Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man

Summary Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4±1.4pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8–12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.     

Effects of an antral mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic secretion in dogs

The purpose of this study was to determine the role of gastrin and cholecystokinin in the cephalic phase of gastrin release and gastric and pancreatic secretion in conscious dogs. Sham feeding in intact dogs increased gastric acid output to about 65% of histamine maximum and pancreatic protein to 23% of caerulein maximum. Significant increases in plasma gastrin and pancreatic polypeptide but not cholecystokinin occurred. Similar effects were obtained using insulin hypoglycemia or 2-deoxy-D-glucose glucocytopemia. Atropine eliminated gastric acid response to sham feeding, insulin, or 2-deoxy-D-glucose, significantly reduced the pancreatic protein response by about 60%, and abolished plasma pancreatic polypeptide but not plasma gastrin. Blocking of cholecystokinin receptors by L-364,715 did not affect gastric or pancreatic secretory responses to sham feeding, insulin, or 2-deoxy-D-glucose and failed to influence the accompanying increments in plasma gastrin and pancreatic polypeptide. In antral-mucosectomized dogs, sham feeding-induced acid output reached only 17% of histamine maximum but the increase in pancreatic protein output was similar to that in intact dogs. In these animals, background stimulation with G17I (62 pmol/kg per h) potentiated the gastric acid response to sham feeding but had little effect on pancreatic protein output. This study provides evidence that unlike gastric acid, the pancreatic protein response to physiological or pharmacological cephalic stimulation does not depend on vagally released gastrin but probably on direct vagal stimulation of the pancreas.     

Cholecystokinin-33 potentiates and vasoactive intestinal polypeptide inhibits gastric inhibitory polypeptide--induced insulin secretion in the perfused rat pancreas

Gastric inhibitory polypeptide (GIP), cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) stimulate insulin secretion. In this study we investigated whether CCK-33 and VIP could influence the insulinogenic effect of simultaneously administered GIP and 6.7 mmol/l glucose in the perfused rat pancreas. We found that at 0.1 nmol/l, GIP markedly potentiated glucose-induced insulin release whereas CCK-33 and VIP had a weak stimulatory effect and only during the late phase. At this low dose level, CCK-33 potentiated but VIP inhibited the late phase of insulin release stimulated by glucose and GIP. At 1.0 nmol/l, GIP, CCK-33, and VIP markedly potentiated both phases of glucose-induced insulin secretion. At this dose level CCK-33 and GIP exerted additive stimulatory effects on the late phase of insulin release triggered by glucose. In contrast, 1.0 nmol/l VIP inhibited insulin secretion augmented by glucose and GIP. In summary 1) GIP, CCK-33 and VIP all potentiate glucose-induced insulin secretion from the perfused rat pancreas, and 2) CCK-33 potentiates and VIP inhibits GIP-induced insulin secretion. We suggest that interactions of this kind are of importance for the precise regulation of insulin secretion.     

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.     

Release of gastric inhibitory polypeptide (GIP) by intraduodenal acidification in rats and humans and abolishment of the incretin effect of acid by GIP-antiserum in rats.

Intraduodenal infusion of 0.05-0.5 N hydrochloric acid dose-dependently increases serum levels of immunoreactive gastric inhibitory polypeptide (GIP) in rats. Immunoreactive GIP released by duodenal acidification is biologically active because it augments the glucose-induced release of immunoreactive insulin (IRI). This augmentation of glucose-induced IRI release by intraduodenal acid can be abolished for 30 min by simultaneous intravenous infusion of GIP-antiserum. From this it is concluded that the initial capacity to augment the glucose-induced insulin release (incretin activity) of hydrochloric acid is due to its ability to release GIP. Later on, other gut factors with incretin activity might be released by hydrochloric acid. Also, in humans, intraduodenal infusion of 0.1 N hydrochloric acid releases GIP without changing serum levels of glucose or insulin. The GIP release is a direct effect of intraduodenal acid and is not mediated via secretin release. Injection of secretin in supraphysiologic doses does not change serum levels of immunoreactive GIP. However, such secretin injections induce a short-term insulin release and a decrease in serum glucose concentration.     

