , T o r o n t o , Canada:  each c a p s u l e  c o n t a i n s 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 t h r e e hours a t 37°C (hydrolyzed fat)  (see APPENDIX) and mixed w i t h 15oz s t a n d a r d meat meal and  ingested w i t h i n three minutes.  F o r f i v e hours f o l l o w i n g the meat meal mixed w i t h u n h y d r o l y z e d or h y d r o l y z e d cream, HP s e c r e t i o n was c o l l e c t e d a t 15 minute i n t e r v a l s . volume of each sample was measured, and t o t a l d e s c r i b e d above.  The  a c i d was determined as  Venous b l o o d was drawn f o r serum I R - G a ,  I R - G I P , IRI  and  g l u c o s e d e t e r m i n a t i o n s a t f a s t i n g , 15, 30, 4 5 , 6 0 , 9 0 , 120, 150, 180, 210, 240, 270, and 300 minutes f o l l o w i n g the m e a l . performed t w i c e i n each dog.  Those t e s t s were each  7  4.  Serum G l u c o s e and IRI Responses to i . v . G l u c o s e , IRI  G l u c o s e L o a d , and Serum  and IR-GIP Responses t o I n t r a g a s t r i c  P a n c r e a t i c e n d o c r i n e f u n c t i o n was examined by i . v .  Glucose Load.  and  intragastric  g l u c o s e t o l e r a n c e t e s t s w i t h d e x t r o s e s o l u t i o n ( I g / k g body weight)  and  P a l - a - d e x 100 ( J . T. Baker Chemical C o . , P h i l 1 i p s b u r g , New J e r s e y ; 2 g / k g body w e i g h t ) ,  respectively.  50% d e x t r o s e s o l u t i o n w i t h an equal volume of  s a l i n e was i n f u s e d over a two t o f o u r minute p e r i o d . intragastrically  P a l - a - d e x was g i v e n  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 a t l e a s t 18 h o u r s , 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, 3 0 , 45 and 60 minutes a f t e r  i.v.  g l u c o s e l o a d , and a t f a s t i n g , 15, 30, 6 0 , 9 0 , 120, 150, and 180 minutes after  i n t r a g a s t r i c glucose load.  dog.  B l o o d samples were c e n t r i f u g e d w i t h i n one hour, the serum s e p a r a t e d  and kept f r o z e n u n t i l  The t e s t s were performed t w i c e i n each  glucose, IRI,  and IR-GIP d e t e r m i n a t i o n s  were  performed.  A f t e r completing a l l dogs:  the c o n t r o l  under g e n e r a l i n t u b a t i o n  s t u d i e s , PDL was performed on a l l  a n e s t h e s i a , b o t h t h e 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 s e p a r a t e d from the duodenum by i n t e r p o s i t i o n of the omentum. of t e s t s was r e p e a t e d : f i v e hour a c i d ,  F o l l o w i n g PDL, the f i r s t  series  24 hour study was s t a r t e d one week a f t e r PDL and  I R - G a , I R - G I P , IRI  and g l u c o s e i n response t o meal  i n g e s t i o n were e s t i m a t e d a t f o u r t o e i g h t weeks ( s i x weeks i n average) a f t e r PDL, w h i l e  1  serum g l u c o s e , IRI  serum g l u c o s e and IRI  i n response to i . v .  and IR-GIP i n response t o i n t r a g a s t r i c  glucose, and  g l u c o s e were  2  8  e s t i m a t e d a t two and t e n weeks, and two weeks a f t e r PDL,  Liver function on a l l of f o u r dogs.  respectively.  t e s t s were performed t e n days and s i x weeks a f t e r PDL Serum g l u t a m i c o x a l o a c e t i c t r a n s a m i n a s e was  slightly  i n c r e a s e d i n t h r e e of f o u r dogs, serum a l k a l i n e phosphatase s l i g h t l y moderately  increased in a l l  t h r e e of f o u r dogs.  dogs, and serum albumin s l i g h t l y  to  increased  Changes of serum amylase and c a l c i u m were  in  not  consistent.  Body w e i g h t of the dogs was s t a t i o n a r y  to s l i g h t l y  one dog i n which marked l o s s o f body weight was o b s e r v e d .  i n c r e a s e d except Marked  s t e a t o r r h e a was not observed i n any dog.  A f t e r completing a l l all  dogs.  Marked atrophy of the pancreas and m i l d t o moderate  gastroduodenitis  5.  t e s t s f o l l o w i n g PDL, autopsy was performed  were observed i n a l l  on  hemorrhagic  dogs s t u d i e d .  Assays.  Serum I R - G a , IR-GIP and IRI  c o n c e n t r a t i o n s were measured i n  d u p l i c a t e u s i n g the Schwarz/Mann G a s t r i n Radioimmunoassay K i t , of K u z i o e t a l , 1 9 and the Amersham Radioimmunoassay K i t , serum g l u c o s e c o n c e n t r a t i o n s  The c r o s s r e a c t i v i t y D r . J . C . Brown, U n i v e r s i t y  the method  respectively;  and  u s i n g a Beckman g l u c o s e a n a l y z e r .  check of the GIP a n t i b o d y ,  GP01 (purchased from  of B r i t i s h C o l u m b i a ) , i s as f o l l o w s :  0.1%; i n s u l i n , 0.02%, C - t e r GIP m i n u s ) ,  135%; N - t e r GIP m i n u s ) ,  motilin, 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. considered statistically significant.  Values of less than 0.05 were  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  t h e 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  (Fig. 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 b a s a l IR-GIP c o n c e n t r a t i o n s were found between t h e p r e and post-PDL d o g s .  The mean peak IR-GIP c o n c e n t r a t i o n s  b e f o r e and a f t e r PDL were 468 ± 52 pg/ml  a t 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 statistically  s i g n i f i c a n t (p < 0.05) F i g . 4 ) .  I n t e g r a t e d serum IR-GIP  response d u r i n g t h e f i v e hour p e r i o d f o l l o w i n g the meat meal a l o n e was s i g n i f i c a n t l y g r e a t e r than t h a t p r i o r t o PDL (28 ± 10 n g / m l / f i v e  hours  b e f o r e 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 p r o c e d u r e r e v e a l e d s i g n i f i c a n t d e c r e a s e i n IRI  s e c r e t i o n a f t e r PDL (p < 0.05)  the  (Fig. 5).  The mean serum g l u c o s e c o n c e n t r a t i o n s at each of the subsequent t i m e 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 t h o s e p r i o r t o PDL (Fig.  6).  3.  F i v e Hour A c i d ,  IR-Ga, IR-GIP,  IRI  and G l u c o s e Responses to a Meat  Meal P l u s U n h y d r o l y z e d Cream.  A f t e r f e e d i n g a meat meal p l u s cream the peak a c i d o u t p u t from the HP p r i o r t o PDL o c c u r e d at 150 minutes (0.0576 ± 0.227 mEq/15 m i n u t e s ) , and remained a l m o s t a t the same l e v e l f o r t h e remainder of t h e two hour period.  A f t e r PDL a c i d response e s s e n t i a l l y d i d not change except f o r a  s m a l l i n c r e a s e a f t e r 135 minutes ( F i g . 7 ) .  Integrated acid response  d u r i n g the f i v e hour p e r i o d f o l l o w i n g the meal a f t e r PDL was  12  insignificantly  g r e a t e r than t h a t p r i o r to PDL (121 + 45 m E q / f i v e hours  b e f o r e PDL v s . 137 ± 51 m E q / f i v e hours a f t e r P D L ) .  The mean f i v e hour serum g a s t r i n c o n c e n t r a t i o n s a f t e r PDL were l o w e r t h a n b e f o r e PDL ( F i g . 8) but i n t e g r a t e d f i v e hour serum IR-Ga response t o t h e meal a f t e r PDL was g r e a t e r than t h a 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 a l t h o u g h t h e r e was no s i g n i f i c a n t  n g / m l / f i v e hours b e f o r e P D L ) ,  difference.  F o l l o w i n g t h e meal, the mean serum IR-GIP c o n c e n t r a t i o n s were l o w e r i n the dogs a f t e r PDL than b e f o r e PDL.  The peak IR-GIP response was  s i g n i f i c a n t l y l o w e r a f t e r PDL (844 ± 67 pg/ml b e f o r e PDL v s . 655 + 129 pg/ml a f t e r PDL, p < 0 . 0 5 )  (Fig. 9).  I n t e g r a t e d serum IR-GIP r e s p o n s e to  the meal d u r i n g t h e f i v e hour p e r i o d a f t e r PDL was s i g n i f i c a n t l y  lower  than t h a t p r i o r t o PDL (144 + 21 n g / m l / f i v e hours b e f o r e PDL v s . 116 ± 23 n g / m l / f i v e hours a f t e r PDL, p < 0 . 0 5 ) .  B e f o r e PDL i n t e g r a t e d serum IR-GIP response to a meal p l u s u n h y d r o l y z e d cream d u r i n g the f i v e hour p e r i o d was s i g n i f i c a n t l y  higher  than t h a t t o a meat meal a l o n e (144 + 21 v s . 28 ± 10 n g / m l / f i v e h o u r s , p < 0.01)  and a f t e r PDL i n t e g r a t e d serum IR-GIP response t o a meat meal p l u s  u n h y d r o l y z e d cream d u r i n g t h e f i v e hour p e r i o d was a l s o h i g h e r than t h a t t o a meat meal a l o n e but not s i g n i f i c a n t  (116 ± 23 v s . 63 + 15 n g / m l /  five  hours).  F o l l o w i n g the meal the mean serum IRI c o n c e n t r a t i o n s at each subsequent t i m e p o i n t i n the dogs a f t e r PDL were l o w e r than t h o s e p r i o r  to  13  PDL.  The time of t h e peak v a l u e of serum IRI c o n c e n t r a t i o n s was almost  identical  t o t h a t of serum IR-GIP c o n c e n t r a t i o n s ( F i g . 9 and 1 0 ) .  The mean serum g l u c o s e c o n c e n t r a t i o n s a t each subsequent t i m e p o i n 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 l o w e r than those i n the same dogs p r i o r t o 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 m g / d l , p 0.05)  4.  F i v e Hour A c i d ,  I R - G a , I R - G I P , IRI  ( F i g . 11).  and G l u c o s e Responses to a Meat  Meal P l u s H y d r o l y z e d Cream.  F o r the 135 minute p e r i o d f o l l o w i n g  the meal the mean a c i d response  from the HP was l o w e r than t h a t p r i o r t o PDL, but not significant.  