Pancreatic exocrine secretion and plasma gut hormones response after intraduodenal infusion of elemental diet in patients with chronic pancreatitis

We studied the responses of pancreatic polypeptide (PP) and cholecystokinin (CCK) using specific RIAs, and simultaneously exocrine pancreatic secretion and gall bladder contraction were checked by using triple lumen tube to intraduodenal ingestion of 100 Kcal/hr semi-digested liquid meal: Clinimeal (Eisai, Tokyo) or Elemental Diet: ED (Morishita, Osaka) in 10 patients with chronic pancreatitis (CP). Intraduodenal infusion of Clinimeal did not result in a significant physiological rise of CCK and PP from the basal values. Pancreatic secretions (volume and bicarbonate output) were slightly increased paralleled to the gall bladder contraction in chronic pancreatitis. On the other hand, intraduodenal ED can significantly stimulate the release of CCK from the small intestine and PP from the pancreas with the near range of physiological concentration. This level of CCK can evoke a significant increase in pancreatic secretion and gall bladder contraction. These results suggest that in CP the physiological regulation was disturbed and pancreatic secretion was not observed after ordinary meal ingestion. Infusion of ED which contained similar components of digestive product partially improved the responses of gut hormones and pancreatic secretion. Therefore, impaired gut hormone release in CP primarily is due to the inappropriate stimuli because of pancreatic exocrine dysfunction, and not other factors(s).     

Effect of pancreatico-biliary diversion on endogenous CCK secretion, pancreatic enzyme synthesis, and amylase release]

Pancreatico-biliary diversion (PBD) by jejunal transposition in rats caused pronounced hyperplasia of pancreas. The increase of pancreatic trypsinogen contents exceeded the pancreatic growth, while pancreatic lipase and amylase contents relatively reduced. The high level of plasma CCK at the early period of PBD gradually decreased. The plasma secretin levels remained unchanged for 14 days after PBD. The plasma CCK levels were not elevated in fasting, but increased after intrajejunal infusion of 0.1 N HCl or Clinimeal. In acini prepared from PBD rats, the responsiveness to CCK8 was decreased when amylase release was expressed relative to DNA. The dose-response curve for CCK8 was shifted 3 fold toward higher concentrations of CCK8 4 days after PBD, but on 7 and 14 days after PBD returned to the same curve as the transected rats (control).     

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

Duodenal calcium outputs in health and pancreatic disease.

To investigate the relationship between the duodenal outputs of calcium and diseases of the pancreas, we measured calcium secretion into the duodenum (during saline perfusion and after stimulation with an intravenous infusion of cholecystokinin (CCK) or secretin) in healthy controls, patients with chronic alcoholic or idiopathic pancreatitis, and patients with pancreatic cancer. The effects of acute and chronic hypercalcaemia and previous cholecystectomy were also studied. Our results indicate a characteristic increase in duodenal calcium outputs in response to CCK in chronic pancreatitis which is unaffected by the level of serum calcium, aetiology of the pancreatitis, previous cholecystectomy, and the presence or absence of radiological pancreatic calcifications. Although unproven, indirect observations support a pancreatic source for the increased calcium secretion. As we measured the outputs of calcium into the duodenum, previously described increases in calcium concentration are not merely a reflection of reduced volume secretion in chronic pancreatitis. Duodenal calcium outputs were significantly reduced in patients with cancer of the pancreas.     

Cholecystokinin secretion in patients with chronic pancreatitis and after different types of pancreatic surgery.

Cholecystokinin (CCK) secretion may be affected in patients with chronic pancreatitis (CP), but little is known on the effect of pancreatic surgery on CCK secretion. We measured CCK secretion (radioimmunoassay, RIA) in response to bombesin infusion (100 ng/kg/20 min) for 120 min to test CCK secretory capacity, to ingestion of a liquid diet (400 kcal) for 120 min, and in response to a solid fat-rich meal (500 kcal) for 120 min. These studies were performed in 45 patients with CP (25 with exocrine insufficiency), 15 patients after duodenum-preserving pancreatic head resection (DPRHP), 18 patients after the Whipple operation, 12 patients after distal pancreatectomy (DP), and 35 control subjects. In CP patients, the CCK secretory capacity was preserved, but the postprandial CCK response was reduced, depending on meal composition and the presence of exocrine insufficiency. In patients after Whipple's operation, CCK secretory capacity and postprandial CCK secretion were significantly (p < 0.05) reduced. In patients after DPRHP, CCK secretory capacity was not affected, but the postprandial CCK response was significantly (p < 0.05) reduced, depending on meal composition and the presence of exocrine insufficiency. In patients after DPRHP, fasting plasma CCK levels were significantly (p < 0.01) increased, pointing to the absence of feedback inhibition on CCK secretion by intraluminal enzymes. After DP, the CCK secretory capacity was not affected. In conclusion: alterations in CCK secretion are observed in patients with chronic pancreatitis and after pancreatic surgery. These alterations are related not only to the disease process (exocrine insufficiency) but also to the type of surgery and type of stimulus.     