Effect of ethanol ingestion on postprandial gastric emptying and secretion,biliopancreatic secretions,and duodenal absorption in man

Although abdominal complaints are frequent in both acute and chronic alcoholism, little is known of the effect of ingestion of ethanol with a meal on the function of the upper digestive tract. We have studied the effects of oral ethanol (1 g/kg body wt) taken with food on (1) the gastric emptying rate of a solid-liquid meal as measured by a dual radioisotope technique in six normal subjects; and (2) the gastric response (emptying and secretion), biliopancreatic secretions, and duodenal nutrient absorption after an homogenized meal, as evaluated by a gastroduodenal intubation-marker perfusion technique on seven healthy volunteers. In the latter experiments, radioimmunoassays of gastrin, secretin, cholecystokinin, pancreatic polypeptide, motilin, somatostatin, gastric inhibitory polypeptide, and vasoactive intestinal polypeptide were performed serially. As compared with the control experiment, alcohol induced the following effects: (1) marked delay of gastric emptying of solids, smaller slowing effect on gastric emptying of the liquid phase of the solid-liquid meal and of the homogenized meal; (2) no significant change in gastric acid secretion; (3) no change in the overall postprandial pancreatic enzyme outputs, but a delay of lipase secretion; (4) no change in the early bile salt postprandial output, but a reduced bile salt secretion from the second postprandial hour onwards; (5) no significant change in carbohydrate and lipid duodenal absorption; and (6) a significantly greater postcibal gastrin release. The mechanisms for these effects of alcohol on upper digestive tract function remain to be clarified.     

Correlation of endogenous somatostatin, gastric inhibitory polypeptide, glucagon and insulin with gastric function in the conscious calf

Levels of endogenous somatostatin, gastric inhibitory polypeptide (GIP), glucagon and insulin were measured during gastric (abomasal) emptying in the conscious calf. Isotonic NaHCO3 infused into the duodenum increased rates of emptying of a saline test meal and of gastric acid secretion, but had no effect on basal levels of blood glucose, somatostatin, GIP, insulin or glucagon. By contrast, intraduodenal infusion of 60 mM-HCl caused complete inhibition of gastric emptying, reduction of acid secretion, and an immediate increase in plasma somatostatin from 121.3 +/- 9.4 (S.E.M.) to 286.3 +/- 16.3 pg/ml (P less 0.01) but levels of GIP, insulin, glucagon and glucose were unaltered. Intravenous injection of somatostatin (0.5 microgram/kg) suppressed the antral electromyographic recording and gastri efflux so long as plasma somatostatin levels remained above approx. 200pg/ml. This suggest that somatostatin can be released by intraduodenal acidification and that it inhibits gastric function by an endocrine effect. Since somatostatin retards gastric emptying it may therefore have an indirect role in nutrient homeostasis by limiting discharge of gastric chyme to the duodenum.     

Does gastric acid release plasma somatostatin in man?

Food and insulin hypoglycaemia raise plasma concentrations of somatostatin. Both also stimulate gastric acid secretion but it is not clear whether gastric acid itself has any effect on somatostatin secretion. We, therefore, studied the effect on plasma concentrations of somatostatin of infusion of 0.1 N HC1 into the stomach and duodenum of healthy subjects. Plasma somatostatin did not rise with a small dose of HC1 given intragastrically (15 mmol) or intraduodenally (4 mmol). After an intraduodenal infusion of 60 mmol HC1 over 30 minutes, sufficient to reduce intraluminal pH to 2, plasma somatostatin rose moderately in five subjects from a mean value (+/- SEM) of 32 +/- 3 pg/ml to a peak at 10 minutes of 54 +/- 11 pg/ml. It is concluded that: (a) intragastric acid infusions do not release circulating somatostatin in man; and (b) that intraduodenal acidification albeit at grossly supraphysiological doses is a moderate stimulus of plasma somatostatin release. Therefore, gastric acid is unlikely to be a major factor mediating postprandial plasma somatostatin release in man.     

Comparison of intraduodenal and intravenous administration of amino acids on gastric secretion in healthy subjects and patients with duodenal ulcer.

The ability of an amino acid mixture given intraduodenally or intravenously to stimulate gastric secretion is compared in healthy subjects and in duodenal ulcer patients. Graded amounts of amino acids by both routes produced a similar increase in acid output in healthy subjects, reaching about 30% of the maximal response to pentagastrin. Serum gastrin concentrations remained virtually unchanged but serum alpha amino acid nitrogen levels were about twice as high with intravenous as with intraduodenal administration. Intravenously administered amino acids produced a significantly higher acid output in patients with duodenal ulcer than in healthy subjects, but did not produce a significant increase in gastric acid or pepsin secretion when combined with a pentagastrin infusion as compared with pentagastrin alone. Cimetidine (2 mg/kg/h) added to intravenous amino acid infusions caused almost complete suppression of acid secretion. This study indicates that amino acids are capable of stimulating gastric secretion after intraduodenal and after intravenous administration. The response to the latter is significantly higher in patients with duodenal ulcer than in healthy subjects, does not appear to involve gastrin release, is not affected by pentagastrin, and is strongly suppressed by histamine H2-blocker.     

