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.     

Pancreatic secretory response to ordinary meals: studies with pure pancreatic juice

We have studied the pancreatic secretory response to a normal meal in 5 subjects with an external drainage of the main pancreatic duct carried out after biliary tract surgery. Pancreatic juice was collected at 60-min intervals from 10 AM to 7 PM, starting 2 h before and ending 7 h after lunch, and was analyzed for volume, bicarbonate content, and protein content. Large doses of pancreatic extract were given between and during meals. Both bicarbonate and protein output increased rapidly after the beginning of the meal and the increase persisted, with minor fluctuations, for the entire 7-h study period between lunch and dinner. The peak postprandial bicarbonate and protein outputs were higher (on average by 20% and 26%, respectively) than bicarbonate and protein outputs induced by exogenous infusion of submaximal doses of secretin and cerulein. The profile and magnitude of the bicarbonate secretory pattern elicited by food were not substantially different from those of protein secretion. In an additional patient who had undergone a duodenocephalopancreatectomy plus two-thirds distal gastrectomy before the study, the pancreatic response to meals showed an initial phase characterized by an increase in pancreatic secretion during the first postprandial hour followed by a tendency to decrease in the subsequent 2 h, and a later phase (from the fourth postprandial hour to the end of the study) characterized by a more marked and more persistent increase in pancreatic secretion than occurred in the initial 3 h. These data indicate that (a) the pancreatic secretory response to ordinary meals is much more prolonged than is generally believed. The late phase of the response is not dependent on gastric emptying of food into the duodenum, but is probably related to the arrival of chyme in the distal ileum. (b) The pancreatic secretory response to a normal meal is quantitatively slightly higher than that produced by exogenous pancreatic stimulation with submaximal doses of secretin and cerulein. (c) The pattern of postprandial bicarbonate secretion is similar to that for protein.     

Gastric secretion and emptying after ordinary meals in duodenal ulcer.

We have studied the gastric response to an ordinary solid-liquid meal in 12 patients with active duodenal ulcer and 8 healthy volunteers. Our method employs gastric and duodenal markers to quantify acid, pepsin, and volume outputs in response to the meal, without manipulating intragastric pH. Intragastric volume, rate of gastric emptying, delivery of acid into the duodenum, and serum gastrin response were also measured simultaneously. On a separate day, peak acid output in response to betazole (1.5 mg per kg subcutaneously) was determined. Our results indicate an inappropriately prolonged gastric secretory response to meals in duodenal ulcer disease, without a concomitant increase in peak postprandial secretory rates or an increase in serum immunoreactive gastrin levels. Further, the stomach in duodenal ulcer disease did not "retain" the additional acid secreted in the later postprandial period, and abnormally high rates of acid delivery into the duodenum occurred. Our data are consistent with a dual defect in the duodenal mechanisms regulating both acid secretion and acid delivery into the duodenum.     

Antroduodenal motor response to solid-liquid and homogenized meals.

The effect of the physical state of food on antroduodenal motor activity and the pattern of the emptying of an aqueous phase marker were examined in 6 healthy volunteers using an intestinal perfusion technique and intraluminal pressure transducers. Ingestion of a solid-liquid meal produced marked phasic changes in pressure in the distal antrum, lasting 92 +/- 10 min (mean +/- SE), while, in contrast, ingestion of the same nutrients in a homogenized state resulted in complete absence of distal antral changes in pressure lasting 133 +/- 12 min. The motor responses of the proximal antrum and duodenum were similar for the two meals. Both meals emptied during a 3-hr period, the pattern of emptying of the aqueous phase marker being similar for the two meals except for the first 40 min, when emptying was more rapid after the solid-liquid meal. The homogenized meal emptied despite the absence of changes in distal antral pressure. The gastrin response was similar for the two meals and is therefore not responsible for the different patterns of antral motility and gastric emptying.     

Measurement of gastric functions during digestion of ordinary solid meals in man.

A method of measuring gastric secretions and emptying rates after ingestion of an ordinary (solid-liquid) meal has been developed and validated. The technique quantifies movements of volume across the pylorus using constant duodenal perfusion with a nonabsorbable marker, polyethylene glycol (PEG), which, in turn, quantifies emptying into the duodenum of another marker, [14C]PEG, incorporated in the meal. Acid and pepsin outputs can be determined without manipulation of the intragastric pH. Employing this method, we have simultaneously quantified acid, pepsin, and total secretory outputs; rates of gastric emptying of meal and secretions; and serum gastrin levels during digestion. These data characterize physiological responses to ordinary food in health.     