Inhibition of Cholecystokinin-Stimulated Pancreaticobiliary Output in Man by the Cholecystokinin Receptor Antagonist MK-329

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) Cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with ⁵¹Cr-ethylenediaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 ± 0.2 pM to levels similar to those observed postprandially, averaging 9.2 ± 1.3pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 ± 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p < 0.01), 89% (NS), and 75% (p < 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p < 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

Neurotensin and the exocrine pancreas

It has been postulated that neurotensin (NT) has a physiological role in the regulation of the exocrine pancreas, but this is controversial. Using the Thomas cannula canine model, the effect of intravenous NT, in physiological and pharmacological doses on exocrine pancreatic secretion, and on plasma pancreatic polypeptide, secretin and cholecystokinin (CCK) levels is reported. The infusion of physiological doses of NT alone (0.2 pmol/kg per min) did not stimulate pancreatic secretion; however, in conjunction with secretin, NT stimulated protein and bicarbonate output, the latter synergistically. Higher doses of NT (20 and 100 pmol/kg per min) resulted in a dose-dependent stimulation of pancreatic volume, bicarbonate and protein secretion. Cholinergic blockade with atropine reduced pancreatic secretion stimulated by low doses of NT (2–20 pmol/kg per min), but at higher doses (100 pmol/kg per min) protein secretion was reduced whilst bicarbonate secretion was enhanced. The infusion of graded doses of NT had no effect on plasma secretin or CCK levels. In contrast, NT did release pancreatic polypeptide in a dose-dependent manner, but only at pharmacological infusion levels. NT, acting synergistically with other hormones, may thus play a role in exocrine pancreatic stimulation.     

Effects of porcine pancreastatin on postprandial pancreatic exocrine secretion and endocrine functions in the conscious rat

The inhibitory effect of a newly discovered polypeptide, pancreastatin, on postprandial pancreatic exocrine secretions and endocrine functions was examined in the conscious rat with a chronic external bile, pancreatic and gastric fistula. The infusion of 100 and 200 pmol/kg/h of pancreastatin significantly inhibited meal-stimulated pancreatic secretion of fluid and protein but not bicarbonate in a dose-dependent manner. The infusion of 100 and 200 pmol/kg/h of pancreastatin increased plasma pancreastatin concentrations (mean +/- SE) up to 133.5 +/- 15.9 and 209.8 +/- 14.5 pM, respectively. However, the same doses of pancreastatin failed to inhibit postprandial insulin and gastrin releases and did not affect blood glucose levels. It is suggested that pancreastatin may be an inhibitor of postprandial pancreatic exocrine secretion. However, the doses used in the present study may not have been high enough to affect endocrine functions.     

Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.Dr. Staples was a USC Medical Student during this protocol.     

Effect of pancreastatin on insulin secretion and the exocrine pancreas in rats]

Pancreastatin, a 49-amino-acid C-terminal amidated peptide, was isolated from porcine pancreas in 1986. It has been reported to inhibit insulin release and exocrine pancreatic secretion, but both these effects have been disputed. In the isolated perfused rat pancreas we therefore studied the effect of pancreastatin on insulin and exocrine pancreatic secretion. Neither basal exocrine pancreatic secretion, nor exocrine secretion stimulated by CCK-8, bombesin or secretin were affected by pancreastatin. 20 or 200 pM pancreastatin, however, significantly inhibited stimulated insulin release. We conclude that pancreastatin seems to be yet another inhibitory peptide, which--for unknown reasons--inhibits insulin release both in vivo and in vitro, but exocrine pancreatic secretion only in vivo.     