statistically  The peak a c i d o u t p u t s from the HP b e f o r e 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 a t 195 m i n u t e s , r e s p e c t i v e l y ( F i g . 1 2 ) .  I n t e g r a t e d HP a c i d o u t p u t  d u r i n g t h e f i v e hour p e r i o d a f t e r PDL was s m a l l e r than t h a t p r i o r t o PDL (198.39 m E q / f i v e hours b e f o r e PDL v s . 176.73 m E q / f i v e hours a f t e r P D L ) , but t h e r e was no s i g n i f i c a n t  difference.  I n t e g r a t e d serum IR-Ga response d u r i n g the f i v e hour p e r i o d  after  PDL was s m a l l e r than t h a t p r i o r t o PDL ( 9 . 9 + 4 . 0 n g / m l / f i v e hours b e f o r e PDL v s . 4 . 6 + 1.8 n g / m l / f i v e hours a f t e r P D L ) , but t h e r e was no significant  difference.  The mean serum IR-GIP c o n c e n t r a t i o n s d u r i n g the 60 minute p e r i o d 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  t o t h o s e p r i o r to PDL,  14  and they remained lower t h e r e a f t e r 14).  compared t o those p r i o r to PDL ( F i g .  I n t e g r a t e d serum IR-GIP response to the meal d u r i n g the f i v e  p e r i o d a f t e r PDL was i n s i g n i f i c a n t l y  hour  s m a l l e r than t h a t p r i o r to PDL (152 ±  18 n g / m l / f i v e hours b e f o r e PDL v s . 1 1 9 + 2 3  n g / m l / f i v e hours a f t e r P D L ) .  Serum IR-GIP response to meat meal p l u s h y d r o l y z e d cream a f t e r PDL was very s i m i l a r t o t h a t of meat meal p l u s u n h y d r o l y z e d cream a f t e r PDL. B e f o r e PDL, i n t e g r a t e d serum IR-GIP response to meat meal p l u s h y d r o l y z e d cream d u r i n g t h e f i v e hour p e r i o d was s i g n i f i c a n t l y  h i g h e r than t h a t  to  meat meal a l o n e (152 ± 18 v s . 28 ± 10 n g / m l / f i v e h o u r s , p < 0 1 0 1 ) , and almost i d e n t i c a l  t o t h a t of meat meal p l u s u n h y d r o l y z e d cream (152 ± 18  v s . 144 + 21 n g / m l / f i v e h o u r s ) .  A f t e r PDL, i n t e g r a t e d serum IR-GIP  response t o meat meal p l u s h y d r o l y z e d cream d u r i n g the f i v e hour p e r i o d was i n s i g n i f i c a n t l y 15 n g / m l / f i v e  h i g h e r t h a n t h a t t o meat meal a l o n e (119 + 23 v s . 63 ±  hours).  The mean serum IRI c o n c e n t r a t i o n s 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  t o t h o s e p r i o r t o PDL ( F i g . 1 5 ) .  F o r the 180 minute p e r i o d f o l l o w i n g the meal a f t e r PDL, the mean serum g l u c o s e response was g r e a t e r than p r i o r t o PDL, but t h e  difference  was not s i g n i f i c a n t ( F i g . 1 6 ) .  5.  Serum G l u c o s e and IRI Responses t o i . v .  Glucose Load.  The mean serum g l u c o s e c o n c e n t r a t i o n s f o l l o w i n g significantly  i.v.  g l u c o s e were  h i g h e r 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 40.4 vs. 16.1 15.8  yU/ml at 15 minutes, two weeks after PDL, p < 0.05;  yU/ml at 15 minutes ten weeks after PDL, p < 0.05; 30.8 vs.  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 45 minutes, two weeks after PDL, p < 0.05; 18.4 vs. 9.6  yU/ml at  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 l u c o s e ,  IRI,  and IR-GIP Responses to I n t r a g a s t r i c  Glucose  Load.  The mean f a s t i n g serum g l u c o s e v a l u e s b e f o r e and a f t e r PDL were 68 + 4 mg/dl and 79 ± 4 statistically  m g / d l , r e s p e c t i v e l y , and t h e d i f f e r e n c e was n o t  significant.  A f t e r PDL, the mean serum g l u c o s e  c o n c e n t r a t i o n s were s i g n i f i c a n t l y l o w e r a t 15 minutes (110 ±7 v s . 159 ± 15 mg/dl, p < 0.05),  a t 30 minutes (122 + 10 v s . 183 ± 11 m g / d l , p < 0 . 0 1 ) , -  and a t 45 minutes (138 ± 12 v s . 175 + 11 m g / d l , p < 0.05) intragastric  following  g l u c o s e l o a d and reached peak v a l u e s a t a l a t e r time (155 ±  10 mg/dl a t 90 minutes a f t e r PDL and 183 ± 11 mg/dl a t 30 minutes  before  P D L ) , p e r s i s t i n g h i g h e r l e v e l s than p r i o r t o PDL (151 ± 12 v s . 87 ± 8 mg/dl a t 120 m i n u t e s , p < 0 . 0 1 ; 116 ± 14 v s . 8 3 + 6 p < 0.05)  mg/dl a t 150 m i n u t e s ,  ( 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 l u c o s e v a l u e s b e f o r e and a f t e r PDL, and thus o n l y showing the d e l a y e d 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  i n t e g r a t e d g l u c o s e r e s p o n s e b e f o r e and a f t e r PDL (10211 + 1213 m g / d l / 1 8 0 minutes b e f o r e PDL v s . 9180 ± 1184 m g / d l / 1 8 0 minutes a f t e r P D L ) . serum IRI  The mean  response was h i g h e r at each t i m e p o i n t a f t e r 60 minutes  f o l l o w i n g g l u c o s e l o a d 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 120 minutes (11.8  yU/ml b e f o r e PDL v s . 26.8  The mean i n t e g r a t e d IRI PDL and 764 ± 164 difference.  at  yU/ml a f t e r PDL, p < 0 . 0 5 ) .  responses were 843 ± 192  yUml/180 minutes  y U / m l / 1 8 0 m i n u t e s , and t h e r e was no s t a t i s t i c a l  before  17  The mean serum IR-GIP response a f t e r PDL remained r a t h e r h i g h e r the l a t t e r  120 minute p e r i o d t h a n b e f o r e PDL.  response was very s i m i l a r t o t h a t of serum IRI  for  The p a t t e r n of serum IR-GIP response ( F i g . 2 1 ) .  The  mean i n t e g r a t e d serum IR-GIP response a f t e r PDL was g r e a t e r than t h a t b e f o r e PDL 3 7 . 3 ng/ml/180 minutes b e f o r e PDL v s . 5 1 . 5 ng/ml/180 minutes a f t e r P D L ) , but was not  significant.  18  DISCUSSION  (A)  GASTRIC SECRETION G a s t r i c h y p e r s e c r e t i o n i n the dog f o l l o w i n g  (PDL) i s a w e l l  r e c o g n i z e d phenomenon.  has not y e t been d e f i n e d .  p a n c r e a t i c duct  ligation  However, the mechanism behind  The p o s s i b i l i t y  it  t h a t the pancreas w i t h  o b s t r u c t e d ducts produce a g a s t r i c s e c r e t a g o g u e , namely a g a s t r i n - l i k e substance,  has been d i s p r o v e d by b i o a s s a y and immunoassay of the  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 h y p e r s e c r e t i o n  PDL t o secondary l i v e r d a m a g e . 22  The m a l d i g e s t i o n of f a t  atrophic  following  and  m a l a b s o r p t i o n of e s s e n t i a l f a t t y a c i d s was thought t o be a cause of h e p a t i c damage and g a s t r i c  It  hypersecretion.  has been suggested t h a t an augmented g a s t r i n response t o  i s a primary f a c t o r  feeding  i n the p r o d u c t i o n of g a s t r i c h y p e r s e c r e t i o n o c c u r i n g  when p a n c r e a t i c enzymes a r e excluded from the d i g e s t i v e stream,1 whereas Greenlee still  4  c o n s i d e r e d g a s t r i n i s not a main f a c t o r  produces an i n c r e a s e i n g a s t r i c a c i d .  as a f t e r  antrectomy, PDL  A l t h o u g h the i n c r e a s e i n  d a i l y a c 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 r d i n a r y meal a f t e r PDL c o n f i r m s the p r e v i o u s o b s e r v a t i o n of o t h e r s , » 2 3 t h e r e was only a modest i n c r e a s e of HP a c i d and d e c r e a s e of 2  g a s t r i n response t o a meat meal a f t e r PDL as compared t o t h a t b e f o r e PDL. These f i n d i n g s d i f f e r from o t h e r s who r e p o r t e d an augmented response as w e l l PDL.1> 3 2  gastrin  as an augmented HP a c i d response t o f e e d i n g i n dogs  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,  l e a s t i n p a r t , to the d i f f e r e n t c o n d i t i o n s of the experiments; i n p r e s e n t experiment the dogs were f e d w i t h cream ( u n h y d r o l y z e d and  at the  after  19  hydrolyzed) different  mixed w i t h o r d i n a r y meals which might have r e s u l t e d i n the  secretary responses.  Wormsley and G r o s s m a n  c l o s i n g the GF produced marked i n h i b i t i o n stimulation,  observed t h a t  of the response of the HP t o  s u g g e s t i n g endogenous i n h i b i t i o n  from the main stomach i n t o the duodenum. the p r e s e n t s t u d y ,  24  r e l a t e d to passage of a c i d  The GF was k e p t c l o s e d d u r i n g  and a l t h o u g h 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 t h e antrum and duodenum was p r o b a b l y suppressed by a n t r a l  and duodenal  caused by an as y e t unknown mechanism f o l l o w i n g PDL. i s known t o i n h i b i t directly  gastrin r e l e a s e ,  but i t  2 5  s u p p r e s s e s t h e G c e l l s o r whether i t  g a s t r i n r e l e a s e from the a n t r a l mucosa. innervated antral  It  hyperacidity  Antral  acidification  i s unknown whether a c i d r e l e a s e s an i n h i b i t o r  of  has been shown t h a t when  pouches were p e r f u s e d w i t h a c i d o r a l k a l i n e s o l u t i o n s  in  dogs w i t h a HP u s i n g chemical o r vagal s t i m u l a t i o n of the antrum, gastrin-like  immunoreactivity  appeared i n a l l  p e r f u s a t e s but was found t o  be seven times h i g h e r i n the a c i d p e r f u s a t e s , i n d i c a t i n g the of the antrum may not b l o c k r e l e a s e o f g a s t r i n , but i t  acidification  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 t o the lumen **. 