Pancreatic Polypeptide Concentrations Research Articles

Impaired pancreatic polypeptide response to a meal in type 1 diabetic patients: vagal neuropathy or islet cell dysfunction?

The pancreatic polypeptide (PP) response to a mixed meal was investigated in seven insulin-dependent diabetics without measurable signs of diabetic autonomic neuropathy, and in seven healthy subjects. Since acute changes in metabolic regulation might influence the meal-induced PP response, the insulin-dependent diabetic patients were studied during normo- and hyperglycemic experimental conditions at blood glucose levels of 5 and 15 mmol/l, respectively. The PP response was identical on the two occasions, the response being significantly smaller than in the healthy subjects. Thus, PP response is independent of short-term changes in metabolic control. Since the response was attenuated in the insulin-dependent diabetic patients, who had no otherwise measurable signs of neuropathy, the PP response to a meal could be a sensitive indicator of dysfunction of the reflex arc controlling PP secretion in insulin-dependent diabetic patients. Alternatively, the reduction in PP secretion in these patients reflects dysfunction of the PP secreting cells of the pancreas. Iv injection of cholecystokinin-8 elicited a small but significant increase in PP concentrations, while iv secretin did not increase PP concentrations at all in healthy subjects. These stimuli are therefore less suitable in the assessment of vagal neuropathy.

Cholinergic regulation of phase II interdigestive pancreatic secretion in humans.

Small fluctuations in cholinergic input may be involved in the regulation of human interdigestive pancreatic secretion. To determine the effects of small changes in cholinergic tone on phase II interdigestive trypsin secretion, we gave cholinergic agonists or antagonists to 17 healthy fasting subjects who underwent gastrointestinal intubation. Duodenal trypsin outputs, gastroduodenal motility, and plasma levels of pancreatic polypeptide (PP) as a marker of cholinergic tone were measured during intravenous infusion of bethanechol (0, 5, or 40 micrograms.kg-1.h-1) or atropine (0, 4, or 16 micrograms.kg-1.h-1) given during phase II alone or in combination based on a 3 x 3 factorial design. Data were evaluated by a response surface analysis of the average log values for the test period (using the average of log values of the control period as a covariate). Bethanechol increased trypsin output (p < 0.05) and plasma concentrations of PP (p < 0.05) within the ranges of spontaneous fluctuations of trypsin output and PP during phase II, but did not disrupt the periodicity of pancreatic secretion or the characteristic cyclical pattern of interdigestive motility and induction of phase III activity. Atropine markedly decreased trypsin output (p < 0.05) and plasma concentrations of PP (p < 0.05) and abolished the cycling of interdigestive pancreatic secretion and motor activity. These data suggest the hypothesis that cholinergic pathways participate in the control of interdigestive pancreatic secretion during phase II, while enzyme secretion during phase III may be regulated by other mechanisms.

Erythromycin effects on gastric emptying, antral motility and plasma motilin and pancreatic polypeptide concentrations in anorexia nervosa.

In primary anorexia nervosa, gastric motility is often impaired and ensuing symptoms further discourage eating. Prokinetic agents have been shown to accelerate gastric emptying in affected patients. This study investigated whether emptying of a radiolabelled semisolid 1168 kJ meal and antral contractility were enhanced by intravenous erythromycin. Eight women and two men with anorexia nervosa (21-46 years, 50-75% of ideal body weight) received 200 mg erythromycin or placebo under crossover double blind conditions. Gastric emptying and antral contractility were recorded scintigraphically for 90 minutes. In addition, plasma motilin and pancreatic polypeptide concentrations were determined. With placebo, antral contractions were of regular 3 cycles/minute frequency. With erythromycin, less frequent and partly arrhythmic long duration contractions set in and emptying was accelerated: after 90 minutes, the activity remaining in the stomach was markedly less than with placebo in all patients (Sign test, p < 0.002). Basal motilin and pancreatic polypeptide concentrations were normal and showed a normal response to the meal in all patients. Motilin concentrations decreased slightly more and pancreatic polypeptide concentrations increased markedly more with erythromycin than with placebo, possibly because the meal reached the intestine earlier. In conclusion, erythromycin accelerated emptying markedly and in most patients induced an antral motor activity characterised by long duration contractions occurring at often irregular intervals.