Advances in nutritional management of chronic pancreatitis

Nutrition has an important role in the management of chronic pancreatitis (CP), with two main goals for treatment of patients. The first goal is to provide optimal nutrition support and the second is to decrease pain by minimizing stimulation of the exocrine pancreas. Because cholecystokinin (CCK) stimulates secretion from the exocrine pancreas, one approach is to decrease CCK levels through modulation of diet. If postprandial pain is a limiting factor, alternative enteral therapies that minimally stimulate the pancreas may be beneficial. Nutritional counseling, antioxidants, and pancreatic enzymes may play a role in effective management of CP as well. In addition, because idiopathic CP is associated with cystic fibrosis gene mutations, therapies directed toward cystic fibrosis may also benefit these patients.     

Rapid endoscopic secretin stimulation test and discrimination of chronic pancreatitis and pancreatic cancer from disease controls.

BACKGROUND & AIMS: The cholecystokinin (CCK)/secretin pancreatic function tests to diagnose pancreatic exocrine insufficiency are time consuming and invasive. Our aim was to develop a rapid pancreatic function test performed during upper endoscopy that could discriminate between patients with normal from impaired exocrine pancreatic secretion. METHODS: We prospectively evaluated 412 patients for possible pancreatic diseases. During upper endoscopy, 1 CU/kg of secretin was given intravenously and duodenal juice (collected for 10 min) was assayed for concentrations of bicarbonate and lipolytic and trypsin activity. Final diagnosis was by histology, imaging, and a previously validated scoring system (for chronic pancreatitis). Of 412 patients, 117 patients had normal pancreas, 72 patients had chronic pancreatitis, and 116 patients had pancreatic adenocarcinoma. The remaining 107 patients had miscellaneous disease of the peripancreatic region. In 28 patients we also validated the secretin test with the standard CCK pancreatic function test. RESULTS: There was no difference between bicarbonate or trypsin concentrations among the groups. Lipolytic concentration was significantly lower in chronic pancreatitis (115 +/- 18) and in pancreatic adenocarcinoma (87 +/- 10) compared with patients with normal pancreas (229 +/- 23; P < 0.03 and P < 0.0001, respectively). The overall accuracy of the endoscopic secretin test was 79%, with positive and negative predictive values of 73% and 85%, respectively. The concentration of lipolytic activity obtained by the endoscopic secretin test in 28 patients correlated moderately well (r = 0.41, P < 0.03) with lipolytic output obtained by the CCK pancreatic function test. CONCLUSIONS: Lipolytic concentration in duodenal juice after intravenous secretin collected for 10 minutes during upper endoscopy was significantly lower in chronic pancreatitis and pancreatic adenocarcinoma compared with patients with normal pancreas, but was not accurate enough for routine clinical use.     

Chronic Alcohol-Induced Alterations in the Pancreatic Secretory Control Mechanisms

Chronic alcohol ingestion appears to increase susceptibility of the pancreas to pancreatitis through multiple mechanisms. The aim of the current study was to determine the effect of chronic low- and high-dose alcohol consumption on the neurohormonal control of the exocrine pancreas in rats. Male Wistar rats were fed Lieber DeCarli liquid control-, low-, and high-dose alcohol diets for 3 months. Pancreatic exocrine secretion was measured under basal and 2-deoxy-d-glucose (2-DG)-, CCK-, bethanechol-, or meal-stimulated conditions while on chronic alcohol diets and after 2-DG or CCK stimulation during alcohol withdrawal in awake rats. Chronic alcohol ingestion was associated with a dose-related inhibition of basal pancreatic protein secretion, which was reversed upon alcohol withdrawal. Low-dose alcohol feeding had no effect on bethanechol-stimulated pancreatic secretion but altered 2-DG-stimulated pancreatic secretion. In chronic high-dose alcohol rats, meal- and bethanechol-stimulated protein secretion was significantly potentiated during early and late phases. The response to CCK appeared to be disinhibited, whereas the response to 2-DG was uniformly blunted. Upon withdrawal of low-dose alcohol, the response to 2-DG was potentiated, whereas with the withdrawal of high-dose alcohol, the response to CCK was potentiated. Adaptation to chronic alcohol consumption differs depending on the alcohol dose. The most significant effects were seen after high-dose alcohol withdrawal, with apparent loss of central inhibitory regulation combined with exaggerated response at the acinar cell level. This combination of factors could increase susceptibility to acute alcoholic pancreatitis through a hyperstimulation mechanism.     

Somatostatin analog, SMS 201-995, inhibits pancreatic exocrine secretion and release of secretin and cholecystokinin in rats.