2  antral  Some workers have p o s t u l a t e d t h a t a c i d i n the p y l o r i c g l a n d area  caused r e l e a s e of an a n t r a l suppresses the a c t i v i t y significance,  if  inhibitory  hormone " a n t r a l  chalone" ,28 that 2 7  of t h e 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  any, i s s t i l l  t o be s t u d i e d .  A p o s s i b l e e x p l a n a t i o n of  some of t h e f i n d i n g s c o u l d be t h a 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 t h e r o p e r a t i v e trauma. match w i t h our o b s e r v a t i o n s . o t h e r s were a l l  I feel  however t h a t t h i s does not  Only one of the f o u r dogs l o s t w e i g h t ,  h e a l t h y and a t e w e l l .  A u t o p s y , t o o , d i s c l o s e d no  s i g n i f i c a n t a b n o r m a l i t i e s a p a r t from some adhesions and v e r y  mild  the  20  inflammation.  (Photo 1)  G a s t r i c and duodenal a c i d i f i c a t i o n plasma l e v e l antral  of s o m a t o s t a t i n . 2 9  and duodenal  inhibitory  results  i n a marked r i s e i n  S o m a t o s t a t i n may be i n v o l v e d i n  r o l e of t h i s p e p t i d e i n a n t r a l  feedback i n h i b i t i o n  secretion.  of g a s t r i c  The name b u l b o g a s t r o n e has been g i v e n to a h y p o t h e t i c a l  and duodenal  humoral  s e c r e t e d from t h e duodenal b u l b where pH dependent g a s t r i c  3 0  inhibition interfering  operates.  w i t h the s t i m u l a t o r y  The p r i n c i p a l  a c t i o n of g a s t r i n at the o x y n t i c  inhibits  gastrin release is  humoral mechanism of g a s t r i c  duodenal a c i d i f i c a t i o n  glands  unknown.  acid i n h i b i t i o n  by  i s the r e l e a s e of s e c r e t i n from the e n d o c r i n e S  i n t h e duodenal mucosa, and i t  has been demonstrated t h a t  inhibition  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  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  l e v e l through  acid  The mechanism seems to suppress a c i d s e c r e t i o n by  and whether b u l b o g a s t r o n e  cells  the  mechanisms but f u r t h e r s t u d i e s are needed  t o determine the p h y s i o l o g i c a l  factor  the  a non-competitive  mechanism.31  the secretion  at the p a r i e t a l  cell  Tasse e t al32 showed t h a t  t h e serum g a s t r i n l e v e l s i n dogs having undergone  the  E x a l t o - M a n n - W i l l i a m s o n procedure remains unchanged, whereas the plasma secretin concentrations alterations gastric  i n these animals are i n c r e a s e d ,  in circulatory  indicating  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  acid hypersecretion following  the p r o c e d u r e ,  h y p e r s e c r e t i n e m i a would be caused by s t i m u l a t i o n  and  the  postoperative  of s e c r e t i n r e l e a s e from  the gut mucosa secondary t o enhanced s e c r e t i o n of g a s t r i c a c i d .  Secretin  21  was shown t o suppress t h e r e l e a s e of g a s t r i n i n response t o food dogs.33 it  in  There have been no s t u d i e s 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  has been shown t h a 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 t h  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  It  seems r e a s o n a b l e to assume t h a t marked a c i d i f i c a t i o n  the post b u l b a r duodenum w e l l below 4.5  (the threshold for  of  secretin  r e l e a s e i n the dog) r e l e a s e s 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 s u b s e q u e n t l y suppress t h e HP a c i d s e c r e t i o n a f t e r PDL.  It  has been shown t h a t c h o l e c y s t o k i n i n (CCK) i s p r e d o m i n a n t l y  inhibitory  the  hormone r e l e a s e d by s t r o n g a c i d i f i c a t i o n of t h e duodenum.  K a k a j i m a and Magee showed t h a t duodenal a c i d i f i c a t i o n over a pH range of seven t o t h r e e r e l e a s e d mainly s e c r e t i n and, a t a lower pH, m a i n l y CCK.35  S u p p r e s s i o n 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 a m i l y of hormones ( g l u c a g o n , v a s o a c t i v e i n t e s t i n a l  polypeptide  ( V I P ) , and GIP) and by one c h e m i c a l l y u n r e l a t e d p e p t i d e , c a l c i t o n i n . t h e s e hormones a l s o e x e r t a d i r e c t i n h i b i t o r y cells.  a c t i o n on the  The q u e s t i o n o f . w h e t h e r t h e s e humoral f a c t o r s  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 .  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  All  perietal  i n h i b i t r e l e a s e of P o s s i b l e r o l e of  be d i s c u s s e d l a t e r  in  this  p a r t of the communication.  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 p r o b a b l y ,  at l e a s t p a r t l y ,  f o r the only modest i n c r e a s e i n the f i v e hour HP s e c r e t i o n . findings  i n d i c a t e t h a t the i n t e s t i n a l  responsible A l s o these  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  acid  s e c r e t i o n by the mechanism t h a t the p e r s i s t e n c e of u n d i g e s t e d and unabsorbed food p r o d u c t s prolonged s t i m u l a t i o n striking  i n the small i n t e s t i n e  of g a s t r i c s e c r e t i o n .  results  in  Chey a t a l  inappropriately  showed the most  2  i n c r e a s e of HP a c i d outputs d u r i n g the t w e l v e t o 24 hour p e r i o d  of d a i l y meal study i n PDL dogs, s u g g e s t i n g t h a t both g a s t r i c and intestinal  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  The mechanism of i n t e s t i n a l y e t been d e f i n e d .  Until  recently,  g e n e r a l l y used when r e f e r r i n g T h i s term i s u n s a t i s f a c t o r y i n v o l v e d i n the i n t e s t i n a l "entero-oxyntin",  an a n t r a l  i n the r e s p o n s e .  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 "intestinal  g a s t r i n " was the name  t o the m e d i a t o r of the i n t e s t i n a l  s i n c e s e v e r a l d i f f e r e n t s u b s t a n c e s may be phase of g a s t r i c s e c r e t i o n ,  name " e n t e r o - o x y n t i n " principal secretion,  namely  t y p e o f g a s t r i n , CCK, and h i s t a m i n e .  E x p e r i m e n t a l s t u d i e s suggest t h a t the main i n t e s t i n a l an as y e t u n i d e n t i f i e d  phase.  hormone from t h e i n t e s t i n a l has been proposed.24  phase s t i m u l a n t  mucosa, f o r which  "Entero-oxyntin"  hormone r e s p o n s i b l e f o r t h e i n t e s t i n a l  phase of  having unique p a t t e r n of g a s t r i c s t i m u l a t i o n  accounted f o r by g a s t r i n , CCK, or h i s t a m i n e .  To d a t e ,  is  is the  the  gastric  t h a t cannot be no s t u d i e s have  been performed t o d e t e r m i n e the p o s s i b l e r o l e of CCK and h i s t a m i n e i n intestinal  phase of g a s t r i c  secretion.  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 potent s t i m u l a t i o n  the  of g a s t r i c s e c r e t i o n d u r i n g i n t e s t i n a l  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  perfusion  meal s t i m u l a t e s  s e c r e t i o n by a mechanism i n v o l v i n g the r e l e a s e of a n t r a l  and a  hormone.  of  gastric  23  Thompson et a\'  if  s p e c u l a t e d t h a 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 b o m b e s i n - 1 i k e s u b s t a n c e (entero-bombesin) releases antral intestinal  gastrin.  Orloff  phase hormone (IPH)  that,  et al38 have r e c e n t l y  from hog i n t e s t i n a l  in  turn,  isolated  mucosa.  IPH i s  g a s t r i n and augments t h e maximum g a s t r i c s e c r e t o r y r e s p o n s e t o  It  is well  documented t h a t f a t  the not  gastrin.  added t o t h e meal i n t h e duodenum  s u p p r e s s e d t h e a c i d s e c r e t i o n of t r a n s p l a n t e d 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 humorally mediated and Kosaka and L i m "enterogastrone"  f o r t h e humoral  inhibitor  agent.  7  proposed the name  Q u i g l e y and Meschan39  showed t h a t t h e p r o d u c t s o f l i p o l y s i s were more p o t e n t i n h i b i t o r s g a s t r i c m o t i l i t y than c o r r e s p o n d i n g n e u t r a l Sircus^O indicates that fats exerts t h e i r i s present. in fat  It  fat,  effect  of  and the o b s e r v a t i o n of only i f  pancreatic  juice  i s w e l l known t h a t p a n c r e a t i c l i p a s e p l a y s a dominant  a b s o r p t i o n , and t r i g l y c e r i d e  role  i s h y d r o l y z e d by l i p a s e to f a t t y a c i d s  and g l u c e r o l .  GIP o b t a i n e d from an e x t r a c t of duodenal mucosa has been i s o l a t e d , purified,  and c h e m i c a l l y c h a r a c t e r i z e d . 1 5  This substance i n h i b i t s  a c i d and p e p s i n s e c r e t i o n s t i m u l a t e d by p e n t a g a s t r i n , insulin-hypoglycemia in dogs, activity  of d e n e r v a t e d f u n d i c  enterogastrone.  It  8  and a l s o i n h i b i t s and a n t r a l  histamine,  gastric  and by  spontaneous motor  pouches, q u a l i f y i n g  as an  has been s p e c u l a t e d t h a 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 r e l e a s e i n duodenal u l c e r d i s e a s e . Contrary to t h i s  a s s u m p t i o n , an exaggerated GIP r e l e a s e f o l l o w i n g  oral  g l u c o s e o r the t e s t meal was observed i n p a t i e n t s w i t h duodenal ulcer.11.12  i t was suggested t h a t r a p i d g a s t r i c emptying o r i n c r e a s e d  24  intestinal  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 i n c r e a s e d GIP  Cataland et a U  2  claimed t h a t the p o s s i b i l i t y  t h a t p a t i e n t s w i t h duodenal  u l c e r may r e l e a s e a form of GIP w i t h weak g a s t r i c a c i d properties.  