Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats

We investigated the possible role of endogenous secretin and cholecytokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r=0.665, 0.736 and 0.517, respectively) (P<0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r=0.721 and 0.546, respectively) (P<0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P<0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats. The results of this study were presented at The 7th International Symposium of Gastrointestinal Hormones in Shizuoka, Japan, Nov. 1–4, 1988, and appeared in abstract form in Biomedical Research 1988;9(Suppl. 1):114. This work was supported in part by grants from the Japanese Ministry of Education and the Ministry of Welfare. The authors are grateful to Y. Hirasawa, B.S. and M. Takeda, B.S. for their technical assitance.     

Gallbladder emptying and cholecystokinin and pancreatic polypeptide responses to a liquid meal in patients with diabetes mellitus

To investigate gallbladder motility and its regulation in patients with diabetes mellitus (DM), we examined the gallbladder response to an intraduodenal test meal by measuring the temporal course of plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) levels. Eighteen patients with type 2 DM and 7 healthy subjects (controls) were enrolled. The gallbladder volume was calculated by the sum-of-cylinders method from ultrasonographic images, and plasma CCK and PP were measured by radioimmunoassays. No significant difference was found in either the gallbladder response or in the CCK response between patients with DM and controls. However, the fasting plasma PP level of patients with DM was more than tenfold higher than that of controls. The integrated PP response (IPPR) of patients with DM to the test meal was 8.3-fold higher than that of controls. When patients with DM were grouped according to whether they had been treated with insulin or not, the fasting plasma PP of patients with DM without insulin treatment was significantly higher than the level in those treated with insulin. These results suggest that overproduction of PP-like immunoreactive substance(s) may occur in patients with DM, but the high plasma PP immunoreactivity does not appear to be related to the fasting gallbladder volume or to gallbladder emptying and filling.     

Effect of natural peptide YY on pancreatic secretion and cholecystokinin release in conscious dogs

The effects of natural peptide YY on pancreatic secretion under different stimulatory conditions and on fatty acid-induced cholecystokinin release were examined in five conscious dogs with pancreatic and gastric fistulas. Intravenous infusion of natural peptide YY at 1 and 0.2 g/kg/hr caused 60 and 40% inhibition of secretin- and cholecystokinin-stimulated secretion, respectively, and 40–50 and 20–40% inhibition of intraduodenal oleate stimulated secretion, respectively. A significant but transient decrease in the plasma cholecystokinin level was observed in response to peptide YY under oleate stimulation. The present study demonstrates that peptide YY has a potent inhibitory effect on both exogenously and endogenously stimulated pancreatic secretion and has a mild suppressive effect on fatty acid-induced cholecystokinin release, suggesting that this peptide is an important colonic inhibitor of pancreatic secretion.This work was supported in part by a grant from the Ministry of Education, Japan (A 59440057) and in part by NIH grant AM30415.     

Effects of ethanol on meal-stimulated secretion of pancreatic polypeptide and cholecystokinin: Comparison of healthy volunteers,heavy drinkers,and patients with chronic pancreatitis

Tiscornia and Dreiling (Physiopathogenic Hypothesis of Alcoholic Pancreatitis: Supranormal Ecbolic Stimulation of the Pancreon Units Secondary to the Loss of the Negative Component of Pancreas Innervation. Pancreas 1987;2:604–612.) proposed that hypertonicity of intrapancreatic cholinergic neurons provoked by chronic alcoholism may contribute to the pathogenesis of chronic pancreatitis (CP). In the present study, the validity of this hypothesis was investigated in humans by studying the effects of atropine, cisapride, and ethanol on the meal-stimulated secretion of pancreatic polypeptide (PP) and cholecystokinin (CCK) in healthy volunteers, heavy drinkers, and CP patients. In healthy volunteers, the early phase PP response (0–40 min) to a test meal was completely blocked by atropine, whereas it was augmented by cisapride, an enhancer of acetylcholine release from cholinergic nerves. The early phase PP response to a test meal was inhibited by ethanol in healthy volunteers, whereas, in heavy drinkers, the response was augmented and the inhibition by ethanol was abrogated. In CP patients, ethanol tended to enhance the early phase PP response. Ethanol did not affect the early phase CCK response to a test meal in any group, but it significantly enhanced the late phase CCK response (40–120 min) in CP patients. These results suggest that: (i) oral ethanol may inhibit the post-prandial activation of the cholinergic neural pathway to the pancreas in healthy subjects, (ii) in heavy drinkers, postprandial cholinergic tone may be augmented and become resistant to the inhibition by ethanol, and (iii) the ethanol-induced increase in the postprandial CCK response in CP patients may play some role in the pathophysiology of this disease.     