We studied the effect of a synthetic octapeptide somatostatin analog, SMS 201-995 (sandostatin), on pancreatic exocrine secretion and on plasma secretin and cholecystokinin (CCK) levels in vivo in anesthetized rats. The exocrine pancreas was stimulated by either intravenous infusion of both secretin (0.06 CU/kg/h) and cholecystokinin octapeptide (CCK-8) (0.03 micrograms/kg/h) or intraduodenal infusion of oleic acid (pH 6.5) in a dose of 0.25 mmol/h. Intravenous administration of SMS 201-995 in three different doses of 100, 200, and 400 ng/kg/h resulted in dose-related inhibition of pancreatic secretion in terms of volume, bicarbonate, and amylase stimulated by exogenous secretin and CCK. Intraduodenal oleic acid stimulated pancreatic secretion, including volume, bicarbonate, and amylase, and this was accompanied by a significant elevation in the plasma concentrations of secretin and CCK. Intravenous administration of SMS 201-995 in the three different doses described above caused dose-dependent suppression of the increase in pancreatic exocrine secretion as well as the plasma concentration of secretin and CCK induced by intraduodenal infusion of oleic acid. It is concluded that SMS 201-995 inhibits pancreatic exocrine secretion and the release of endogenous hormones, such as secretin and CCK, in rats.     

Effects of intragastric and intrajejunal ethanol administration on canine pancreatic exocrine secretion and duodenal pH

The effect of ethanol on pancreatic exocrine secretion and intraduodenal pH was investigated in 3 dogs, after making pancreatic, gastric, and jejunal fistula. After intragastric and intrajejunal administration of ethanol the intraduodenal pH went down and pancreatic juice, pancreatic bicarbonate output was increased. The integrated value of pancreatic juice, pancreatic bicarbonate and pancreatic protein output was greater in case of intrajejunal administration rather than intragastric administration of the ethanol. After intragastric and intrajejunal administration of the ethanol the plasma concentration of CCK was unchanged. The decrease of intraduodenal pH and increase of pancreatic exocrine secretion was though be mainly due to the secondary action of gastric acid secretion stimulated by ethanol.     

Plasma concentrations of neurotensin and CCK in patients with chronic pancreatitis with and without enzyme substitution.

The peptide hormones neurotensin (NT) and cholecystokinin (CCK) are commonly attributed with a physiological role in the stimulation of exocrine pancreatic secretion. However, on the other hand, little is known about the effect of diminished exocrine pancreatic function and of the resulting maldigestion on postprandial plasma levels of these two gastrointestinal peptides. We investigated, therefore, the effect of enzyme substitution therapy on the magnitude and time course of plasma concentrations of both hormones in patients suffering from severe chronic pancreatitis. Pancreatic insufficiency led to elevated NT-concentrations, in response to a standard meal, which could be reduced by enzyme replacement therapy. Prior to enzyme therapy, the mean integrated postprandial release of NT amounted to 2800 +/- 250 pg/ml after 60 min in patients with severe chronic pancreatitis. This amount was significantly reduced to 1250 +/- 150 pg/ml after 60 min after enzyme therapy, compared to 810 +/- 90 pg/ml after 60 min in healthy volunteers after the standard meal. The integrated postprandial CCK level in patients investigated was significantly lower (35 +/- 4.8 pmol/L after 60 min) without any substitution therapy, compared to the integrated peptide amount in healthy volunteers (145 +/- 13.5 pmol/L after 60 min). Enzyme therapy in patients suffering from chronic pancreatitis led to an increased postprandial CCK-level (80 +/- 9.6 pmol/L after 60 min). Elevated CCK-plasma concentrations have not been demonstrated in these patients with pancreatic insufficiency. We therefore suggest that CCK might not play a major role in feedback regulation in patients with chronic pancreatitis. However, in light of elevated NT plasma concentrations in patients with chronic pancreatitis, NT-mediated influence on the pancreas deserves further study.     

Pancreatic enzyme supplement improves dysmotility in chronic pancreatitis patients

BACKGROUND AND AIMS: Impaired gallbladder contraction and rapid gastric emptying in patients with chronic pancreatitis may be the result of depleted pancreatic exocrine function. The authors tested whether oral pancreatic enzymes can improve the dysmotility or not. METHODS: Study subjects consisted of 15 patients with chronic pancreatitis and 18 healthy controls. The gastric emptying time and gallbladder contraction were studied. All patients were initially studied using a test meal without pancreatic enzymes, followed on separate days by a test meal with a single and a triple dose of pancreatic enzymes. Blood samples were taken before and 2 h after the test meal to determine the pancreatic polypeptide levels. RESULTS: In patients with chronic pancreatitis, gallbladder contraction at 15 min after the meal was impaired. The gastric emptying time was faster and the ratio of pre- to postprandial pancreatic polypeptide levels was enhanced. A single dose and a triple dose of oral enzymes further improved the gastric emptying time and the pancreatic polypeptide ration, but did not improve the gallbladder contraction rate at 15 min. CONCLUSIONS: It was demonstrated that the oral pancreatic enzymes improved the gastric dysmotility, confirming the previous findings that suggested the depleted pancreatic enzyme output caused the dysmotility.     