The effect of acute hyperglycemia on meal-stimulated gastric, biliary, and pancreatic secretion, and serum gastrin.

The effects of hyperglycemia on pancreatic, biliary, and gastric secretory responses to meals have not been hitherto quantified in man. In the present study seven normal volunteers were fed on two occasions a 500-ml liquid test meal containing fat and protein. During one of the meals the subjects were made acutely hyperglycemic with intravenous glucose, whereas in control experiments, each subject received intravenous saline in place of glucose. A jejunal perfusion method was used to measure pancreatic outputs of trypsin and biliary outputs of bile salts for 150 min after the meal; the same method was used to quantify indirectly the amount of acid secreted by the stomach in the 150-min period. Serum gastrins were also measured basally and at intervals after the meal. Hyperglycemia suppressed serum gastrin, gastric acid production, trypsin secretion, and bile salt output in response to the test meal.     

Role of cholecystokinin in the regulation of gastric emptying and pancreatic enzyme secretion in humans. Studies with the cholecystokinin-receptor antagonist loxiglumide

The role of cholecystokinin (CCK) in the regulation of gastric emptying and pancreatic enzyme secretion was evaluated by infusing the CCK-receptor antagonist loxiglumide. Gastric emptying rates and pancreatic secretory outputs were measured in five healthy volunteers by the double-indicator perfusion technique using a multiple-lumen tube in the duodenum. Placebo or loxiglumide (22 mumol.kg-1.h-1) was infused throughout each experiment. Five hundred-milliliter liquid intragastric meals of (a) fat, protein, and glucose (Ensure; Abbott, Chicago, IL); (b) glucose, 20 g/dL; and (c) guar gum, 1.1 g/dL, were given in random order. In addition, the effect of a physiologic CCK-8 dose (20 pmol.kg-1.h-1) after an intragastric 500-mL saline meal (0.154 mol/L) was tested. Intravenous CCK-8 induced a marked retardation of the gastric emptying rate of the saline solution (P less than 0.05) while stimulating pancreatic secretory outputs; both effects were completely abolished by the infusion of loxiglumide. Loxiglumide markedly accelerated the gastric emptying rates (by approximately 40%) and simultaneously diminished lipase (by approximately 75%) and trypsin (by approximately 50%) outputs of both the mixed meal (P less than 0.01) and the pure glucose meal (P less than 0.05). Additional experiments using gamma camera scintigraphy confirmed the accelerating effect of loxiglumide on gastric emptying of the mixed meal (P less than 0.01). The gastric emptying rate of the guar meal, which did not release CCK, was not influenced by the infusion of loxiglumide. Loxiglumide distinctly augmented plasma CCK levels after the mixed (2.6 times) and the pure glucose (2.1 times) meals while markedly reducing (approximately 76%) pancreatic polypeptide release (P less than 0.02). It is concluded that endogeneous CCK exerts a major role in the regulation of both gastric liquid emptying and pancreatic secretion in humans.     

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.     

Effects of nutrients on gastrointestinal motility and gastric emptying after Billroth-I gastrectomy in dogs

We wanted to clarify the way in which nutrients influence gastrointestinal motility and gastric emptying following distal gastrectomy with Billroth-I gastroduodenostomy. Four gastrectomized dogs were equipped with extraluminal strain gauge transducers. Gastric emptying was measured radiographically. Four intact dogs were used as controls for emptying studies. Following gastrectomy, gastric emptying of both acaloric and nutrient meals was rapid in the initial period of the experiments. Gastric outflow was supported by propagating duodenal contractions. Compared with control dogs, the early emptying of nutrient meals was accelerated. In the following period, nutrients markedly slowed gastric emptying compared with acaloric meals due to a segmenting contractile pattern of the duodenum and a significant diminution of gastrointestinal motility. Results suggest that after Billroth-I gastrectomy (1) the control of gastric emptying by nutrients acts too late to slow the initial enhanced gastric outflow, and (2) the duodenal contractile patterns influence gastric emptying.The study was supported by the Deutsche Forschungsgemeinschaft, grant Eh 64/3-1.     

Effects of cholecystokinin receptor blockade on circulating concentrations of glucose, insulin, C-peptide, and pancreatic polypeptide after various meals in healthy human volunteers.