Duration and potency of anticholecystokinin action of subcutaneous and oral loxiglumide on cerulein-stimulated pancreatic exocrine secretion

Summary The duration and the potency of the antiCCK activities of loxiglumide given by sc and oral routes were examined in rats. Pancreatic juice flow and protein output in response to an iv bolus injection of cerulein (100 ng/kg body wt) were measured at specified time intervals from 1–12 h after loxiglumide administration. Subcutaneous loxiglumide (10 g/kg body wt) effectively suppressed cerulein-stimulated protein output for 4 h and pancreatic juice volume for 6 h, when total outputs during a 60-min period after cerulein stimulation were compared with the control value without loxiglumide pretreatment. Oral dose of loxiglumide exerted longer-term anti-CCK activity (protein output: 6 h, pancreatic juice: 8 h) than the same sc dose. In addition, oral loxiglumide showed more potent suppression of protein output than the same sc dose at the corresponding time interval. Higher oral dose of loxiglumide (50 mg/kg body wt) caused longer inhibition on both protein (8 h) and pancreatic juice secretion (12 h). These results suggest that the half-life of loxiglumide given by oral route is longer than that by sc route or that the bioavailability of oral loxiglumide is higher than that of sc dose. The present study demonstrates that loxiglumide, given either by sc or by oral route, has long duration of action in antagonizing responses to exogenously administered cerulein.     

Duodenum preservation in pancreatic head resection to maintain pancreatic exocrine function (determined by pancreatic function diagnostant test and cholecystokinin secretion)

Background/Purpose

Organ-preserving surgery, such as pylorus-preserving pancreatoduodenectomy (PPPD), duodenum-preserving pancreatic head resection (DPPHR), or medial pancreatectomy (MP), is one of the recent advances in pancreatic surgery. There was a previous report that preservation of the duodenum maintained pancreatic function. However, concerning the resected pancreas, patients were divided into two groups; one group included pancreatic head resections such as Whipple, PPPD, and complete DPPHR, and the other group included MP that removed only the pancreatic neck and preserved the pancreatic head and distal pancreas. The present study was designed to clarify the significance of duodenum preservation, in comparison with duodenum removal, in patients with pancreatic head resection, in terms of pancreatic function, determined by a pancreatic function diagnostant (PFD) test and cholecystokinin (CCK) secretion.

Methods

The subjects were 61 patients (10 with Whipple, 41 with PPPD, and 10 with complete DPPHR). PFD tests and postprandial plasma CCK secretion were used for evaluation.

Results

There was a significant difference between pre- and postoperative PFD values in the patients who received Whipple or PPPD; however, there was no difference in those who had complete DPPHR. Concerning the postoperative PFD value, complete DPPHR was superior to Whipple and PPPD. Regarding postprandial CCK secretion, the pre- and postoperative values were significantly different in the patients with Whipple or PPPD, but there was no difference in those with complete DPPHR. Comparing the three kinds of operations, complete DPPHR was superior to the other two procedures in its maintenance of pancreatic function. There was the significant correlation between CCK and PFD in our patients in the Spearman Rank Correlation (P < 0.0029) and Fisher’s r to z (P < 0.0058).

Conclusions

When pre- and postoperative pancreatic exocrine function and postprandial CCK secretion were measured in patients with pancreatic head resection, it was found that preservation of the entire duodenum was an important factor for maintaining pancreatic function.     