The prime r o l e of GIP i s t o p o t e n t i a t e  insulin release,^  a n  d  there is s t i l l  has the e n t e r o g a s t r o n e - l i k e  effect.  secretion.H  inhibitory  glucose-induced  some c o n t r o v e r s y In i n n e r v a t e d  as t o whether GIP  stomach p r e p a r a t i o n s  t h e dog9 and i n normal manlO 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  s e c r e t i o n by GIP was found t o be weak.  The p o s s i b l e involvement  c h o l i n e r g i c mechanism a n t a g o n i s t i c  of  acid  of a  to the a c t i o n of GIP on the stomach has  been suggested by t h e o b s e r v a t i o n t h a t the a c i d i n h i b i t o r y  effect  of  this  hormone i n the denervated g a s t r i c pouch o f the dog can be b l o c k e d by the i.v.  i n f u s i o n of u r e c h o l i n e . 9  GIP does not e x e r t i t s rather  indirectly  An e x p l a n a t i o n f o r t h e s e o b s e r v a t i o n s  inhibitory  effect  directly  v i a the r e l e a s e of an i n h i b i t o r ,  on the p a r i e t a l  activity  of g a s t r i c somatostatin-1 ike  the  proposed  immunoreactivity.  i n f u s i o n of HCl  r e l e a s e d GIP i n humans and r a t s , w h i l e Brown e t  f a i l e d t o show IR-GIP r e l e a s e i n dogs by H C l . HCl by i t s e l f  but  of GIP i s p r o b a b l y mediated v i a r e l e a s e  E b e r t e t a l ^ demonstrated t h a t i n t r a d u o d e n a l dose-dependently  cell  from the corpus of  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 . M c i n t o s h e t a l ^ l t h a t the a c i d i n h i b i t o r y  that  i s c a p a b l e of s t i m u l a t i n g  GIP, suggesting  s i g n i f i c a n c e o f a c i d induced GIP s e c r e t i o n . a l 4 2 t h a t when HCl i s added t o an o r a l  LeRoith et a l  It  1 6  al  1 5  showed t h a t  physiological  has been shown by S p i t z  glucose load,  the b l o o d l e v e l s  et  of  g l u c o s e , GIP and i n s u l i n were h i g h e r than a f t e r  glucose alone.  GIP r e l e a s e a f t e r  of g l u c o s e was observed  intra-duodenal  when exogenous g a s t r i n ,  administration  pentagastrin,  and CCK were g i v e n . 4 3  Augmented  Flaten44  0  n  25  t h e o t h e r hand, s t u d i e d 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 o r i n s u l i n r e l e a s e i n man and showed no augmentation of GIP o r i n s u l i n by duodenal a c i d i f i c a t i o n .  The  conflicting  r e s u l t s from p r e v i o u s s t u d i e s seem t o i n d i c a t e the importance of emptying as w e l l acidification.  as s p e c i e s 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  gastric  duodenal  A reason f o r the augmented GIP s e c r e t i o n , which i s  most i m p o r t a n t f i n d i n g of the p r e s e n t s t u d y ,  the  i n the dogs a f t e r PDL  a d m i n i s t e r e d meat meal a l o n e c o u l d be i n c r e a s e d a c i d s e c r e t i o n coming i n t o the duodenum and the upper  intestine.  Another e x p l a n a t i o n f o r the i n c r e a s e of IR-GIP response to a meat meal a l o n e 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  motility.  It  has  been shown by F a u l e y and Ivy t h a t the emptying t i m e of the stomach i s decreased by PDL i n dogs and the authors suggested t h a t hunger, polyphagia,  i s the f a c t o r p r i n c i p a l l y  decrease,  and Y e s c o  4 5  4 6  or  concerned i n the c a u s a t i o n of  described a s i m i l a r r e s u l t .  Long et  al  4 7  d e s c r i b e d abnormally 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 pancreatic insufficiency al  4 8  and a s c r i b e d i t  the  in  t o m a l d i g e s t i o n , w h i l e Regan et  showed no primary g a s t r i c motor d e f e c t i n p a t i e n t s w i t h e x o c r i n e  pancreatic i n s u f f i c i e n c y .  The d i s c r e p a n t f i n d i n g  of these s t u d i e s seems t o  be due t o d i f f e r e n c e s of the t e c h n i q u e used f o r the measurement of emptying. dogs.  4 9  gastric  CCK and s e c r e t i n have been shown t o i n h i b i t g a s t r i c m o t i l i t y CCK was found t o be i n c r e a s e d 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 .  the p r e s e n t s t u d y ,  5 0  in In  a l t h o u g h CCK and s e c r e t i n c o n c e n t r a t i o n s were not  measured, both hormones might have been i n c r e a s e d i n the dogs a f t e r PDL as above d i s c u s s e d .  26  It  seems t o be an i n t r i g u i n g h y p o t h e s i s , t h e r e f o r e ,  that  gastric  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 p e p t i d e such as CCK and s e c r e t i n .  In the p r e s e n t s t u d y ,  was not measured, but as shown i n F i g . 19, g a s t r i c d e l a y e d a f t e r PDL.  Oral glucose t o l e r a n c e t e s t  assessment of g a s t r i c e m p t y i n g .  5 1  If  so, t h i s  gastric  emptying  empyting was p r o b a b l y  has been suggested f o r i s noteworthy,  the  as the  r e s u l t s of the p r e s e n t study do i n d i c a t e t h a t marked l o w e r i n g of pH of duodenal c o n t e n t s due t o augmented a c i d s e c r e t i o n t o g e t h e r w i t h l a c k a l k a l i n e (pancreatic)  of  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 c h r o n i c p a n c r e a t i t i s were shown t o have a significantly  h i g h e r GIP response t o a t e s t m e a l .  The authors  5 2  t h a t the e l e v a t e d IR-GIP l e v e l s seen i n p a t i e n t s w i t h c h r o n i c c o u l d be due t o l a c k of i n h i b i t i o n  suggested  pancreatitis  of IR-GIP r e l e a s e by i n s u l i n ,  and  concluded t h a t perhaps IR-GIP r e l e a s e t o a t e s t meal was dependent upon t h e r a t e of a b s o r p t i o n of n u t r i e n t ( f a t ) secrete i n s u l i n . greatly  and the c a p a c i t y of the @ - c e l l  The most i m p o r t a n t f i n d i n g  of the p r e s e n t study t h a t  the  i n c r e a s e d GIP a f t e r PDL i n response to meat meal alone but  somewhat decreased f o r  fat  (unhydrolyzed  and h y d r o l y z e d )  e x p l a i n e d by a l a c k of n e g a t i v e feedback i n h i b i t i o n because serum IRI  cannot be  of IR-GIP by  insulin,  response a f t e r PDL was more lowered i n response t o  cream-added meal than to the meat meal  GIP i s r e l e a s e d a f t e r fat  to  i s a most powerful  the  alone.  ingestion of glucose, f a t ,  s t i m u l u s f o r GIP r e l e a s e .  h y d r o l y z e d b e f o r e GIP r e l e a s e i s i n i t i a t e d .  It  1 5  and amino a c i d ,  and  F a t has to be  has been shown t h a t l o n g  27  c h a i n 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 i m u l a t e s GIP r e l e a s e . *  Fatty  5  a c i d s must be absorbed and m e t a b o l i z e d by the GIP p r o d u c i n g c e l l .  The  e x a c t mechanism whereby the a b s o r p t i o n caused r e l e a s e i s not known. et a l  5 3  observed t h a t c h i l d r e n w i t h c y s t i c f i b r o s i s  i n c r e a s e i n IR-GIP s e c r e t i o n i f the t r i g l y c e r i d e ,  had t h r e e  fold  g i v e n p a n c r e a t i c enzymes w h i l e  ingesting  w h i l e they had no IR-GIP response to t r i g l y c e r i d e  and suggested t h a t h y d r o l y s i s of t r i g l y c e r i d e r e l e a s e can normally o c c u r a f t e r  fat  Ross  only,  i s r e q u i r e d b e f o r e GIP  ingestion.  IR-GIP response t o a meat meal was markedly augmented by m i x i n g u n h y d r o l y z e d cream:  the peak IR-GIP c o n c e n t r a t i o n s  and the  IR-GIP response t o an u n h y d r o l y z e d cream-added meal was g r e a t e r than t h o s e t o a meat meal a l o n e i n d i c a t i n g was r e l e a s e d by adding f a t .  significantly  g r e a t e r amount of GIP  A f t e r PDL, IR-GIP response t o a meat meal  p l u s u n h y d r o l y z e d cream was s i g n i f i c a n t l y GIP was not p r o p e r l y  integrated  r e d u c e d , and t h i s  indicates  r e l e a s e d by f a t due t o f a i l e d h y d r o l y s i s t o  a c i d by l a c k of p a n c r e a t i c l i p a s e .  It  that  fatty  can of c o u r s e not be e x c l u d e d t h a t  GIP s e c r e t i o n was suppressed by o t h e r y e t u n i d e n t i f i e d  gut p e p t i d e s  or  neural mechanisms which were r e l e a s e d o r augmented by c l o c k i n g p a n c r e a t i c external  secretion.  A g a i n , presumably augmented a c i d s e c r e t i o n may have o c c u r r e d i n main stomach f o l l o w i n g  the f a t - a d d e d 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 T h i s i n c r e a s e i n GIP r e l e a s e d by augmented passage of a c i d i n t o intestinal  lumen was p r o b a b l y masked by t h e f a t - i n d u c e d G I P .  lumen. the  the  28  Another important f i n d i n g difference  of the p r e s e n t study i s t h a t t h e r e was no  i n the GIP r e s p o n s e between the u n h y d r o l y z e d and h y d r o l y z e d  cream a f t e r PDL.  A p o s s i b l e e x p l a n a t i o n f o r t h e s e unexpected f i n d i n g s  t h a t GIP response i s not determined by a s i n g l e f a c t o r , 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.  