This study used a cholecystokinin (CCK) antagonist to evaluate whether CCK that is released after regular meals regulates meal-stimulated insulin secretion. Several experiments were performed in eight to 10 healthy male volunteers, each in duplicate. The subjects received different meals either with or with i.v. infusion of 5 mg/kg/h of the CCK antagonist loxiglumide (Rotta, Italy). The mixed solid-liquid meals of 600, 800, or 1,000 kcal consisting of regular German food were given orally. In addition, studies were carried out in which a liquid test meal of 750 kcal was infused into the duodenum over a 2-hour period to exclude effects of the CCK antagonist on gastric emptying. Finally, the subjects received an oral load of 100 g glucose either with or without i.v. infusion of loxiglumide. Loxiglumide at the dose used completely abolishes the actions of endogenous CCK and of exogenous CCK when given at doses that mimic postprandial circulating concentrations of this peptide at various target organs such as gallbladder, pancreas, stomach, and intestine. Loxiglumide also markedly reduced the increase in pancreatic polypeptide seen after the intraduodenal infusion of nutrients. However, loxiglumide at this dose did not alter the increase in circulating concentrations of glucose, insulin, and C-peptide after any of the various oral meals, after the intraduodenal administration of nutrients, and after the oral load of glucose. Although the present study does not rule out that in some conditions CCK may increase insulin secretion in humans, the results do rule out that CCK acts as a major physiologic incretin in healthy humans.     

Rapid gastric emptying, rather than delayed gastric emptying, might provoke functional dyspepsia

It has been suggested that there could be three possible mechanisms of gastric dysfunction in patients with FD: (i) delayed gastric emptying, (ii) impaired gastric accommodation of food intake, and (iii) hypersensitivity to gastric distention. Postprandial fullness seems to be the most severe symptom in patients who report aggravation of their symptoms after meals. Therefore, it has been assumed that delayed gastric emptying and consequent prolonged antral distension could reduce hunger, increase satiety, and even cause gastric discomfort, all of which would pose a significant barrier to adequate nutrition. We previously reported that postprandial water intake inhibits gastric antral motility along with an increase of cholecystokinin (CCK) in normal subjects. We assumed that the rapid increase of CCK after water intake was initiated by a feedback mechanism related to the inflow of fatty chyme into the duodenum that inhibits gastric antral activity. This duodeno-gastric interaction is known as the "duodenal break." We also reported that total gastric emptying was more rapid after the intake of a high-viscosity liquid meal than after a low-viscosity meal, because the low-viscosity liquid meal inhibits gastric emptying after rapid initial inflow into the duodenum. Considering these results, we hypothesized that rapid gastric emptying, rather than delayed gastric emptying, could be a cause of FD. In some patients with postprandial distress syndrome (PDS), we have found a significant correspondence between PDS-related dyspepsia and accelerated gastric emptying in the early postprandial period. It is worth emphasizing that the duodenum and the duodeno-gastric interaction (duodenal break) could have an important role in the pathophysiology of FD. We consider that rapid gastric emptying might be a more important factor than delayed gastric emptying in patients with FD.     

Gastric emptying and pancreatic polypeptide response to carbohydrate meals

This study examined pancreatic polypeptide responses to isocaloric meals of radioactively labeled glucose or starch in six normal and seven vagotomized subjects. Liquid glucose meals were ingested with the subject both erect and supine and starch meals were ingested in the upright posture as a solution and as solid balls. In normal subjects, each meal left the stomach at a similar rate and the resultant pancreatic polypeptide responses were not significantly different from one another. Emptying rates varied markedly in vagotomized subjects depending upon the physical consistency of the carbohydrate ingested and the patient's posture. Despite these differences, pancreatic polypeptide responses to each meal were almost identical. These studies demonstrate that the pancreatic polypeptide response to carbohydrate meals is still present several years after vagotomy and is unaffected by alterations in the rate of gastric emptying after vagotomy and by the physical consistency and chemical nature of the carbohydrate ingested.     

The gastric response to a transpyloric duodenal tube.

The quantification of gastric, pancreatic, biliary, and small bowel functions in man often requires the use of intestinal tubes. In this study, the presence of a transpyloric tube did not alter gastric emptying, acid secretion, or serum gastrin levels in response to an ordinary solid meal.     

Effect of ethanol upon gastric emptying.