Role of cholecystokinin in pancreatic bicarbonate secretion in dogs

We investigated the effects of endogenous and exogenous cholecystokinin (CCK) on pancreatic exocrine secretion, in particular that of bicarbonate. In six dogs prepared with gastric cannulas and Thomas duodenal cannulas, intraduodenal administration of corn oil (Lipomul) incubated with hog pancreatic enzymes significantly increased pancreatic secretion of both bicarbonate and protein. Increase in pancreatic secretion of both bicarbonate and protein was accompanied by the increase in plasma CCK concentration. However, the increase in bicarbonate as well as protein secretion was blocked by proglumide, a CCK antagonist, given intravenously. In contrast, intraduodenal infusion of undigested Lipomul failed to stimulate the pancreatic exocrine secretion or release of endogenous CCK. These observations indicate that endogenous CCK plays an important role in secretion of both bicarbonate and protein stimulated by digested corn oil. In a group of four dogs with pancreatic fistulas, intravenous infusion of CCK potentiated the stimulatory effect of secretin on pancreatic bicarbonate secretion. The stimulatory effect as well as potentiating effect of CCK on pancreatic bicarbonate secretion was blocked by infusion of proglumide. We conclude that endogenous CCK plays a significant role in fat-stimulated pancreatic secretion, and it is apparent that both endogenous CCK and secretin are equally important for stimulation of pancreatic bicarbonate secretion, which results from potentiation of the action of the two hormones.     

Roles of gastrointestinal hormones in pancreatic cancer

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.     

Pancreatic polypeptide and intestinal motility in dogs

This study was designed to determine the potential role of endogenous PP in the control of intestinal motility by correlating plasma PP levels with motility patterns in fasted and fed dogs without and with administration of exogenous PP and rabbit PP antiserum. After an overnight fast, when the interdigestive myoelectric activity was recorded in each dog, mean basal PP at phase I averaged 35±7 pM with peaks of 52±5 pM coinciding with phase III (MMC) in duodenum. Postprandial rise in PP reached the peak level of 280±70 pM at the end of 1 hr after a meal when MMC was interrupted and replaced by fed-type motility pattern. Exogenous PP in a dose of 100 pmol/kg/hr infused when the phase III of the MMC passed mid-jejunum raised plasma PP to the level of 130±27 pM but failed to affect the spike activity or MMC periodicity. PP given in doses of 200 and 400 pmol/kg/hr, which raised plasma PP to 298±25 and 453±24 pM, respectively, increased dose dependently (but did not abolish) the MMC intervals and an overall spike activity due to the prolongation of phase II of the MMC. After termination of PP infusion, phase III-like activity appeared within 7–10 min. Injection of highly specific PP antiserum, which caused almost complete disappearance of plasma PP both in fasted and fed dogs, did not affect the MMC interval but increased spike activity in fasted animals and failed to affect significantly spike activity in fed animals. We conclude that PP does not play any role in fasted intestinal motility but may contribute, at least in part, to the postprandial suppression of MMC.     

Intraduodenal cholecystokinin octapeptide (CCK-8) can stimulate pancreatic secretion in the calf

Summary The effect of CCK-8 administered into the duodenal lumen and into the systemic blood on pancreatic, secretion and duodenal migrating myoelectric complex (MMC) was studied in four calves. Simultaneous MMC recordings and collections of pancreatic juice were performed on valves that had been fasted overnight. Intraduodenal (o, 100, and 300 pmol/kg body wt) and intravenous (0, 30, and 100/pmol kg) infusions of CCK-8 were made for 5 min during the no spiking activity (NSA) phase of duodenal MMC associated with a nadir of periodic pancreatic secretion. CCK-8 was also administered during continuous atropine infusion (5 μg/kg/min). Both intraduodenal and intravenous infusions of CCK-8 resulted in marked pancreatic responses in juice outflow, bicarbonate output, and protein output. Atropine decreased pancreatic response (protein output) to intravenous CCK-8 and markedly inhibited the response (juice flow, bicarbonate, and protein output) to intraduodenal CCK-8. Infusions of CCK-8 did not affect the duration of MMC in the duodenum. Plasma CCK increased significantly after intravenous infusion, but remained unchanged after intraduodenal infusion. In conclusion, CCK-8 can stimulate pancreatic secretion from the duodenal lumen, possibly via a cholinergic mechanism in the calf.     