etc.  identified  or u n i d e n t i f i e d ,  intestinal  Some p o s s i b l e change o f i n t e s t i n a l  s h o u l d a l s o be c o n s i d e r e d :  but i s a net  GIP response might be  i n f l u e n c e d by many f a c t o r s , which i n c l u d e many k i n d s of peptides,  is  regulatory  motility,  vagal  mucosal a b s o r b a b i l i t y  control,  for  fat  even h y d r o l y z e d f a t might have been u n a b l e t o  be absorbed due t o an as y e t unknown mechanism a f t e r PDL, r e s u l t i n g  in  much reduced GIP r e s p o n s e to the h y d r o l y z e d f a t mixed w i t h the meat m e a l .  The HP a c i d response t o meat meal p l u s u n h y d r o l y z e d cream was p r o l o n g e d , a l t h o u g h the t i m e and the peak c o n c e n t r a t i o n s were s i m i l a r the case s t i m u l a t e d by meat meal a l o n e .  T h i s i s p r o b a b l y due t o  o s m o l a r i t y of the i n g e s t e d meal by adding f a t .  increased  Cook showed i n h i b i t i o n  g a s t r i c emptying was r e l a t e d to the molar (and osmolar) c o n c e n t r a t i o n 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 r e a t e r the  to  delay.  of of  5 4  The e x p l a n a t i o n f o r t h e g r e a t e r HP a c i d s e c r e t i o n s t i m u l a t e d by i n g e s t i o n of meat meal p l u s h y d r o l y z e d cream than by i n g e s t i o n of meat meal p l u s u n h y d r o l y z e d cream i s not c l e a r . Serum IR-Ga responses to b o t h 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 ,  indicating  gastrin  is  not s o l e l y r e s p o n s i b l e f o r t h e g r e a t e r HP s e c r e t i o n .  The a t t e n u a t e d HP s e c r e t i o n ( e s p e c i a l l y i n the e a r l y phase) s t i m u l a t e d by meat meal p l u s h y d r o l y z e d 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 t h o u g h serum IR-Ga response was most markedly decreased  a f t e r PDL compared to o t h e r two s t i m u l a n t s ,  a g a i n g a s t r i n i s not  r e s p o n s i b l e f o r the d e c r e a s e i n the HP s e c r e t i o n . some g a s t r i c  inhibitory  solely  The p o s s i b i l i t y  that  hormone(s) was r e l e a s e d by t h e d i g e s t e d f a t  even  i n the absence of p a n c r e a t i c e x o c r i n e f u n c t i o n can not be e x c l u d e d .  Fat  induced GIP was shown to suppress meal s t i m u l a t e d g a s t r i n , 4 3 but possibility  t h a t GIP p l a y e d any e n t e r o g a s t r o n e e f f e c t  the  on t h e HP a c i d  s e c r e t i o n i n the p r e s e n t study i s d e b a t a b l e , as t h e r e i s no apparent c o r r e l a t i o n among the I R - G I P , IR-Ga and HP s e c r e t i o n . a x i s i s not apparent i n the p r e s e n t  study.  A p o s s i b l e d e f i c i e n c y i n the p r o t o c o l u s i n g the GP01 a n t i s e r u m .  A "gastrin-GIP"  i s t h e measurement of GIP  T h i s 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 D r . John Brown.  The measurement of t h i s  therefore  r e s u l t s i n lower amounts than i n o t h e r s t u d i e s u s i n g d i f f e r e n t  antisera  r e c o g n i z i n g both ( o r more) m o i e t i e s .  different  Do t h e s e p o l y p e p t i d e s of  m o l e c u l a r w e i g h t s have d i f f e r e n t a c t i o n s o r are they r e l e a s e d i n amounts i n response t o d i f f e r e n t s t i m u l i ? these q u e s t i o n s .  Others w i l l  In d e f e n c e , I contend t h a t t h i s  varying  have to look  i s a purer  into  antiserum  than the o t h e r s and r e f l e c t s the r e s u l t s f o r the l o w e r m o l e c u l a r w e i g h t GIP.  Thus the p r e s e n t study c l e a r l y i n d i c a t e s t h a t d e f e c t i v e s e c r e t i o n 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  gastric  h y p e r s e c r e t i o n 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 t u d i e s s u g g e s t t h a 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 the i n h i b i t o r y  effect  n o r m a l l y e x e r t e d by f a t  of  and i t s b y - p r o d u c t s .  with  Many  30  s t u d i e s have been performed t o i d e n t i f y the hormones r e l e a s e d by f a t the g u t .  It  has been shown t h a t f a t r e l e a s e s CCK from the  in  intestinal  mucosa but t h e r e i s l i t t l e doubt t h a 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 ,  since fat  induces s u p p r e s s i o n of  h i s t a m i n e - s t i m u l ated a c i d s e c r e t i o n t h a t cannot be reproduced by CCK o r s e c r e t i n r e g a r d l e s s o f t h e dose used.55 enterogastrone,  VIP i s another c a n d i d a t e f o r  and i n h i b i t s g a s t r i c a c i d s e c r e t i o n i n dogs.56  r e c e n t study of Holm-Benzen e t a l  5 7  However,  showed t h a t exogenously a d m i n i s t e r e d  VIP i s m e t a b o l i z e d 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 t h a t VIP p r o b a b l y does not e x e r t any hormonal e f f e c t on a c i d s e c r e t i o n i n man. appears to s a t i s f y most c o m p l e t e l y the c r i t e r i a  A l t h o u g h GIP  f o r b e i n g the  e n t e r o g a s t r o n e d e s c r i b e d by Kosaka and L i m , f u r t h e r s t u d i e s a r e needed b e f o r e a hormonal s t a t u s can be a s c r i b e d to GIP and b e f o r e physiological  r o l e as the e n t e r o g a s t r o n e r e l e a s e d by f a t  its  is proved.  31  (B)  GLUCOSE METABOLISM PDL was the model f i r s t u t i l i z e d by B a n t i n g and B e s t * * t o  extract  5  i n s u l i n from t h e 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  t i s s u e was f o r a t l e a s t a s h o r t p e r i o d of t i m e . e x t e n s i v e d e g e n e r a t i o n of the pancreas a f t e r d u c t c o u l d o f t e n l e a d t o d i a b e t e s i n dogs. will  finally  deteriorate  Dragstedt ^  reported  5  and i . v .  Whether the e n d o c r i n e  r e s e r v e o f i n s u l i n as a cause of  L i t t l e i s known about f u n c t i o n a l  intragastric  alterations  development  f o l l o w i n g PDL  In the p r e s e n t  g l u c o s e t o l e r a n c e t e s t performed two weeks  PDL showed d e l a y e d serum g l u c o s e and IRI m o t i l i t y was d e c r e a s e d a f t e r PDL.  response, i n d i c a t i n g  The serum IRI  phase of i n s u l i n r e l e a s e .  accordance w i t h the o b s e r v a t i o n of K a l k e t a l 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  6 0  glucose  indicating  This finding  is  that in patients  in with  response to o r a l g l u c o s e was not  significantly  l o w e r than i n the c o n t r o l s w h i l e t h a t to i . v .  significantly  l e s s than i n t h e c o n t r o l s .  glucose-stimulated "entero-insular  after  gastric  response to i . v .  was c l e a r l y d i m i n i s h e d i n the PDL dogs (two and t e n weeks) f a i l u r e of the i n i t i a l  the  g l u c o s e l o a d f o u r t o s i x months a f t e r PDL i n dogs.  e s p e c i a l l y c o n c e r n i n g the e a r l y onset of d i a b e t e s . experiment,  function  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 .  They s t r e s s e d an i n s u f f i c i e n t of d i a b e t e s .  that  o c c l u s i o n of the p a n c r e a t i c  Heptner et a l ! 8 observed i m p a i r e d g l u c o s e t o l e r a n c e f o l l o w i n g intragastric  islet  axis"  patients,  but i n t h e d i a b e t i c p a t i e n t s  beta c e l l  sensitivity  g l u c o s e was  They suggested t h a t i s probably i n t a c t  the  in these  t h e r e i s c l e a r l y l o s s of  pancreatic  t o g l u c o s e which may be due to damage t o  " g l u c o r e c e p t o r s " on the b e t a c e l l membrane or a l t e r n a t i v e l y d i s o r d e r beyond t h e membrane l e v e l .  relfect a  They a l s o suggested t h a t  this  probably r e p r e s e n t s a d i s o r d e r of the p o s t u l a t e d 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 t o ten minute response was i m p a i r e d . Further,  Pupo e t a l  significantly  6 1  showed t h a t the a l l o x a n - d i a b e t i c dogs had  d e c r e a s e d e a r l y - p h a s e i n s u l i n response t o g l u c o s e p u l s e s and  s l o w e r plasma g l u c o s e d i s a p p e a r a n c e r a t e s , w h i l e t h e s e m i l d l y  diabetic  dogs a c h i e v e d comparable i n s u l i n l e v e l s and h i g h e r g l u c o s e l e v e l s d u r i n g a p r o l o n g e d g l u c o s e i n f u s i o n than p r e - a l l o x a n c o n t r o l  values, indicating  the  p a t t e r n of b l u n t e d e a r l y phase i n s u l i n s e c r e t i o n and c o n t i n u e d 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 g e n e t i c  determination  and may be induced i n m i l d a l l o x a n d i a b e t e s , a model i n which t h e r e i s an acquired b e t a - c e l l  insulin  deficiency.  The f i n d i n g t h a t serum IR-GIP response t o i n t r a g a s t r i c  glucose load  was very s i m i l a r t o t h a t of serum g l u c o s e 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 t h a 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  Thus i t  a x i s " remains i n t a c t i n t h i s p e r i o d a f t e r PDL.  has been shown t h a t t h e PDL dogs had e a r l y onset (two to  weeks) of d i a b e t e s ,  i.e.,  b l u n t e d e a r l y phase i n s u l i n  i n d i c a t i n g an a c q u i r e d b e t a - c e l l  insulin  ten  secretion,  deficiency.  