Effect of graded exercise on esophageal motility and gastroesophageal reflux in trained athletes

We evaluated the effect of graded exercise on esophageal motility and gastroesophageal reflux. We studied eight trained cyclists using a catheter with three strain-gauge transducers connected to a solid-state datalogger and an ambulatory intraesophageal pH monitor. Each study lasted 4 hr during which subjects exercised on a stationary bike for 1 hr at 60% of peak O2 uptake (O2 max), 45 min at 75% of O2 max, and for 10 min at 90% of O2 max. Subjects rested 1 hr before exercise (control period) and for 30 min between exercise sessions. Studies were performed after an overnight fast and subjects received only intravenous infusion of 5% glucose solution during the study. Plasma concentrations of gastrin, motilin, glucagon, pancreatic polypeptide (PP), and vasoactive intestinal peptide (VIP) were determined at rest and before and after each exercise session. The duration, amplitude, and frequency of esophageal contractions declined with increasing exercise intensity, and the differences were significant (P < or = 0.05) for all three variables at 90% O2 max. The number of gastroesophageal reflux episodes and the duration of esophageal acid exposure were significantly (P < or = 0.05) increased during exercise at 90% O2 max. Plasma hormone concentrations showed no significant changes between rest and the various exercise sessions. Thus, exercise has profound effects on esophageal contractions and gastroesophageal reflux which are intensity dependent. These effects are not mediated by the hormones measured.

Pancreatic secretion in chronic alcoholics. Effects of acute alcohol or wine on response to a meal.

To gain further insight on the effects of alcohol on human pancreatic enzyme secretion, we tested the effects of a 12% (v/v) alcohol solution, wine, and a glucose solution added to a meal on trypsin output in duodenal aspirate of nonalcoholic volunteers and compared the results to those of chronic alcoholics. Plasma concentrations of gastrin, cholecystokinin, and pancreatic polypeptide were monitored pre- and postprandially. Similar blood alcohol concentrations were determined in nonalcoholics and alcoholics following wine and the alcohol solution. Nonstimulated trypsin output (basal) was higher in alcoholics but not significantly so when compared to nonalcoholics. However postprandial trypsin output, 2014 +/- 301 mg/5 hr was significantly greater in alcoholics (P < 0.05) compared to nonalcoholics 1271 +/- 118 mg/5 hr. Alcohol and wine when added to the meal significantly (P < 0.05) inhibited trypsin output in both groups. Basal and postprandial levels of gastrin and cholecystokinin were similar in nonalcoholics and alcoholics. Basal plasma pancreatic polypeptide levels were similar in both groups, but the postprandial increments in pancreatic polypeptide levels observed in nonalcoholics were not observed in alcoholics. We conclude that chronic alcoholics have increased postprandial pancreatic enzyme secretion, and that this secretion, as that of nonalcoholics, can be affected by alcohol or wine. The postprandial hypersecretion of enzymes in alcoholics is not related to increased plasma levels of cholecystokinin or gastrin. It is possible that the impaired release of pancreatic polypeptide may participate in the mechanism for increased pancreatic enzyme secretion in chronic alcoholics.

Relationship of postprandial motilin, gastrin, and pancreatic polypeptide release to intestinal motility during vagal interruption.

Experiments were performed to determine how postprandial motilin, gastrin, and pancreatic polypeptide plasma concentrations measured during vagal blockade relate to coincident small intestinal motility patterns. Feeding produced a postprandial pattern of intestinal motility coincident with a sustained increase in gastrin and pancreatic polypeptide and a decline in motilin plasma concentrations. Vagal blockade replaced the fed pattern with one similar to migrating motor complex (MMC) activity. Highest motilin plasma concentrations were observed during phase III of this MMC-like activity, as occurs in the fasted state. Vagal blockade reduced but did not abolish the postprandial increase in plasma gastrin and pancreatic polypeptide concentrations. Termination of vagal cooling produced a decline in motilin and an elevation in gastrin and pancreatic polypeptide concentrations, coincident with the return of the fed pattern. In conclusion, during vagal blockade in the fed state (i) motilin, but not gastrin or pancreatic polypeptide plasma concentrations, fluctuate with the MMC-like activity, and any measurement of motilin concentration under these circumstances must be interpreted on the basis of gut motility patterns, and (ii) gastrin and pancreatic polypeptide concentrations are marginally elevated, but these changes are not enough to disrupt the MMC or have any motor effect. Lastly, the fed pattern and the postprandial changes in motilin, gastrin, and pancreatic polypeptide concentrations are in part dependent upon intact vagal pathways.