Exogenous administration of estradiol and cholecystokinin alters exocrine pancreatic function in rats

Summary This study was conducted in rats to investigate the influence of exogenously administered estradiol (ESD) and/or cholecystokinin (CCK) on components and secretions of the pancreatic acini. Intact male rats were treated for 14 d with exogenous administration of ESD, CCK, or ESD+CCK. After 14 d CCK treatment induced significant increases in DNA and RNA contents, and DNA/RNA ratio in the pancreas, indicating hyperplasia and hypertrophy of the pancreas, however, ESD treatment did not have these effects. Both ESD treatment and CCK treatment induced significant increases in amylase and trypsinogen contents in pancreatic acini and each decreased secretion from acini in response to CCK. Combined treatment with ESD plus CCK augmented these effects on enzyme contents and secretion. The results indicate that exogenous administration of CCK has trophic effects on the exocrine pancreas, increasing effects on enzyme contents and inhibitory effects on amylase secretion. In contrast, exogenous administration of ESD had no trophic effects on pancreas, but had increasing effects on enzyme contents and inhibitory effects on amylase secretion. The results suggest that the effects of exogenous ESD and CCK on pancreas are not similar to each other, but both ESD and CCK may be involved in regulating pancreatic exocrine functions.     

Protein meal-stimulated pancreatic polypeptide secretion in Prader-Willi syndrome of adults

Children with Prader-Willi syndrome (PWS) are characterized by obesity, hyperphagia, hypogonadism, and mental retardation with underlying hypothalamic dysfunction and are known to have blunted or absent pancreatic polypeptide (PP) secretion in response to protein meals. In this communication, adults (26 +/- 3 years of age) with PWS were compared with age-matched normal obese and normal weight controls in regards to plasma glucose, insulin, PP, cholecystokinin (CCK), cholesterol, and triglyceride after a high protein meal. Compared with normal weight controls, adults with PWS showed a smaller and delayed rise in plasma insulin, and relatively smaller and delayed PP elevation whereas obese controls revealed hyperglycemia, markedly higher insulin, and moderately higher PP, cholesterol, and triglyceride levels than those with PWS. There was a small increment of CCK levels after a protein meal in all groups of adults. After a protein meal, the molar ratio of PP to CCK doubled in normal weight and PWS groups, and this ratio tripled in the normal obese group, suggesting no reduced PP secretion in PWS in response to CCK stimulation. PP hyposecretion in PWS thus appears to be a part of multiple endocrinopathy associated with hypothalamic dysfunction.     

Effects of endogenous and exogenous secretin on plasma pancreatic polypeptide concentrations in dogs

Summary The effects of exogenous and endogenous secretin with or without intravenous glucose infusion upon islet hormone secretion were studied in four conscious mongrel dogs fitted with a duodenal fistula. Intravenous infusion of secretin for 1 h at doses of 0.5 and 4 U/kg raised plasma secretin concentrations to physiological and pharmacological levels respectively, without affecting plasma insulin and pancreatic polypeptide concentrations. In contrast, bolus injections of secretin at high concentrations produced significant increases of plasma insulin at 0.5 U/kg and 4 U/kg and of pancreatic polypeptide at 4 U/kg. Plasma glucagon did not change during intravenous infusion of low dose secretin (0.5 U · kg^–1 · h^–1), but decreased during infusion of 4 U · kg^–1 · h^–1 or bolus injection of secretin (0.5 U/kg). Intravenous infusion of glucose together with secretin (0.5 U/kg and 4 U/kg) did not affecf plasma insulin, glucagon, or pancreatic polypeptide levels significantly compared with the changes caused by glucose infusion alone. Intraduodenal instillation of HCl, which produced plasma secretin concentrations similar to those evoked by intravenous infusion of secretin (4 U · kg ^–1 · h^–1), led to a rise in plasma pancreatic polypeptide. It is concluded that the stimulatory effects of secretin on insulin and pancreatic polypeptide and the inhibitory effect on glucagon are pharmacological, and that increase of plasma pancreatic polypeptide after intraduodenal infusion of HCl is not mediated by endogenous secretin.     