Effect of atropine on pancreatic responses to endogenous and exogenous cholecystokinin

The role of cholinergic innervation in endogenous release of cholecystokinin from the intestinal mucosa and in exocrine pancreatic secretion was examined by means of atropine administration in 3 chronic gastric-fistula and pancreatic-fistula dogs during pancreatic responses to various rates of intraduodenal amino acid mixture and to various doses of intravenous cholecystokinin producing equal rates of pancreatic protein secretion. Atropine infused in a dose of 100 µg/kg-hr caused a deep and prolonged decrease in pancreatic flow rate, protein and bicarbonate output, reaching a maximum of about 80% of the pre-atropine level of pancreatic secretion. The inhibition occurred regardless of the level of pancreatic response examined. Atropine also caused an inhibition of pancreatic responses to smaller doses of exogenous cholecystokinin but did not affect responses to larger doses. The maximal observed pancreatic protein secretion in response to intraduodenal administration of amino acids was about 80% of the highest response to cholecystokinin. This study suggests that the release of cholecystokinin from the intestinal mucosa might be cholinergically dependent.     

Pancreatobiliary responses to an intragastric amino acid meal: comparison to albumin, dextrose, and a maximal cholecystokinin stimulus

Little is known about how gastric and pancreatobiliary responses differ after intake of elemental diets from responses to polymeric food. We therefore compared pancreatic and biliary secretions after gastric instillation of albumin (7 g%, with dextrose 21 g%) with an elemental diet in 6 healthy volunteers. The elemental diet contained amino acids (7 g%, with dextrose 21 g%) in the same molar composition as the albumin. Furthermore, we studied the effect of a pure intragastric dextrose solution (21 g%) on pancreatobiliary secretions, as glucose constitutes a major component of elemental diet formulas. The various pancreatobiliary responses were tested against a maximal i.v. cholecystokinin stimulus. The dextrose, amino acid, and albumin meals emptied at similar rates, and gastric emptying was completed within 3 h. Similar pancreatobiliary responses were observed after the albumin and amino acid meals, but response to both the amino acid and albumin meals was smaller than to the intravenous cholecystokinin stimulus. The glucose meal caused a marked and sustained stimulation of pancreatobiliary outputs, which did not differ significantly from the other test meals. However, lower cholecystokinin levels were observed after the glucose meal compared with distinct cholecystokinin release after the albumin and amino acid meals. We conclude first that there are no major differences in secretory responses between elemental (amino acid) and polymeric (protein) meals and second, that intragastric pure glucose meals strongly stimulate pancreatobiliary secretions. The marked pancreatic and biliary responses to intragastric dextrose cannot be fully explained on the basis of cholecystokinin release, suggesting that this response is probably mediated by neural mechanisms.     

RESPONSE OF CIRCULATING SOMATOSTATIN, INSULIN, GASTRIN AND GIP, TO INTRADUODENAL INFUSION OF NUTRIENTS IN NORMAL MAN

We have studied the effect of direct infusion of nutrients into the duodenum of normal subjects on circulating plasma somatostatin, insulin, gastrin and gastric inhibitory polypeptide (GIP) levels. Six normal subjects were given on four separate occasions 150 ml of isotonic solutions containing 100 calories of carbohydrate, protein, or fat, and a control solution of saline, by infusion into the second part of the duodenum. Plasma somatostatin rose slightly after carbohydrate, mean basal 30 +/- 3 pg/ml, peak 46 +/- 16 pg/ml at 15 min; and more markedly after protein, peak 57 +/- 9 pg/ml at 30 min. However, fat was the most potent intraduodenal stimulus to plasma somatostatin release into circulation, peak 101 +/- 11 pg/ml at 30 min. The plasma insulin rise was greatest after carbohydrate, peak 68 +/- 10 i.u., but there was a significant rise after protein also, peak 34 +/- 6 i.u. Plasma gastrin rose significantly after protein only, peak 70 +/- 22 pg/ml. Plasma GIP rose markedly after carbohydrate, basal 506 +/- 50 pg/ml, peak 1480 +/- 120 pg/ml. Protein was also a potent stimulus of circulating plasma GIP release, peak 1200 +/- 190 pg/ml, while fat was the least potent, peak 730 +/- 190 pg/ml. Thus, calorie for calorie, fat is the most potent intraduodenal nutrient stimulus of circulating somatostatin. We postulate therefore that somatostatin may be an enterogastrone--a circulating hormone released by intraduodenal fat which inhibits gastric acid secretion. Fat is the least potent intraduodenal nutrient stimulus of circulating GIP release. This is evidence against the hypothesis that circulating GIP acts as an enterogastrone.     