Parotid salivary gland function in patients with exocrine pancreatic insufficiency

Parotid function tests were performed on 12 patients with pancreatic insufficiency due to chronic pancreatitis. The concentrations of sodium and bicarbonate in stimulated parotid juice were reduced compared to controls (p less than 0.001). The secretion of 75Se-selenomethionine by the parotid salivary gland and exocrine pancreas following a Lundh test meal was measured in 12 patients with normal pancreatic function and 16 patients with exocrine pancreatic insufficiency. Eight of these patients had chronic pancreatitis both parotid and pancreatic secretion of the isotope were impaired. In pancreatic carcinoma the pancreatic excretion was impaired with no significant impairment of parotid secretion. The combined pancreatic/parotid radio-selenium test may be useful in differentiating between chronic pancreatitis and pancreatic carcinoma as the cause of pancreatic insufficiency.     

Effects of cholecystokinin-receptor blockade on pancreatic and biliary function in healthy volunteers

This study used the specific cholecystokinin (CCK)-receptor antagonist loxiglumide to evaluate whether endogenous CCK, which is released after a meal, regulates pancreatic and biliary functions. Eight healthy volunteers were studied twice on separate days. The subjects received a continuous intraduodenal infusion of a 750-kcal liquid test meal for 2 hours either with or without IV infusion of 5 mg.kg-1.h-1 of loxiglumide. Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK. Loxiglumide markedly decreased the meal-stimulated outputs of amylase, trypsin, and chymotrypsin by 55%-70% of control values but only slightly decreased duodenal volume (25% inhibition of mean integrated secretion). Loxiglumide abolished gallbladder emptying induced by infusion of nutrients and even increased gallbladder volumes when compared with prior fasting values. Correspondingly, loxiglumide almost abolished the output of bilirubin after infusion of nutrients. However, loxiglumide failed to alter the increase in circulating concentrations of glucose, insulin, and C peptide after infusion of nutrients. The present results show that CCK is one of several factors that regulate pancreatic protein secretion after absorption of nutrients. However, CCK is probably not involved in regulation of pancreatic secretion of fluid. In contrast, gallbladder function is mainly regulated by CCK, both in terms of its emptying after intestinal absorption of nutrients and in terms of maintenance of its fasting volume. Cholecystokinin does not play a major physiological role as an insulinotropic factor.     

Integrated actions of cholecystokinin on the gastrointestinal tract: use of the cholecystokinin bioassay

This article has centered on the hormonal actions of CCK on a variety of different target tissues. Until the development of specific assays for measuring plasma levels of the hormone, it was not possible to distinguish physiologic from pharmacologic effects. However, by the methods described earlier it now has become clear that CCK, in physiologic concentrations, stimulates gallbladder contraction, delays gastric emptying, potentiates insulin secretion, and may affect satiety. Actions of CCK that have been studied by radioimmunoassay methods and determined also to be physiologic include stimulation of pancreatic exocrine secretion. Other actions of CCK that may be physiologic but have not been thoroughly investigated include effects on bowel motility, relaxation of lower esophageal sphincter pressure, regulation of sphincter of Oddi pressure, effects on analgesia, and modification of behavior. Some of these actions may be attributable to endogenous, but neurally released CCK and, therefore, would not be hormonal actions. However, continued investigations with specific CCK receptor antagonists together with accurate measurements of circulating levels of CCK should make it possible to define the physiologic importance of CCK on these other potential sites of action. The variety of CCK's physiologic effects emphasizes its integrative function on both digestive and metabolic processes. After a meal, in a highly coordinated fashion, CCK (1) regulates the movement of nutrients through the gastrointestinal tract, (2) contracts the gallbladder and stimulates pancreatic exocrine secretion to facilitate digestion, and (3) potentiates amino acid-induced insulin secretion and delays gastric emptying to maintain euglycemia. An effect to reduce food intake following food ingestion would be a logical extension of these integrated actions. Thus, CCK appears to have an essential role in regulating the intake, processing, and distribution of essential nutrients.