Gut regulatory peptides and intestinal permeability in acute infantile gastroenteritis.

The plasma concentrations of seven gut regulatory peptides were measured in 11 infants suffering from acute gastroenteritis. Samples were taken at the time of the acute illness, upon reintroduction of feeding, and three months after recovery. These results were compared with controls. In the infants with diarrhoea, a massive increase in the fasting plasma mean (SEM) concentrations of enteroglucagon was found at the time of illness (1292 (312) v 79 (27) pmol/l), with concentrations of pancreatic glucagon, peptide tyrosine tyrosine, and motilin also being increased (17.8 (3.1) v 6.3 (1.1) pmol/l, 114.6 (15.2) v 37.0 (11.0) pmol/l, 217.6 (44.1) v 98.5 (18.3 pmol/l) respectively). The preprandial concentrations of motilin were found to be still increased at recovery (183.9 (35.4) pmol/l), but the concentrations of the other three peptides had returned to normal values. No differences in plasma concentrations of vasoactive intestinal polypeptide, neurotensin, or pancreatic polypeptide were found. An increased intestinal permeability was demonstrated at the time of diarrhoea by the urinary ratio of lactulose to mannitol, suggesting simultaneous gut damage. The effects of regulatory peptides may be relevant to the pathophysiology of gastroenteritis in infants.

Interdigestive gastroduodenal motility and cycling of putative regulatory hormones in severe obesity.

The aim of the present study was to evaluate interdigestive gastrointestinal motility and its coordination with plasma concentrations of motilin and pancreatic polypeptide (PP) in 14 patients with severe obesity and in 10 control subjects with normal body weight. Motor activity of the stomach, duodenum, and proximal jejunum was recorded by using an eight-lumen catheter. Blood samples were drawn for determination of interdigestive motilin and PP plasma concentrations. We observed no difference in total duration of the migrating motor complex (MMC) or of phases I, II, or III of the MMC. Gastric phase-III activity occurred less frequently in severely obese patients (only 15% originating in the stomach) than in controls (65%; p less than 0.01). Plasma motilin concentrations were decreased in obese patients in phase I (127 +/- 17 pg/ml in controls versus 87 +/- 10 pg/ml in obese), in phase II (189 +/- 26 pg/ml controls versus 134 +/- 15 obese) and in phase III (195 +/- 29 pg/ml controls versus 153 +/- 28 pg/ml obese). Peak motilin release occurred in synchrony with phase-III activity and was greater in controls than in obese patients. Plasma PP concentrations did not differ from those of controls during any phase of the MMC. These results further suggest a potential role for motilin in regulating gastrointestinal motor activity and indicate a potential defect in this regulatory mechanism in severe obesity. Whether the relationship between disordered motor activity and motilin release is etiologic with regard to the pathophysiology of obesity remains to be determined.

Potential regulators of feeding behavior In anorexia nervosa

We recruited 10 patients with anorexia nervosa and 6 age- and height-matched control subjects. Basal and postprandial concentrations of glucose, insulin, cholesterol, amino acids, gastrin, and pancreatic polypeptide (PP) were measured in response to a standard mixed meal. The only satiety signal that was significantly different between the anorectic group and the control group was PP (P less than 0.001). Tryptophan-LNAA and tyrosine-LNAA ratios were not significantly different in the two groups; however, there was a trend toward a lower tryptophan-LNAA ratio in the anorectic group. Gastrin concentrations were significantly decreased in the anorectic group (P less than 0.001) as were basal insulin concentrations (P less than 0.05). Decreased gastrin concentrations may play a role in the gastric symptoms associated with anorexia nervosa. Previous findings that PP release is diminished in obesity, together with the present findings of PP increase in anorexia nervosa, suggest that this peptide may play a role in appetite control mechanisms.

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.

Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro‐entero‐pancreatic hormones in man Feedback control of cholecystokinin and gastrin secretion

The effect of the potent specific cholecystokinin (CCK) receptor antagonist loxiglumide on meal-stimulated plasma concentrations of CCK, gastrin, pancreatic polypeptide (PP), neurotensin, glucose-dependent insulinotropic polypeptide (GIP), insulin and C peptide was investigated in a placebo-controlled study in 10 healthy male volunteers. Intravenous infusion of loxiglumide (10 mg kg-1 h-1) significantly augmented integrated incremental IR-CCK levels 7.3-fold after stimulation by a standard breakfast (504 +/- 54 vs 3.665 +/- 365 pmol-1 135 min-1, P less than 0.001), as measured by a specific CCK radioimmunoassay. Basal IR-CCK concentrations were not affected by administration of loxiglumide. Oral treatment with bile acids (2 g ursodeoxycholic acid plus 2 g chenodeoxycholic acid) together with the meal abolished this augmentation, whereas high-dose substitution with pancreatic enzymes (4.2 g pancreatin) reduced elevated IR-CCK levels by only 38%. CCK-like bioactivity, determined by a bioassay using rat pancreatic acini, was not detectable in all samples that contained loxiglumide at plasma concentrations of 100-250 micrograms ml-1. Plasma gastrin concentrations in response to the breakfast were elevated 3.2-fold during loxiglumide infusion and not influenced by substitution with bile acids or pancreatic enzymes. Meal-stimulated integrated incremental plasma PP concentrations were significantly suppressed (55-65% inhibition, P less than 0.01) by loxiglumide. Infusion of the CCK receptor antagonist only slightly increased postprandial peak plasma glucose, insulin and C-peptide levels, whereas GIP and neurotensin levels were not significantly influenced. These findings suggest: (i) CCK secretion is under feedback control by intraduodenal bile acids and to a lesser extent by pancreatic enzymes; (ii) simultaneous extraction of CCK and loxiglumide results in circulating plasma CCK-like bioactivity of zero; (iii) gastrin secretion is feedback controlled via an indirect mechanism probably involving CCK-induced somatostatin secretion; (iv) release of PP is under inhibitory control of CCK; (v) CCK does not play a major role as insulinotropic hormone in the entero-insular axis in humans.

Effects of glucose on circulating and ileal intraluminal peptide YY and pancreatic polypeptide release

Peptide YY (PYY) and pancreatic polypeptide (PP) are related hormones released systemically after a meal. The effects of glucose stimulation and vagal involvement on circulating and ileal luminal PYY and PP concentrations were evaluated in awake dogs. An oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGT), 2-deoxyglucose bolus (2-DG), or atropine pretreatment prior to OGTT were administered to awake dogs with 25-cm ileal Thiry-Vella fistulas. Circulating and ileal intraluminal PYY and PP levels were measured by radioimmunoassay. No changes were noted in circulating PYY, and circulating PP increased (p < 0.05) only after administration of 2-DG. Ileal luminal PP recovery was minimal (less than 60 pg/mL) and was unchanged after all tests. Ileal luminal PYY recovery increased significantly after both OGTT and IVGT. Pretreatment with atropine abolished the luminal PYY response to OGTT, and 2-DG did not affect luminal PYY recovery. Blood glucose and insulin levels were similar in all groups. Peripheral cholinergic control of luminal PYY release is suggested by our findings, whereas a central mediation of circulatory PP release is supported by 2-DG stimulation.

Porcine diazepam-binding inhibitor is immunohistochemically colocalized with somatostatin in the D cells of human and porcine gastrointestinal tract and in pancreatic islet cells.

The cellular distribution of a novel porcine peptide, diazepam-binding inhibitor (DBI), was immunohistochemically mapped in the human and porcine gastrointestinal tract and pancreas. Using a rabbit antiserum, raised against porcine DBI, immunoreactive epithelial cells were found in the gastric antrum and duodenal mucosa and in the parenchymal cells of the islets of Langerhans of both species. The immunoreactivity could not be absorbed by high concentrations of insulin, somatostatin (SS-14, SS-28), glucagon, or pancreatic polypeptide but was abolished by porcine DBI. Using semithin, consecutive sections, the immunoreactive intestinal and islet cells were found to be identical to the somatostatin-producing D cells. Since it has been shown that porcine DBI interferes with the secretion of insulin, the peptide may act as a modulator of islet hormone release, possibly in a paracrine manner.