Nutrient and hormonal regulation of the threshold of glucose-stimulated insulin secretion in isolated rat pancreases

This study demonstrates that the threshold of glucose-stimulated insulin secretion can be regulated in vivo by long term hormonal and nutrient modifications. The sensitivity of the pancreatic B-cell to glucose stimulation was determined by examining the pattern of insulin release from pancreases perfused with linear glucose gradients. Male rats infused with ovine PRL for 4 days and rats receiving five hourly injections of glucose had a lower threshold and enhanced rates of insulin release at all stimulatory glucose concentrations. Infusion of bGH for 4 days was without effect on glucose gradient-stimulated insulin release. Fasting the rats for 48 h resulted in an elevation of the threshold and a substantial reduction in the extent of insulin release. To determine possible processes involved in these long term modifications of the threshold of glucose-stimulated insulin secretion, the in vitro effect of potentiators of insulin release was examined. Forskolin, glucagon, cholecystokinin, and carbamylcholine were able to lower the threshold and increase the extent of insulin release. This suggests that the long term regulation of insulin secretion may modulate processes controlling cAMP concentrations and the hydrolysis of phosphoinositides in pancreatic B-cells. Also, the proposed incretin gastric inhibitory polypeptide was capable of lowering the threshold and increasing insulin secretion at stimulatory glucose concentrations. The consequences of a decreased threshold is a markedly enhanced insulin secretion at normal serum glucose concentrations.     

Pancreatic juice enhances fat-stimulated release of enteric hormones in dogs

The presence of pancreatic juice in the intestinal lumen results in the hydrolysis of dietary fat. The hydrolytic products of dietary fat are potent stimulants of pancreatic exocrine secretion and potent inhibitors of gastric acid secretion. In this study, residual pancreatic enzyme activity in the intestinal lumen may account for the observed increase of triglyceride-stimulated pancreatic exocrine secretion and the release of peptides during diversion of pancreatic juice. The presence of pancreatic juice enhanced the pancreatic protein output that was stimulated by the intraduodenal administration of a triglyceride (corn oil, 2 g/kg/h) by 240% (p less than .05). The presence of pancreatic juice during the intraduodenal administration of a triglyceride nearly abolished the output of gastric acid as well as the release of gastrin (p less than .05) that had been stimulated by the intragastric placement of a 10% peptone meal. Pancreatic juice in the duodenum significantly enhanced the triglyceride-stimulated release of cholecystokinin-33/39, secretin, neurotensin, peptide YY, pancreatic polypeptide, and insulin (p less than .05) when compared with the release of these enteropancreatic hormones during the diversion of pancreatic juice. This study shows that the presence of pancreatic juice in the duodenal lumen enhances the fat-stimulated release of enteric hormones that have a stimulatory action on the enteroacinar and enteroinsular axis as well as an inhibitory action (enterogastrone-like activity) on the postprandial regulation of gastric function.     

Regulation of the release of cholecystokinin by bile salts in dogs and humans

The objective of these studies was to investigate the role of bile salts in the regulation of release of cholecystokinin in response to nutrients in dogs and humans. In dogs, the intraduodenal administration of a bile salt sequestrant, cholestyramine (2, 4, or 8 g/h), resulted in a dose-related enhancement of the release of cholecystokinin-33/39 and pancreatic protein secretion in response to intraduodenal administration of amino acids. Intraduodenal administration of cholestyramine alone did not affect basal levels of cholecystokinin-33/39 or pancreatic protein secretion. Total diversion of bile also significantly increased the release of cholecystokinin and pancreatic protein secretion in response to intraduodenal administration of amino acids. Replacement of the bile salt pool by intraduodenal administration of taurocholate completely reversed the enhancement effect of both cholestyramine and bile diversion. In humans, oral ingestion of cholestyramine (12 g) significantly increased the release of cholecystokinin-33/39 and gallbladder contraction in response to the oral ingestion of either a triglyceride or amino acids. These results support a physiologic role of bile salts in the negative feedback regulation of release of cholecystokinin in response to luminal nutrients.     

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.     

