Effects Of Pancreatic Polypeptide Research Articles

Effect of Pancreatic Polypeptide on Gastric Motor Function and Food Intake in Humans

Effect of Pancreatic Polypeptide on Gastric Motor Function and Food Intake in Humans

Effect of pancreatic polypeptide on gastric accommodation and gastric emptying in conscious rats.

Pancreatic polypeptide (PP) is an anorexigenic hormone released from pancreatic F cells upon food intake. We aimed to determine the effect of PP on gastric accommodation and gastric emptying in conscious Wistar HAN rats to investigate whether effects on motor function could contribute to its anorexigenic effects. Intragastric pressure (IGP) was measured through a chronically implanted gastric fistula during the infusion of a nutrient meal (Nutridrink; 0.5 ml/min). Rats were treated with PP (0, 33 and 100 pmol·kg(-1)·min(-1)) in combination with N(G)-nitro-L-arginine methyl ester (L-NAME; 180 mg·kg(-1)·h(-1)), atropine (3 mg·kg(-1)·h(-1)), or vehicle. Furthermore, the effect of PP was tested after subdiaphragmal vagotomy of the stomach. Gastric emptying of a noncaloric and a caloric meal after treatment with 100 pmol·kg(-1)·min(-1) PP or vehicle was compared using X-rays. PP significantly increased IGP during nutrient infusion compared with vehicle (P < 0.01). L-NAME and atropine significantly increased IGP during nutrient infusion compared with vehicle treatment (P < 0.005 and 0.01, respectively). The effect of PP on IGP during nutrient infusion was abolished in the presence of L-NAME and in the presence of atropine. In vagotomized rats, PP increased IGP compared with intact controls (P < 0.05). PP significantly delayed gastric emptying of both a noncaloric (P < 0.05) and a caloric (P < 0.005) meal. PP inhibits gastric accommodation and delays gastric emptying, probably through inhibition of nitric oxide release. These results indicate that, besides the well-known centrally mediated effects, PP might decrease food intake through peripheral mechanisms.

Tu1976 A Method to Directly and Continuously Assess Gastric Emptying in Conscious Rats: Effect of Pancreatic Polypeptide and Atropine

Introduction: Gastric emptying (GE) in rats is mostly determined after gavaging a radioactive or colored meal, with determination of the percentage of food remaining in the stomach after sacrificing the animal as a measure for gastric emptying. We hereby present a novel method to directly and continuously assess gastric emptying of a liquid meal in conscious rats without the need to sacrifice animals. Methods: After an overnight fast, 6 Wistar HAN rats were placed in a custom-made Bolmann cage to minimize movement artefacts. Rats were treated with atropine (1 mg kg-1; subcutaneous), pancreatic polypeptide (PP; 100 pmol kg-1 min-1; intravenous infusion) or vehicle (administered on 2 occasions). 15 minutes after the start of the treatment, rats were gavaged with 3 ml of a liquid test meal containing 1% hydroxypropyl methylcellulose solution and 0.5 g ml-1 BaSO4 (0 cal). The abdomen was visualized as a dorsal projection using X-ray imaging (29 kV, 40mAs; Embracemammography device; Selenia software (Hologic)). X-ray imaging was possible throughout the whole experiment. In order to estimate the test meal fraction in the stomach, X-rays were taken every 5-10 minutes and analyzed using Image J software. After manually outlining the stomach, the software was used to calculate the area of the image of the stomach. The area directly after gavage of the meal was set at 100% and GE was expressed as the fraction of the original stomach area over time. The average percentage emptied over 60 minutes was compared. Data were represented as mean±S.E.M. and compared using a paired ttest (p 0.1). Atropine caused a significant delay in GE compared to vehicle (55.6±3.1 vs. 40.3±2.7% emptied over 60 minutes, p<0.01). Similarly, PP-treatment significantly inhibited GE (60.5±3.2 vs. 48.5±1.9% emptied over 60 minutes, p<0.05; Fig.1). Conclusion: Using X-rays to visualize a radio-opaque meal allows to determine gastric emptying in a continuous non-invasive manner. Both atropine and PP significantly delayed gastric emptying rate.