The effect of ethanol upon gastric emptying in healthy human subjects was studied by measuring the gastric emptying rates of three 750 ml meals, the osmolalities, energy densities, and pH of which were similar. Meal A, which contained 80 ml alcohol, emptied more rapidly than meal B, which contained 40 ml ethanol and 63.3 g dextrose; and meal B emptied more rapidly than meal C, which contained 126.6 g dextrose but no ethanol. The slower rate of emptying of the dextrose meal (C) was not due to an increased gastric secretory rate, as serial measurements of gastric pH were substantially and significantly higher with this than with the other two meals; nor was it due to a greater degree of duodenogastric reflux, as serial measurements of gastric bile acid concentrations were similar for the three meals. We conclude that the duodenal osmoreceptor mechanism is relatively insensitive to ethanol; that the relationship between energy density and gastric emptying rate does not hold in the case of ethanol; and that the gastro-oesophageal reflux which occurs in response to ethanol is not due to impairment of gastric emptying.     

Gastric, pancreatic, and biliary responses to meals in hyperthyroidism.

Upper gastrointestinal function in response to a mixed nutrient meal was evaluated in hyperthyroid patients, both before and after therapy, and in healthy controls. Gastric secretion, gastric emptying, and pancreatic secretion were all normal and normally integrated postprandially in the hyperthyroid patients. Bile acid output was reduced (P less than 0.05) in this group of patients relative to healthy controls. Duodenal bile acid concentrations, however, were above the critical micellar concentration in most of the hyperthyroid patients, and the bile acid output and concentration remained unchanged in all patients three months after treatment. After radioactive iodine therapy, when gastrointestinal symptoms were returning toward normal, a small but statistically significant increase in gastric secretion was observed. However, gastric emptying and pancreatic secretion, like biliary secretion, remained unchanged. Abnormalities responsible for the diarrhoea and steatorrhoea in hyperthyroidism appear to reside primarily distal to the duodenum. However, reduced bile acid output may be a contributory factor in some patients.     

Postprandial gastric function in pancreatic insufficiency.

Abnormalities in postprandial gastric function could contribute to the maldigestion of pancreatic insufficiency. To measure simultaneously postprandial gastric secretion and emptying and correlate these measurements with intraluminal duodenal changes, we performed intestinal intubation and duodenal perfusion during feeding of a solid-liquid test meal in 10 healthy controls and 10 patients with documented pancreatic insufficiency before and after replacement therapy. In pancreatic insufficiency, intraduodenal pH was significantly decreased late in the postprandial period while simultaneously measured duodenal acid loads were normal, confirming that reduced bicarbonate output rather than increased acid delivery was responsible for higher duodenal acidity in these patients. Significant (P less than 0.05) reductions in postprandial acid, pepsin, and total secretory outputs were noted in untreated patients only during the first postprandial hour. Absolute gastric emptying rates were lower in patients (P less than 0.05) than in healthy subjects, but fractional rates of emptying were similar. Fasting and postprandial hypergastrinaemia were consistently observed in the patients with pancreatic disease. There are postprandial disturbances of secretory function but no primary gastric motor defect in patients with exocrine pancreatic insufficiency.     

Applicability of CCK receptor antagonists in physiologic and therapeutic studies]

The development of potent and specific CCK-receptor antagonists made it possible to evaluate the physiological role of CCK for various gastrointestinal functions. The results of these studies show that CCK is the hormone which principally mediates meal-induced gallbladder emptying. In addition, CCK appears to play an important role in maintaining the fasting muscular tone of the gallbladder. In contrast, CCK-antagonists could inhibit only about 50% of the meal-stimulated pancreatic exocrine secretion. Because of their marked relaxing effect on the gallbladder, CCK-antagonists might become an important clinical tool for treatment of gallbladder spasms and colics. On the other hand, long-term application of CCK-antagonists will increase the risk of stone formation in the gallbladder. CCK-antagonists also had beneficial effects in some animal models of acute pancreatitis. As yet, it is unclear whether CCK-antagonists might become useful for the treatment of human pancreatitis. Since CCK-antagonists only slightly inhibited pancreatic growth, it is unlikely that they will exert major inhibitory effects against growth of pancreatic carcinoma. CCK-antagonists failed to alter gastric emptying of a normal mixed solid-liquid meal, but accelerated gastric emptying of purely liquid meals. Thus, CCK-antagonists are not likely to become useful agents to treat alterations of gastric emptying. The studies with CCK-antagonists further showed that CCK plays only a minor role in the regulation of the motility of the small and large intestine. CCK is probably not involved in the regulation of the gastrocolonic response after a meal. Some reports indicate that CCK-antagonists might increase colonic transit and might therefore be useful to treat constipation.     