D i a b e t e s i s a f r e q u e n t c o m p l i c a t i o n of c h r o n i c p a n c r e a t i t i s ,  being  p r e s e n t i n o n e - t h i r d o r more of the p a t i e n t s w i t h more advanced stage o f pancreatic f i b r o s i s  and a t r o p h y .  A l t h o u g h J o f f e e t al62 have p o s t u l a t e d  t h a t the d i a b e t i c syndrome o f c h r o n i c p a n c r e a t i t i s  r e p r e s e n t s an example  of a c q u i r e d i n s u l i n o p e n i a , r e c e n t o b s e r v a t i o n s suggest a s e l e c t i v e o r qualitative  impairment of the response of t h e b e t a c e l l s t o g l u c o s e  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 t o  various  33  enterohormones.60  The a b i l i t y  of the remaining b e t a c e l l s to  i n s u l i n i n response t o i n t r a g a s t r i c  secrete  g l u c o s e was r e t a i n e d i n a l l  dogs  s t u d i e d d e s p i t e d e s t r u c t i o n of the e x o c r i n e p a n c r e a s , as evidenced by the c o m p l e t e l y a t r o p h i e d pancreas a f t e r PDL, i n disagreement w i t h hypothesis that beta c e l l exocrine tissue.63 intragastric  function  the  i s dependent on the i n t e g r i t y of  A l s o the f i n d i n g  t h a t serum IR-GIP response to  g l u c o s e was r e t a i n e d i n s p i t e of b l u n t e d e a r l y - p h a s e  response t o i . v .  the  insulin  g l u c o s e s u p p o r t s the i d e a of K a l k e t al^O mentioned  above.  Serum IRI  r e s p o n s e to meat meals w i t h and w i t h o u t u n h y d r o l y z e d or  h y d r o l y z e d cream examined a t s i x weeks a f t e r PDL were a p p a r e n t l y compared to t h o s e examined b e f o r e PDL. meal s t i m u l a t e d IRI  An i n t e r e s t i n g  finding  impaired  is  that  responses seem t o 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 i m u l a t e d by the meal, q u a l i f y i n g GIP as an insulinotropic  enterohormone,  although i t  insulinotropic  only i n the presence of h y p e r g l y c e m i a ^  glucose concentrations following w i t h i n 100 mg/dl  (euglycemia).  i s known t h a t GIP i s 4  and the peak  t h e meat meal i n the p r e s e n t study were The e x p l a n a t i o n f o r the GIP dependent  i n s u l i n response t o the meals i n s p i t e of euglycemic background i s c l e a r from the p r e s e n t  not  study.  The serum g l u c o s e response t o meat meal a l o n e was  significantly  i n c r e a s e d a f t e r PDL, w h i l e d e c r e a s e d and unchanged serum g l u c o s e c o n c e n t r a t i o n s were seen i n response to meat meal p l u s u n h y d r o l y z e d cream and meat meal p l u s h y d r o l y z e d c r e x s , r e s p e c t i v e l y . i n f l u e n c e of GIP induced glucagon cannot be e x c l u d e d  The p o s s i b i l i t y of although  the  34  controversial.15,65  35  CLINICAL OBSERVATIONS AND PROJECTIONS FOR THE FUTURE  Pancreatic ductal transplantation  ligation  of the p a n c r e a s  t o pancreatojejunostomy  is currently 6 6  applied in  clinical  and s u r g i c a l p r o c e d u r e as an  a f t e r pancreatoduodenectomy.  alternative  p w i s et  67  al  0  6 7  c l a i m e d the m o d i f i e d p r o c e d u r e i s s a f e r and l e s s prone t o e x o c r i n e and endocrine disturbances, pancreatic f i s t u l a s the conventional distal  and stomal u l c e r a t i o n s  pancreatoduodenectomy, w h i l e P a p a c h r i s t o u e t a l  pancreatectomy w i t h d u c t l i g a t i o n  is a relatively  but a f t e r pancreatoduodenectomy the m o r b i d i t y  6 8  than showed  safe procedure  i s reduced by a  pancreatojejunostomy.  The major o b j e c t i o n s  t o the r o u t i n e use of the p a n c r e a t i c  l i g a t i o n p r o c e d u r e are t h a t i t  abolishes exocrine a c t i v i t y  impair pancreatic endocrine function.59 a r i s e i n another p a t h o l o g i c a l  and t h a t i t may abnormalities  c o n d i t i o n s of the pancreas b e s i d e s 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 . pancreatectomy,  These f u n c t i o n a l  duct  They i n c l u d e p a t i e n t s w i t h  pancreatoduodenectomy and t o t a l pancreatectomy f o r  chronic pancreatitis, pancreatojejunostomy  e n d o c r i n e adenomas, and c a n c e r .  distal trauma,  P a t i e n t s whose  have become stenosed o r i n whom t h e main p a n c r e a t i c  d u c t i s o b s t r u c t e d by cancerous l e s i o n and are born w i t h 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 t h t h e s e c o n d i t i o n s are  o r decreased e x o c r i n e and e n d o c r i n e f u n c t i o n of the p a n c r e a s .  lost  These  p a t i e n t s may have mal a b s o r p t i v e phenomena and d i a b e t e s .  M a l a b s o r p t i o n and s t e a t o r r h e a do not develop u n t i l 90 per c e n t of  36  pancreatic exocrine function normal f u n c t i o n develop.  is lost.  W i t h l e s s than two per c e n t of  s t e a t o r r h e a i s s e v e r e and energy m a l a b s o r p t i o n  will  Marked s t e a t o r r h e a was not observed i n the dogs s t u d i e d i n  present experiment,  and t h i s  i s p r o b a b l y due t o f r e q u e n t  administration  p a n c r e a t i c enzyme mixed w i t h the meat meal f o r assessment of the e v a l u a t i o n a f t e r PDL.  the of  secretory  Thus replacement of p a n c r e a t i c enzyme t h a t  is  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 m a l a b s o r p t i o n phenomena of the p a n c r e a t i c  diseases.  D r a g s t e d t 5 9 has r e p o r t e d t h a t d i a b e t e s o c c u r s o n l y a f t e r o f 80 p e r c e n t o r more of t h e e n t i r e p a n c r e a s .  F u r t h e r , D r a g s t e d t e t al69  have r e p o r t e d t h a t the amounts of i n s u l i n r e q u i r e d t o c o n t r o l after partial  glycosuria  pancreatectomy i s much g r e a t e r than t h a t needed a f t e r  r e s e c t i o n of the p a n c r e a s .  In d i a b e t e s m e l l i t u s ,  decreased and the a n t i - i n s u l i n stimulated.  resection  The a n t i - i n s u l i n  shown t o be depressed and i t  insulin secretion  system such as g l u c a g o n s e c r e t i o n system a f t e r  total is  is  t o t a l pancreatectomy has been  has been suggested t h a t d i a b e t e s a f t e r  total  r e s e c t i o n of t h e pancreas would not r e q u i r e as much exogenous i n s u l i n .  It  has a l s o been r e p o r t e d t h a t g l u c a g o n response to  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 periampurary c a n c e r , * 7  arginine with  and N i s h i w a k i et al have shown t h a t plasma  glucagon response t o 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 PDL.  7 2  7 0  after  37  As s t a t e d i n the DISCUSSION o f the p r e s e n t paper, g l u c a g o n response may have been i n c r e a s e d a f t e r PDL due t o augmented GIP s e c r e t i o n which probably  s t i m u l a t e s glucagon s e c r e t i o n .  In any c a s e , from t h e s e o b s e r v a t i o n s p a n c r e a t i c d i a b e t e s s h o u l d be t r e a t e d  it  can be recommended t h a t  s e p a r a t e l y depending upon  etiology  o r background of the d i s e a s e .  There has been c o n t r o v e r s y  about whether or not i n c r e a s e d  s e c r e t i o n or p e p t i c u l c e r occur i n c h r o n i c p a n c r e a t i t i s .  It  gastric  seems p r o b a b l e  t h a t much of the c o n t r o v e r s y c o n c e r n i n g the c a p a c i t y of the p a t i e n t s p a n c r e a t i c d i s e a s e to s e c r e t e a c i d r e f l e c t s degree of the p a n c r e a t i t i s .  In s u r g i c a l  patients with chronic pancreatitis operation,  differences  i n the nature and  s e r i e s which i n c l u d e  sufficiently  severe to  mostly  require  an i n c r e a s e d i n c i d e n c e of u l c e r has been r e p o r t e d . On the  hand, H a s h i d a e t a l  7 3  have r e c e n t l y  e x p e r i e n c e w i t h complete d u c t a l  r e p o r t e d the K y o t o  obstruction  with  other  University  due t o pancreas head c a n c e r as  evidenced by ERCP o r r e s e c t e d specimen: 33 cases were measured g a s t r i c secretion using Pentagastrin, a n a c i d , 11 p a t i e n t s  had normal  marked h y p e r s e c r e t i o n .  and i t was r e v e a l e d t h a t 21 p a t i e n t s a c i d l e v e l s , and o n l y one p a t i e n t  They a l s o showed t h a t p e r i p h e r a l  t h e g a s t r i c antrum was d i s t u r b e d  u l c e r i n the p a t i e n t s w i t h p a n c r e a t i c  As shown i n the p r e s e n t s t u d y ,  responsible for  showed  circulation  i n dogs a f t e r PDL, s u g g e s t i n g  of mucosal defence i s a t l e a s t p a r t l y  were  of  impairment  the f o r m a t i o n  of  inflammation.  complete d u c t a l  obstruction  induces  g a s t r i c h y p e r s e c r e t i o n and e v e n t u a 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 h y p e r s e c r e t i o n and m a l a b s o r p t i o n phenomena as evidenced by no marked s t e a t o r r h e a i n any dog s t u d i e d . et a l  7 4  However, Saunders  have r e p o r t e d t h a t the presence of o v e r t m a l d i g e s t i o n i s  to g a s t r i c hypersecretion i n t h e i r p a t i e n t s with chronic  related  pancreatitis.  