Intraluminal Heal Recovery of Pancreatic Polypeptide

Pancreatic polypeptide (PP) is a normal constituent of pancreatic islet cells. Enterocytes containing PP have been identified but incompletely characterized. We previously demonstrated independent intravascular and intraluminal release of two related peptides, peptide YY and neuropeptide Y. In this study, using ileal segments in conscious dogs, we evaluated the intravascular and ileal intraluminal presence of PP to test meals. Fasted plasma and recoverable ileal PP concentrations averaged 139 +/- 2 and 65 +/- 4 pg/mL, respectively. A mixed protein meal resulted in a sustained rise of circulating PP levels associated with a brief evaluation of ileal luminal PP levels. Fat meals were followed by elevations in plasma PP levels without luminal changes. Glucose ingestion altered neither plasma nor luminal PP levels. Our data support the existence of ileal PP-containing cells that respond independently of circulatory PP-releasing cells to different ingested stimuli.

Plasma Levels of Gastrointestinal Regulatory Peptides in Patients Receiving Maintenance Hemodialysis

The fasting plasma levels of 9 gastrointestinal regulatory peptides were measured by radioimmunoassay in 13 stable patients with chronic renal failure receiving hemodialysis treatment regularly and compared with those of 10 healthy controls. The plasma concentrations of gastrin-releasing peptide, motilin, neurotensin, pancreatic polypeptide, peptide YY, somatostatin, substance P, and vasoactive intestinal peptide were increased. The plasma level of gastrin was not statistically different from that of the controls (p = 0.077). We conclude that patients with chronic renal failure receiving hemodialysis treatment regularly have increased concentrations of eight of nine measured gastrointestinal regulatory peptides. The elevated levels of gastrointestinal peptides in patients with chronic renal failure may contribute to uremic gastrointestinal symptoms and dysfunctions. It is necessary to make a renal function evaluation before interpreting measured plasma levels of gastrointestinal regulatory peptides.

Effect of synthetic prostaglandin E1 analog (ornoprostil) on gastric emptying and pancreatic polypeptide release after solid-meal ingestion in man

The effect of orally administered ornoprostil, 17S,20-dimethyl-6-oxoprostaglandin E1 methyl ester, on gastric emptying and on pancreatic polypeptide (PP) release after solid meal ingestion, was investigated in man. A radionuclide technique was used to measure gastric emptying of eight healthy volunteers. In addition, four parameters [SI (starting index): the lag time in the start of emptying; K value: the emptying rate; T1/2: the half emptying time; 120 min RR: the percent retention at 120 min] were determined for evaluation. Also, the PP response was analyzed according to two parameters: IPPRSI the integrated PP response for periods up to SI, and IPPR120, the integrated PP response for 120 min. The results demonstrated that 5 micrograms of orally administered ornoprostil significantly reduced the gastric emptying rate of solid meal (T1/2 and 120 min RR, P less than 0.05). However, ornoprostil affected neither the basal PP concentrations nor the cephalic phase of PP secretion which was determined as IPPRSI. This thus suggests that ornoprostil affects the gastric motor function without interfering with the vagal-cholinergic pathway to the stomach.

Screening For Multiple Endocrine Neoplasia Type 1 In Patients With Recognized Pituitary Adenoma

A total of 79 consecutive patients with pituitary tumours were screened for multiple endocrine neoplasia type 1 (MEN-1). The 79 patients included 21 patients with acromegaly, nine with Cushing's disease, 18 with prolactinomas, three with mixed pituitary adenomas (GH and PRL), and 28 patients with no detectable hypersecretion of hormones. The screening consisted of: (1) a family history, (2) a uniform medical history of the patient using a standard questionnaire, and (3) hormonal evaluation including measurements of the serum levels of insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide and pancreatic polypeptide. Ionized calcium and glucose concentration in serum were also measured. We found no patients with the MEN-1 syndrome. In one patient, we found a transient elevation of serum concentrations of pancreatic polypeptide for which we have no explanation. In another patient, the serum gastrin concentration was elevated secondary to achlorhydria. No other endocrine disorders were found, and no patients had relatives with recognized endocrine pancreatic tumours, primary hyperparathyroidism (HPT), or pituitary adenomas.