Clinical endocrinology and metabolism. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide

The 42 amino acid polypeptide glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is released from intestinal K-cells in response to nutrient ingestion. Based on animal studies, the peptide was initially assumed to act as an endogenous inhibitor of gastric acid secretion. Later it was found that GIP is capable of augmenting glucose-stimulated insulin secretion, and subsequent studies provided evidence that, in humans, the peptide predominantly acts as an incretin hormone. A role for GIP in the regulation of lipid homeostasis and in the development of obesity has been inferred from different animal studies. While GIP strongly stimulates insulin release in healthy humans, the peptide has almost completely lost its insulinotropic effect in patients with type 2 diabetes. This is different from the actions of glucagon-like peptide 1, which stimulates insulin secretion even in the later stages of type 2 diabetes. This suggests that a diminished insulinotropic effect of GIP may contribute to the pathogenesis of type 2 diabetes. This review will summarize the actions of GIP in human physiology and discuss its role in the pathogenesis of type 2 diabetes, as well as the therapeutic options derived from these findings.     

Mannitol and glucose

Serum gastric inhibitory polypeptide was measured in dogs prepared with Heidenhain pouches and Mann-Bollman fistulae following the intraduodenal (ID) infusion of isotonic saline, 20% glucose, or 20% mannitol. Following ID 20% glucose, serum GIP concentrations rose significantly (P<0.05) between 30 and 120 min and there was a significant inhibition (P<0.05) of acid secretion in the Heidenhain pouches between 15 and 75 min. A good correlation (r=0.925) was found between the rise in serum GIP and the inhibition of acid secretion. Although neither ID isotonic saline nor 20% mannitol stimulated GIP release, the latter produced a significant (P<0.05) inhibition of acid secretion between 60 and 105 min. We conclude: (1) the inhibitory effect of acid secretion following ID glucose is mediated in part by the release of endogenous GIP; (2) glucose and mannitol probably inhibit gastric acid secretion by different mechanisms.     

Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex

We have recently demonstrated that intraduodenal perfusion of trypsin inhibits phenylalanine-stimulated pancreatic enzyme secretion by suppression of release of cholecystokinin (CCK). It is not known whether trypsin in the duodenum inhibits pancreatic secretion stimulated by a cholinergic mechanism. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Volume and osmoreceptors in the duodenum, which are known to elicit pancreatic secretion through cholinergic pathways, were stimulated by infusing increasing volumes (1.0, 2.5, and 5.0 ml/min) of normal saline or increasing osmolality (300, 400, 500 mosmol) of NaCl solution. Increasing the rates of intraduodenal perfusion of normal saline or increasing the osmolality of the duodenal perfusates caused a dose-related increase in pancreatic trypsin and chymotrypsin outputs without affecting basal plasma CCK levels (0.9 +/- 0.1 pM). The volume- or osmolality-stimulated pancreatic secretions were abolished by atropine, but not by intraduodenal perfusion of trypsin. In contrast, intraduodenal perfusion of phenylalanine (10 mM) produced a significant increase in plasma CCK levels (6.7 +/- 0.8 pM) and a three- to fourfold increase in pancreatic enzyme outputs. Perfusion of the duodenum with bovine trypsin (1 g/L) reduced the plasma CCK levels to basal values and significantly attenuated the phenylalanine-stimulated enzyme secretion to 63% +/- 4% of control. Simultaneous administration of atropine and intraduodenal perfusion of trypsin completely abolished the pancreatic enzyme response to phenylalanine stimulation. These studies indicate that the intestinal phase of human pancreatic enzyme secretion is under both hormonal and neural control. Intraduodenal trypsin inhibits only pancreatic secretion mediated by CCK release, and not that mediated by cholinergic mechanisms. These observations suggest that feedback regulation of pancreatic enzyme secretion is stimulus specific.     

Effect of diversion and replacement of bile on pancreatic secretion

Pancreatic bicarbonate and protein outputs have been studies under basal conditions and in response to a variety of endogenous and exogenous stimuli in conscious dogs with biliary and pancreatic fistulas and with bile diverted and then replaced into the intestine. Infusion of bile into the duodenum and jejunum but not the ileum caused a marked increase in pancreatic protein secretion, and to a lesser degree in bicarbonate output, only in tests performed under basal conditions. Pancreatic dose-response curves to intravenous secretin and caerulein, to intraduodenal hydrochloric acid and amino acids, or to feeding liver meal were not significantly altered by the diversion and subsequent replacement of bile into the duodenum. It is suggested that the release of cholecystokinin or neuroreflex stimulation of pancreas by the bile in the intestine may explain the bile stimulation of pancreatic secretion observed.