They s p e c u l a t e d when t h e r e i s much g a s t r i c j u i c e i n the duodenum and t h e r e 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 pancreatitis,  g a s t r i c j u i c e causes r a p i d and i r r e v e r s i b l e d e n a t u r a t i o n  of  p a n c r e a t i c enzymes, and the m a l d i g e s t i o n of 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 may be worsened. all  It  seems w i s e to a d m i n i s t e r o r a l  p a t i e n t s w i t h e x t e n s i v e p a n c r e a t i c d i s e a s e or r e s e c t i o n ,  s t e a t o r r h e a and g a s t r i c h y p e r s e c r e t i o n become m a n i f e s t , to d i a g n o s e 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  Clinical difficult,  i.v.  before  as i t  is  difficult  period.  r e c o g n i t i o n of e a r l y p a n c r e a t i c i n s u f f i c i e n c y  but may be p o s s i b l e by p e r f o r m i n g  enzymes to  is  thus  glucose tolerance  test.  As shown i n the p r e s e n t s t u d y , g l u c o s e 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 c o u l d be a s i g n of e a r l y o n s e t of  pancreatic  i nsufficiency.  Clinical  i m p l i c a t i o n of the r e s u l t i n the p r e s e n t study t h a t serum  IR-GIP response t o t h e meat meal a l o n e i s s i g n i f i c a n t l y PDL i s complex but of g r e a t i m p o r t a n c e . i s o l a t e d case r e p o r t s of marginal  There have been o n l y a few  u l c e r a t i o n as a c o m p l i c a t i o n  pancreatoduodenectomy, w h i l e G r a n t e t a l overall  augmented a f t e r  7 5  of  have r e c e n t l y r e p o r t e d t h a t  i n c i d e n c e of stomal u l c e r i n p a t i e n t s s u b m i t t e d t o a W h i p p l e  p r o c e d u r e o r t o t a l pancreatoduodenectomy was s i x per c e n t .  the  39  A l t h o u g h t h e s e s u r g i c a l procedures a r e 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 g e t u l c e r s ?  Any study of GIP  s e c r e t i o n a f t e r t h e s e s u r g i c a l procedures has not so f a r been r e p o r t e d . The p o s s i b i l i t y  t h a t augmented GIP s e c r e t i o n p l a y s some p r o t e c t i v e  role  against u l c e r formation  i n these p a t i e n t s  yet unidentified  and hormonal f a c t o r s cannot be e x c l u d e d . The  neural  i n c o - o p e r a t i o n w i t h o t h e r as  p r e s e n t study has not s u f f i c i e n t l y  verified  the r o l e of GIP i n  g a s t r i c h y p e r s e c r e t i o n a f t e r PDL.  F u t u r e work w i l l  inhibiting  e l u c i d a t e the t r u e  r o l e of GIP i n the p a t h o g e n e s i s of g a s t r i c h y p e r s e c r e t i o n and u l c e r formation  i n dogs a f t e r PDL and l e a d t o p r a c t i c a l  application.  40  40-  | | before op. IHI after op. 30CT ill  E  IS  20-  r! 1  10-  a 1 »2 *3 *4 Individual dogs with Heidenhain pouches  Fig.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 dog respectively. *=p<0.05 i'significant change compared with the control period). 3  41  1.5-  "c E  •  before  op.  Minutes  Fig. 2. Acid response from the Heidenhain meal alone before and after pancreatic duct The g a s t r i c f i s t u l a was closed during the Each point represents the mean and standard for 4 dogs(8 experiments).  pouch to meat ligation. experiment. error of values  42  30  60  90 j 120  150 180-210 Minutes  240  270  300  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  200-¥  3 0  6 0  9 0  120  150  180  210  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 Minutes  2  \  0  240 ' 270  300  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. o— — — — o after op.  100-  -J-  -J—L—.1  60  1  E  O  i  50-  30  60  90  120  150 180 Minutes  210  240  270  300  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  30  60  90  120  150 180 Minutes  210  •  • b e f o r e op.  o  o.after  240  270  op.  300  Fig. s Serum gastrin response to meat meal plus cream before and after pancreatic duct l i g a t i o n . Each represents the mean and error of values for 4 dogs(8  4  unhydrolyzed point experiments)  48  ^ 30  1 60  I 90  I  120  i  i  150  180  i  210  i  240  i  270  i  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  30T  •  60  90  120  • before op.  To  T  150  180 210 Minutes  240  — —o after bp.  270  Fig. Serum IRI response to meat meal plus cream before and after pancreatic duct l i g a t i o n . represents the mean and standard error of values (8 experiments). *=p<0.05 * *=p<0. 01.(signif icant change compared control period). 1 0  }  300  unhydrolyzed Each point for 4 dogs with  the  50  100E  O 50-  O  30  60  90  120  150 Minutes  180  210  240  270  300  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"  'c  •  • before op.  °  o after op.  Minutes  Fig 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). X{1  52  150-  hydrolyzed cream  30,  60  90  120  i^f7Serum gastrin response cream before and after pancreatic represents the mean and standard (8 experimetns).  150 180 Minutes  210  240  270  300  to meat meal plus hydrolyzed duct ligation. Each point error of values for 4 dogs  53  "I 30  '  1  1  I  60  90  120  |  |  1  T  —  150 180 Minutes  1  210  240  270  300  Fig. 14 Serum GIP response to meat meal plus cream bofore and after pancreatic duct l i g a t i o n . represents the mean and standard error of values (8 experiments).  hydrolyzed Each point for 4 dogs  54  3 0 -  Minutes  Fig. Serum IRI response to meat meal plus cream before and after pancreatic duct ligation. represents the mean and standard error of values (8 experiments). 1  5  hydrolyzed Each point for 4 dogs  /  55  150-  30.  60  Fig. Serum glucose cream before and after represents the mean and (8 experiments).  90  120  150 180 Minutes  210  240  270  300  hydrolyzed response to meat meal plus duct l i g a t i o n . Each point pancreatic error of values for 4 dogs standard  \  56  i  i  0  30 Minutes  Fig. ' 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<0.01 ***=p<0.005 ( s i g n i f i c a n t change compared with the control period). 1  s  57  50-  0  30  60  minutes  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-  Glucose  —•  before  " °  after  op. o p . (2wks)  no 0) in  o _u2 O  100806040200  30  60  90 120 Minutes  150  180  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<0.05 **=p<0. 01 ( s i g n i f i c a n t change compared with the control period). 3  59  Fig. Serum IRI response before and after pancreatic the mean and standard error d 0  to i n t r a g a s t r i c glucose duct l i g a t i o n . Each point of values for 4 dogs(8  load represents experimetns).  60  before op.  I  30  60  90 120 Minutes  Fia 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 . Each povnt represents T h e mean and standard error of values for 4 dogs (8 experiments). 2 1  61  BIBLIOGRAPHY  1.  Basso N . , McGuigan J . E . , and P a s s a r o J r . E . : l e v e l s a f t e r p a n c r e a t i c duct l i g a t i o n .  Elevated  gastrin  A r c h . Surg. 105:611-614,  1972.  2.  Chey W.Y. and L o r b e r S . H . : s e c r e t i o n i n dogs.  3.  I n f l u e n c e of pancreas on g a s t r i c  Am. J . 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Gastric  inhibitory  on i n s u l i n  and  P r o c . S o c . E x p . B i o l . Med.  71  66.  Hodge H.H. and Young H . B . : resection.  67.  Surgery 8 3 : 3 5 9 - 3 6 0 ,  Powis S . J . A .  and Young H . B . :  Surg. Gynecol. Obstet.  68.  A modified  137:259-262,  pancreatoduodenectomy.  1973.  duct i n pancreatectomy.  in diabetic  dogs.  L i g a t i o n of  Br. J . Surg. 67:260-262,  D r a g s t e d t L . R . , A l l e n J . G . and Smith E . M . : tolerance  following  1978.  P a p a c h r i s t o u D . N . , D ' A g o s t i n o H. and F o r t n e r J . G . : pancreatic  69.  Pancreatic autotransplantation  Extensive  the  1980.  insulin  P r o c . S o c . Exp. B i o l . Med. 5 4 : 2 9 2 ,  1943.  70.  Y a s u g i H . , Mizumoto R.., S a k u r a i H. and Honjo I.:  Changes i n  c a r b o h y d r a t e metabolism and e n d o c r i n e f u n c t i o n of remnant a f t e r major p a n c r e a t i c  71.  Am. J . S u r g . 132:577-580,  M i y a t a M . , Hamaji M . , Yamamoto T . , Sakamoto T . :  An a p p r a i s a l  glucagon s e c r e t i o n .  72.  resection.  s t u d i e s on p a n c r e a t i c  pancreatic duct l i g a t i o n .  1976.  Sakaguchi H. and  pancreatoduodenectomy  191:282-286,  Nishiwaki H., Sakazaki S . , Shin K., Experimental  Nakao K . ,  of r a d i c a l  Ann. S u r g .  pancreas  based on  1980.  S a t a k e K. and Umeyama K . : e n d o c r i n e f u n c t i o n of dogs  after  Jap. J . Gastroenterol. 76:104-111,  1979.  72  73.  H a s h i d a S . , S u z u k i T. and Tobe: pancreatic disease.  Gastric resection in patients with  Proc. 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 . : of a c i d i n p a t i e n t s w i t h p a n c r e a t i c d i s e a s e .  Gastric  Digestion  secretion  17:365-369,  1978.  75.  G r a n t C . S . , van Heerden J . A . :  Anastomotic u l c e r a t i o n  s u b t o t a l and t o t a l pancreatectomy.  following  Ann. S u r g . 1 9 0 : 1 - 5 ,  1979.  73  APPENDIX  I n o r d e r t o a s c e r t a i n the complete h y d r o l y s i s of cream by  incubation  w i t h t h e d i g e s t i v e agent, gas chromatographic a n a l y s i s was p e r f o r m e d .  One hundred and t w e n t y - f i v e g of whipping cream ( S i l v e r w o o d Whipping Cream, S i l v e r w o o d D a i r i e s , T o r o n t o , Canada.  