Pancreatic Polypeptide and Other Pancreatic Hormones in Spontaneously Diabetic BBlW Rats

The BB/W strain of rats develop spontaneous insulin-dependent diabetes. Diabetic BB/W rats have a marked insulinopenia and greatly diminished levels of insulin in their pancreas. Using a radioimmunoassay for rat pancreatic polypeptide (PP), we have examined the content of PP in extracts of the total pancreas and also the regional PP concentration of the three pancreatic lobes. Radioimmunoassays for glucagon, somatostatin (SRIF) and insulin were also made on these extracts. Compared with nondiabetic BB/W rat pancreas, pancreatic extracts from severely diabetic BB/W rats contained 30% as much PP, 31% as much glucagon, 19% as much SRIF, and 0.5% as much insulin. The rat PP radioimmunoassay was used to determine the elution pattern of PP-like antigens in gel chromatography fractions and to measure in vitro secretion of PP from perifused pancreatic slices obtained from diabetic and nondiabetic animals. PP-like immunoreactivity was observed in two zones in the elution from the gel columns when extracts from normal or diabetic rats were chromatographed. The major zone of immunoreactivity eluting at the volume expected for intact monometric rat PP accounted for 67% of the PP-like immunoreactivity in the case of nondiabetic rats and greater than 80% of the PP-like immunoreactivity found in extracts from severely diabetic rats. The minor zone of PP-like immunoreactivity eluted at a volume similar to the position of tetradecapeptide SRIF contained the remainder of detected PP-like immunoreactivity. Tissue slices from diabetic rats secreted more PP and glucagon than slices from nondiabetic rats when slices were perifused with a medium containing leucine, carbachol, and cholecystokinin, even though diabetic pancreas has smaller amounts of PP, glucagon, SRIF, and insulin. Stimulated insulin secretion was virtually absent when tissue slices from diabetic rats were perifused. These results indicate that in the BB/W diabetic rat: (a) pancreatic glucagon, PP, and SRIF are moderately decreased and insulin levels are drastically reduced, (b) lower levels of degraded or low molecular weight form of immunoreactive PP occurs in the diabetic rat pancreas compared to the normal rat, (c) the diabetic pancreas secretes more PP and glucagon and much less insulin than pancreas from nondiabetic rats when perifused under stimulating conditions. The diabetes occurring in the BB/W appears to be a severe type I diabetes characterized by reduced content of insulin, glucagon, SRIF, and PP in the pancreas of these animals. However, secretion of glucagon and PP were not reduced in this in vitro system.

Regulation of Pancreatic Endocrine Function by Cholecystokinin: Studies with MK-329, a Nonpeptide Cholecystokinin Receptor Antagonist*

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.

Parotid secretion patterns during meals and their relationships to the tonicity of body fluids and to gastrin and pancreatic polypeptide in sheep

The flow pattern of unilateral parotid saliva in sheep was compared when a total of 800 g lucerne (Medicago sativa) hay was offered as one, two, four or eight distinct meals. These patterns were related to changes in the tonicity of rumen fluid and plasma and to plasma concentrations of gastrin and pancreatic polypeptide. Sheep having ad lib access to hay overnight were offered fresh hay from 08.00 to 09.00 hours and were then given one, two, four, or eight meals of fresh hay according to a schedule such that the mean deprivation period was 6.5 h for each meal frequency-size. Neither the peak in saliva flow rate nor the time of this peak differed among the different meal sizes. The flow rate decreased rapidly after reaching a maximum at 3.2 min into the meal. After 7 min of eating, the tonicity of plasma and rumen fluid had increased by only 2.2 and 8.2 mosmol/kg respectively. These increases would not cause the rapid decline in parotid flow observed after 3.2 min of eating. There was no postprandial change in the concentration of gastrin in jugular plasma. However, it did increase significantly (P = 0.0043) from 16 to 4 min before eating commenced. There was a postprandial peak in plasma pancreatic polypeptide concentration after 4.5 min of eating. However, the parotid flow rate remained low after the concentration of this peptide returned to prefeeding levels. The rapid decrease in parotid secretion rate observed early in the meal may be due to subsiding central excitation rather than to an inhibitory factor limiting production.