Impaired glucose tolerance is associated with enhanced postprandial pancreatic polypeptide secretion

BackgroundThe purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C‐peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus.MethodsData were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUC_pp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis.ResultsPostprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p < 0.05). AUC_pp was significantly higher in the IGR group (428.76 pg·h/mL, 95% confidence interval [CI] [41.06 –816.46], p = 0.031) and newly diagnosed T2DM group (404.35 pg·h/mL, 95% CI [5.37–803.33], p = 0.047) than in the NGT group. AUC_pp was negatively correlated with body mass index (BMI) (r = −0.235, p = 0.038) and positively correlated with postprandial 60 min blood glucose (r = 0.370, p = 0.001) and AUC_bg (AUC of blood glucose) (r = 0.323, p = 0.007). Multiple linear regression analysis indicated that there was a linear correlation between BMI, AUC_bg, and AUC_pp (p = 0.004, p = 0.001), and the regression equation was calculated as: AUC_pp = 6592.272 + 86.275 × AUC_bg‐95.291 × BMI (R² = 12.7%, p < 0.05).ConclusionsCompared with NGT subjects, IGR and T2DM patients have an enhanced postprandial PP secretion. In T2DMs, the secretion of PP is mainly affected by BMI and blood glucose.     

Effects of a new benzodiazepine derivative cholecystokinin receptor antagonist FK480 on pancreatic exocrine secretion in anesthetized rats

Inhibitory effects of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk][1,4] benzodiazepine-3yl]-1H-indole-2-carboxamide (FK480), a cholecystokinin (CCK) -A receptor antagonist, on pancreatic exocrine secretion were examinedin vivo in anesthetized rats. The antagonism produced by FK480 was competitive in nature because intraduodenal as well as intravenous infusion of FK480 (50–250 nmol/kg/hr) caused a parallel rightward shift of the entire dose-response curve for cerulein-stimulated pancreatic exocrine secretion without altering the maximal increase. The magnitude of the shift was proportional to the dose of FK480. The mean pA2 and ID₅₀ values of intravenously administered FK480 were 8.2 and 24 nmol/kg/hr, respectively, and those of intraduodenally infused FK480 were 7.7 and 168 nmol/kg/hr, respectively. Thus, FK480 given by the intravenous route was about sevenfold more potent than that given by the oral route. The antagonistic effects produced by intravenous FK480 were specific for CCK receptor in that the stimulatory effects of cerulein were inhibited whereas those of bombesin and secretin were not altered. In addition, intravenous administration of 50 nmol/kg/hr FK480 completely suppressed pancreatic exocrine secretion in response to intraduodenal infusion of 10% casein (400 mg/hr). FK480 was active as a CCK receptor antagonist for more than 12 hr because oral administration of FK480 (1.0 mg/kg) had significant inhibitory effects even after 12 hr on cerulein-stimulated pancreatic exocrine secretion. These results indicate that FK480 is a potent, competitive, and specific CCK receptor antagonist on the exocrine pancreasin vivo, having oral bioavailability and a long biological half-life.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Disease of the Pancreas).     

Effect of somatostatin 14 on pure human pancreatic secretion

While it is well known that large doses of somatostatin inhibit human pancreatic enzyme secretion, it is still unknown whether low doses are also effective and whether the peptide is able to inhibit bicarbonate production. Eight subjects with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery were studied. Somatostatin was infused at progressively increasing rates of 0.05, 0.15, 0.45, and 1.35 g/kg/hr, for 30 min/dose, during pancreatic stimulation with secretin, 25 ng/kg/hr, and cerulein, 10 ng/kg/hr. Somatostatin, at the dose of 0.05 g/kg/hr (shown to produce blood levels similar to those measured after a meal) did not affect pancreatic secretion in any of the subjects. The successive three higher doses caused a significant and dose-dependent inhibition of protein concentration and output and of bicarbonate output. Bicarbonate concentration was slightly but significantly reduced only by the two highest doses of somatostatin. At each dose level, the inhibition of protein output was much more marked than the inhibition of bicarbonate output. The maximal inhibition of protein output (at 1.35 g/kg/hr somatostatin) was 73.9±5.4%, and that of bicarbonate output was 55.9±6.4%. The results demonstrate that: (1) the administration of somatostatin at a low dose level does not affect human exocrine pancreatic secretion, at least under the experimental conditions of this study; and (2) the administration of larger doses of somatostatin inhibits pancreatic secretion of both protein and bicarbonate dose-dependently. The inhibitory effect on protein output is significantly greater than that on water and bicarbonate production.     