Ingredients:  F a t 38.2 g,  s a t u r a t e d f a t t y a c i d s 2 1 . 4 g , o l e i c a c i d 1 g, p r o t e i n 2.6 g , 4 . 2 g , c a l c i u m 0.1  carbohydrate  g) was i n c u b a t e d w i t h t h r e e c a p s u l e s of Cotazymes  (Organon C o . , T o r o n t o , Canada. Each c a p s u l e c o n t a i n s 800 u n i t s pancreatic lipase)  of  f o r t h r e e hours a t 37° C .  A f t e r the i n c u b a t i o n ,  r e l e a s e d f a t t y a c i d s were e x t r a c t e d w i t h  e t h e 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 c o n c e n t r a t e d HCl h y d r o l y s i s .  B o r o n t r i f l u o r i d e (BF3) methanol complex was used f o r p r e p a r a t i o n of f a t t y a c i d methyl ( M e t c a l f e L . D . and S c h m i t z A . A . :  the  e s t e r s u s i n g the method of M e t c a l f e e t a l The r a p i d p r e p a r a t i o n of f a t t y  e s t e 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.  acid  33: 363-364,  1961).  The h y d r o l y z e d sample was put i n t o the 50 ml of m y e r - f l a s k c o o l e d i n an i c e b a t h ,  added 7 ml of BF3 r e a g e n t ,  and b o i l e d f o r two m i n u t e s ; 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 t o the neck of t h e m y e r - f l a s k w i t h s a t u r a t e d aquous sodium c h l o r i d e solution.  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  anhydride.  Gas chromatographic a n a l y s i s was done u s i n g H i t a c h i 663 gas chromatograph ( H i t a c h i C o . , T o k y o ) .  F i g u r e s 1 t o 5 show the chromatographic p a t t e r n s conditions.  F i g u r e 1 shows the p a t t e r n a f t e r 3 - h o u r  t h e d i g e s t i v e agent.  Any f a t t y a c i d methyl  F i g u r e s 2 , 3 and 4 i l l u s t r a t e laurate,  incubation without  e s t e r peak cannot be s e e n .  s i n g l e chromatographic p a t t e r n s  methyl p a l m i t a t e and methyl  of  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 t h e p a t t e r n o f sample of 3-hour d i g e s t i v e agent,  and o p e r a t i n g  incubation with  and many peaks of f a t t y a c i d methyl  c o r r e s p o n d t o the c o n t r o l s can be s e e n .  the  e s t e r s which  will  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  Fig.1(forAPPENDIX)• after 3-hr incubation  5  tO 15 Retention time (min)  The chromatographic pattern at 37 °C without the digestive  of  cream agent.  76  OEGS Chromosorb WAW DMCS 80/100 Glass I.D. 3*X2m 160-200'C 4*C/min N 20 ml/min 2  Methyl Laurate C12  5  10 r  Fig. 2(for APPENDIX)• methyl laurate.  »5  R e t e n t i o n time (min)  The chromatographic  pattern  of  77  Methyl Palmitate C16  D E G S Chromosorb WAW DMCS eo/ioo Glass I.D. 3*X2m 1 6 0 - 2 0 0 ' C 4'C/min N ; 20ml/min  5  10 »  Fig. ' 3 ( f o r APPENDIX ) methyl -palmitate.  The  15  Retention time (min)  chromatographic  pattern  of  78  DEGS Chromosorb WAW DMCS 60/100 Glass I.D. 3*X2m 160-200"C 4*C/min N 20ml/min 2  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  O  s  cie:o  cis:i  10 , 15 Retention time (min)  Fig. 5 (for APPENDIX ) . The chromatographic fatty acid methyl esters after 3-hr incubation with the digestive agent.  pattern of at 37°C  80  PHOTOGRAPH I Dog #4 p o s t mortem s p e c i m e n . Duodenum and p a n c r e a t i c d u c t s showing a t r o p h y o f p a n c r e a s , but no i n f l a m m a t i o n .  82  PAPERS WRITTEN:  1.  Stam'sheff s operation for  nephroptosis.  O p e r a t i o n (Japan)  25:661,  1971.  2.  A case of hydrops of the g a l l b l a d d e r due to n o n - c a l c u l o u s duct o b s t r u c t i o n .  3.  S e l e c t i v e angiography stage.  4.  Surgery (Japan) 3 8 : 4 2 7 ,  cystic  1976.  i n c a n c e r of the pancreas a t a r e s e c t a b l e  Am. J . S u r g . 122:402, 1971.  S u r g i c a l s i g n i f i c a n c e o f anatomic v a r i a t i o n s  of the hepatic  artery.  Am. J . S u r g . 122:505, 1971.  5.  Z o l l i n g e r - E l l i s o n syndrome a s s o c i a t e d w i t h p a r a t h y r o i d adenoma and e c t o p i c g a s t r i c t i s s u e i n the l o w e r esophageal mucosa.  Can. J .  Surg.  6.  P e p t i c u l c e r and g l u c o s e h o m e o s t a s i s :  I.  Insulin,  gastrin  g l u c a g o n responses t o o r a l g l u c o s e and i n t r a v e n o u s peptic ulcer patients.  7.  Arch. Jap. C h i r . 48:517,  R e l a t i o n s h i p between GIP and i n s u l i n .  and  arginine  in  1979.  Surg. Ther.  (Japan) 4 1 : 4 4 7 ,  1979.  8.  N e g a t i v e 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 G I P . J.  G a s t r o e n t e r o l . 76:2432,  1979.  Jap.  83  9.  A case of l o n g term combined use of N e o c a r c i n o s t a t i n and humanimmunoglobulin  10.  The i n h i b i t o r y  for colon cancer.  effect  of s u l p i r i d e  in arginine-stimulated  g a s t r i n and growth hormone i n normal patients.  11.  K i s o - t o - R i n s h o 14:138,  subjects  and p e p t i c  1980.  serum ulcer  J a p . J . G a s t r o e n t e r o l . 7 8 : 1 3 6 3 , 1981.  P e p t i c u l c e r and g l u c o s e h o m e o s t a s i s : g l u c a g o n responses t o o r a l duodenal u l c e r p a t i e n t s .  and i . v .  II.  Insulin,  L-arginien  gastrin  i n two groups  Submitted t o G a s t r o e n t e r o l . J a p .  and of  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 cancer).  2.  angiography  (especially  for  liver  The 8 t h Meeting of Japanese S o c i e t y of A n g i o l o g y .  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.  1967.  The 7 t h M e e t i n g  Japanese S o c i e t y of M e d i c a l E l e c t r o n i c s and B i o l o g i c a l  of  Engineering.  1968.  3.  C o r r e l a t i o n of l i v e r  c a n c e r and i t s b l o o d s u p p l y .  o f Japanese S o c i e t y of H e p a t o l o g y .  4.  5.  The 3 r d  1967.  A n a l y s i s of s p l e n i c and p o r t a l c i r c u l a t o r y  dynamics.  Meeting of Japanese S o c i e t y of A n g i o l o g y .  1968.  A n a l y s i s of s p l e n i c and p o r t a l c i r c u l a t i o n  using  radioisotope  The 9 t h Meeting  i n j e c t i o n to s p l e n i c a r t e r y .  Japanese S o c i e t y of N u c l e a r M e d i c i n e .  6.  Angioscanography o f l i v e r c a n c e r .  7.  Hepatoma of i n f a n t .  8.  E x p e r i e n c e of m o d i f i e d S t a n i s c h e f f s  The 9 t h  superselective  Kyoto S u r g i c a l C o n g r e s s .  1970.  of  1969.  Kyoto S u r g i c a l C o n g r e s s .  Okayama S u r g i c a l A s s o c i a t i o n .  Meeting  operation  1969.  1969.  for  nephroptosis.  85  9.  A c a s e of hydrops of the g a l l b l a d d e r due t o n o n c a l c u l o u s c y s t i c obstruction.  10.  K i n k i S u r g i c a l A s s o c i a t i o n . 1972.  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 t h e g a s t r i c mucosal change. Surgical Association.  11.  duct  Kinki  1973.  T r a u m a t i c u r a c h a l c y s t of the k i d n e y .  Kinki Surgical Association.  1977.  12.  Amylase-creatinine clearance r a t i o following of pancreozymin i n c h r o n i c p a n c r e a t i t i s . Association.  13.  intravenous  Kinki  injection  Surgical  1977.  P e p t i c u l c e r and g l u c o s e h o m e o s t a s i s .  Kinki Surgical Association.  1979.  14.  Hiatus hernia associated with peptic u l c e r . Association.  15.  16.  intrahepatic  stones.  The n e g a t i v e feedback c o n t r o l  GIP f o l l o w i n g  Kinki  Surgical  1978.  o f GIP by i n s u l i n .  of Japanese G a s t r o e n t e r o l o g y A s s o c i a t i o n .  17.  Surgical  1979.  Radical operation for Association.  Kinki  ligation  The 2 0 t h Meeting  1978.  of the p a n c r e a t i c duct i n dogs.  Meeting of Japanese G a s t r o e n t e r o l o g i c a l  The 14th  Surgery A s s o c i a t i o n .  1979.  86  18.  19.  Intravenous  arginine,  1979.  P o s t - s p l e n e c t o m y thrombocythemia.  Kinki Surgical Association.  P e r f o r a t e d small  Hematology  intestinal  ulcer.  colon  1979.  Kyoto Emergency Treatment  1979.  Serum g a s t r i n ,  i n s u l i n and glucagon i n response to  in peptic ulcer patients.  intravenous  The 15th Meeting of J a p a n e s e  Surgery A s s o c i a t i o n .  1980.  The s u p p r e s s i v e 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 and growth hormone. Gastroenterological  gastrin  The 6 6 t h Meeting of J a p a n e s e Association.  1980.  D i s s e m i n a t e d i n t r a v a s c u l a r c o a g u l a t i o n a s s o c i a t e d w i t h acute obstructive 1980.  of  1979.  Gastroenterological  24.  Japan C l i n i c a l  Serum CEA l e v e l s a f t e r mumps v i r u s v a c c i n e i n j e c t i o n f o r  arginine  23.  gastrin  Japanese Gastroenterology A s s o c i a t i o n .  Association.  22.  insulin,  The 22nd S p r i n g Meeting  cancer.  21.  glucose stimulated  and g l u c a g o n i n p e p t i c u l c e r p a t i e n t s .  Association.  20.  and o r a l  supprative c h o l a n g i t i s .  Kinki Surgical Association.  87  25.  Treatment of c o l o n c a n c e r w i t h N e o c a r c i n o s t a t i n and human immunoglobulin.  Kyoto Cancer Research A s s o c i a t i o n .  26.  Abdominal trauma.  Kyoto M e d i c a l A s s o c i a t i o n .  27.  Treatment of p e p t i c u l c e r .  1980.  1980.  Kyoto M e d i c a l A s s o c i a t i o n .  1980.  

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