Gastric emptying of oil from solid and liquid meals

Digestion of fat in pancreatic insufficiency (PI) is strongly affected by how rapidly fat enters the duodenum. We postulated that: (1) oil empties faster in PI than in normals and (2) in both, it empties in a load-dependent fashion. We used a gamma camera to test these ideas by comparing gastric emptying of iodine-123 iodinated oil in normal and pancreatic-insufficient subjects after 15 g of free oil were ingested in a small spaghetti meal and 60 g of oil were ingested in a large spaghetti meal and in a milk emulsion. Indium-113m marked gastric emptying of water in the milk. In both groups after all meals, oil emptied fastest initially, slowing later; and oil emptied three to four times faster when 60 g vs 15 g were ingested. There were no significant differences between the groups of subjects with respect to gastric emptying of the spaghetti meals, but the pancreatic-insufficient subjects emptied both oil and water faster from the milk emulsion than did the normal subjects. The slower emptying of oil in the normal subjects was associated with significantly more layering of oil to the top of the intragastric milk emulsion.     

Effect of first part of duodenum on gastric emptying in dogs: response to acid, fat, glucose, and neural blockade.

Five dogs were prepared, each with a gastric and duodenal fistula (5 cm distal to the pylorus), to study the inhibitory role of the first 5 cm of the duodenum on gastric emptying. The basic design of the experiments was to instill the test meal (300 ml at 37 degrees C, containing phenol red 40 mg 1(-1)) into the stomach and collect it at 1- or 2-min intervals for 10 or 20 min from the duodenal fistula. As the test meal emptied from the stomach it bathed the first 5 cm of duodenum and thus stimulated the appropriate receptor. A Foley catheter with an inflated balloon prevented passage into the second part of the duodenum. Test meals of hypertonic glucose (15%, 865 milliosmoles kg-1) or 20 and 80 mM of sodium oleate emptied at the same rate as water when allowed to bathe the first 5 cm of duodenum, whereas test meals of 100 mM of HCl were slowed. In further studies using neural blocking agents, the emptying of water meals was slowed with subcutaneous atropine sulfate (0.03 and 0.15 mg kg-1), intravenous hexamethonium chloride (10 mg kg-1), and norepinephrine bitartrate (0.04 mg kg-1). The emptying of 100 to 120 mM HCl meals was slowed by subcutaneous atropine sulfate (0.03 and 0.15 mg kg-1), intravenous norepinephrine bitartrate (0.04 mg kg-1), and the intravenous alpha-receptor blocking agents phenoxybenzamine HCl (2 mg kg-1) and phentolamine (2 mg kg-1), was unaffected by intravenous hexamethonium chloide (10 mg kg-1), and was unchanged (1.0 mg kg-1) or slightly slowed (2.0 mg kg-1) by the beta-receptor blocker propranolol. In contrast, acid test meals were emptied at the same rate as water when treated with intravenous guanethidine monosulfate (2 mg kg-1) or intramuscular reserpine (1 mg kg-1), indicating that the acid inhibition was mediated by an adrenergic mechanism. The emptying of water meals was unchanged by these two drugs. The authors suggest that the first 5 cm of duodenum contain receptors for inhibition of emptying of acid but not for fat or hypertonic glucose. Furthermore, the neural blocking studies indicate that the inhibitory effect of acid in the first part of the duodenum is an adrenergic mechanism which appears to be neither alpha nor beta-receptor-mediated.     

Gastric emptying after roux-y and billroth-I gastrectomy depends on viscosity of meal and contractile patterns of small intestine in dogs

The aim of the study was to examine gastrointestinal motility after distal gastrectomy and the influence of meal viscosity on gastric emptying. Gastrointestinal motility and gastric emptying of acaloric meals with different viscosities were measured in normal dogs and after a two-thirds gastrectomy with Billroth-I or Roux-Y gastroenterostomy. After distal gastrectomy, gastric emptying depended on the viscosity of the meal, as in normal dogs. Acaloric viscous meals emptied significantly faster in the Billroth-I than in the Roux-Y group due to different contractile patterns of the duodenum and jejunum. In comparison to normal dogs, gastric emptying of viscous meals was accelerated in the Billroth-I and delayed in the Roux-Y group. Several motility parameters of the stomach and intestine differed between the normal and gastrectomized dogs. Thus, after distal gastrectomy, the viscosity of the meal and the contractile patterns of the small intestine are important determinants of gastric emptying.Studies were supported by the Deutsche Forschungsgemeinschaft, grant Eh 64/3-1.