Human pancreatic polypeptide secretion in conditions of exogenous and endogenous hyperglycaemia

Summary The effects of exogenous and endogenous hyperglycaemia on human pancreatic polypeptide secretion have been studied. In normal subjects elevation of plasma glucose concentration by glucose infusion both depressed the basal levels of circulating human pancreatic polypeptide (by 40–50%) and consistently reduced the human pancreatic polypeptide response to the ingestion of a protein-rich meal (areas above pre-meal value: 19.5±4.1 (mean ± SEM) vs. 9.6±2.1, p < 0.01) as well as to caerulein infusion (areas above pre-caerulein value: 8.8±2.2 vs. 4.6±1.4, p < 0.01). In diabetic subjects treated with sulphonylureas or diet (fasting plasma glucose: 166±11mg/dl, n = 24), human pancreatic polypeptide secretion evoked by food was similar to that of 24 healthy individuals (areas above basal value: 46.6±9.9 and 33.6±3.6, respectively). In insulin dependent diabetics (fasting plasma glucose: 231±19 mg/dl, n = 21) the human pancreatic polypeptide response to the meal (area above basal value: 78.2±13.7) was significantly greater than that of the controls as well as that of the noninsulin-dependent group (p < 0.05). Since the administration of pancreatic polypeptide to man has been shown to decrease pancreatic exocrine output, postprandial human pancreatic polypeptide hypersecretion may contribute to the decreased exocrine function of the pancreas often found in insulin-dependent diabetics.     

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

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

Role of endogenous secretin and cholecystokinin in intraduodenal oleic acid-induced inhibition of gastric acid secretion in rats

We investigated a possible role of endogenous secretin and cholecystokinin (CCK) in inhibition of gastric acid secretion induced by intraduodenal administration of oleic acid in rats. Intraduodenal administration of oleic acid emulsion in a dose of 1 mmol/hr resulted in significant inhibition of gastric acid secretion stimulated by intravenous infusion of pentagastrin (0.3 g/kg/hr), and this was accompanied by an increase in the plasma concentration of both secretin and CCK, from 1.2±0.08 pM and 20.6±1.2 pM to 4.3±0.18 pM and 31.6±0.9 pM, respectively (P<0.001). Intravenous infusion of secretin (0.05 CU/kg/hr) inhibited pentagastrin-stimulated gastric acid secretion, but CCK-8 (0.03 /kg/hr) failed, although intravenous infusion of secretin, and CCK in those doses produced plasma levels comparable to the levels achieved in response to oleic acid administration. Furthermore, the oleic acid-induced suppression of gastic acid secretion was blocked significantly by intravenous injection of rabbit anti-secretin serum (0.1 ml), but not by intravenous infusion of a CCK-receptor antagonist, CR 1409 (5 mg/kg/hr). Thus, the results of this study indicate that endogenous secretin rather than CCK is involved in the hormonal mechanism regulating the inhibition of gastric acid secretion by intestinal fat in rats.This work was supported in part by a grant from the Japanese Ministry of Education. Part of this work was presented at the Annual Meeting of the American Gastroenterological Association, May 12–18, 1990, San Antonio, and appeared in abstract form inGastroenterology 98:A124, 1990     

The influence of somatostatin on glucagon and pancreatic polypeptide secretion in the isolated perfused human pancreas

Summary The current study was undertaken to determine whether intraislet somatostatin regulates glucagon or pancreatic polypeptide (PP) secretion in the human pancreas. A high-affinity, high-specificity monoclonal somatostatin antibody (CURE.S6) was used to immunoneutralize somatostatin in the isolated, perfused human pancreas. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs media with either 3.9 or 12.9 mM glucose. Sequential test periods separated by basal periods were performed with infusion of either exogenous somatostatin-14 (SS-14), CURE.S6, or a combined infusion. Infusion of SS-14 did not significantly alter glucagon or PP secretion during low-glucose or high-glucose perfusion. Immunoneutralization of intraislet somatostatin with CURE.S6 resulted in a significant increase of glucagon secretion under low-glucose conditions (ΔX=15±3 pM) (p<0.05), but did not significantly effect glucagon secretion under high-glucose conditions (ΔX=−2±3 pM) (p=NS). PP secretion remained unchanged during CURE.S6 infusion. Combined infusion of SS-14 and CURE.S6 did not significantly alter glucagon or PP secretion. The data suggest that intraislet somatostatin may have an inhibitory role in the regulation of glucagon secretion during low-glucose conditions and that intraislet somatostatin does not regulate PP secretion in the isolated, perfused human pancreas.