Pancreatic Polypeptide Administration Enhances Insulin Sensitivity and Reduces the Insulin Requirement of Patients on Insulin Pump Therapy

The effects of pancreatic polypeptide (PP) infusion were examined in patients on insulin pump therapy to determine whether PP administration can reduce insulin requirements in patients with type 1 diabetes mellitus (T1DM) or type 3c diabetes mellitus (T3cDM; pancreatogenic). Ten subjects with long-standing T1DM (n = 7) or T3cDM (n = 3) on insulin pump treatment received a 72 h subcutaneous infusion of 2 pmol/kg/min bovine PP or saline by portable infusion pump in a single-blinded, randomized, crossover design. Pancreatic polypeptide infusion raised plasma PP levels to 450-700 pmol/liter. Daily insulin infusion requirements (I) fell from 48 ± 6.9 to 40 ± 7.5 U on day 2 (p < .05) and from 46 ± 7.7 to 37 ± 6.6 U on day 3 (p < .05) of PP infusion compared with saline. Corrected for average blood glucose concentration (G), I/G fell in 10/10 subjects during the second 24 h period and in 7/10 subjects during the third 24 h period; sensitivity to insulin, calculated as 1/(I/G), increased 45% ± 12% on day 2 (p < .01) and 34% ± 14% on day 3 (p < .05) of PP infusion. Pancreatic polypeptide responses to a test meal were compared with the change in insulin infusion requirements in 5 subjects; the reduction in insulin requirements seen during PP infusion correlated with the degree of baseline PP deficiency (p < .002). A concurrent subcutaneous infusion of PP enhances insulin sensitivity and reduces insulin requirements in patients with long-standing T1DM and T3cDM on insulin pump therapy. The benefit of PP infusion correlated with the degree of PP deficiency.

The Effect of Pancreatic Polypeptide on Gastric Accommodation in Rats

The Effect of Pancreatic Polypeptide on Gastric Accommodation in Rats

The Effect of Pancreatic Polypeptide on Gastric Emptying, Gastric Accommodation and Satiation in Healthy Volunteers

The Effect of Pancreatic Polypeptide on Gastric Emptying, Gastric Accommodation and Satiation in Healthy Volunteers

The effects of pancreatic polypeptide on locomotor activity and food intake in mice

Pancreatic polypeptide (PP) has been shown to inhibit food intake in both rodents and humans. Acute peripheral administration of PP increases oxygen consumption in obese mice. To further investigate the function of PP in the modulation of energy balance, we examined its effects on spontaneous locomotor activity and food intake in mice by using a 24-chamber Comprehensive Laboratory Animal Monitoring System. Effects of intraperitoneal (i.p.) administration of PP on spontaneous locomotor activity were measured using the optical beam technique. Administration of PP dose dependently inhibited cumulative food intake. The inhibition remained significant for up to 6, 17 and 36 h at doses of 30, 100 and 300 nmol kg(-1) PP, respectively. At 10 nmol kg(-1), PP increased locomotor activity (cumulative beam breaks) significantly for 4 h following administration without affecting food intake and at 30 nmol kg(-1), PP increased locomotor activity by 79% compared with the controls for 5 h post injection. However, at 100 and 300 nmol kg(-1), PP had no significant effect on locomotor activity. This study shows for the first time that PP increases spontaneous locomotor activity in mice.

Effect of pancreatic polypeptide on rat dorsal vagal complex neurons.

1. Pancreatic polypeptide (PP) microinjected into the dorsal vagal complex (DVC) elevates gastric activity through a vagal mechanism. Thus, it was hypothesized that PP alters the activity of nuclei comprising the DVC, i.e. the nucleus tractus solitarii (NTS) and the dorsal motor nucleus (DMN). 2. In vivo and in vitro approaches were used. For in vivo studies, micropipettes were used for recording and injecting vehicle or PP. Neurons were identified as NTS or DMN using orthodromic and antidromic activation, respectively, following vagal stimulation. Gastric-related DVC neurons were located using antral inflation. For in vitro studies, DMN neurons were recorded from medullary slices. 3. Of the twenty-eight NTS and DMN neurons identified, fifteen were activated, six inhibited and seven unaffected after PP microinjection. Forty-two gastric-related neurons were located in the DVC, of which twenty-five were stimulated by PP and seventeen exhibited no change. No gastric-related cells were inhibited. 4. For in vitro studies, 66% of DMN neurons were activated by PP (n = 27/47) while the remaining 33% were inhibited (n = 14/47). Similar results were obtained in normal or synaptic blockade media. 5. These results support the hypothesis that PP alters DVC neuronal activity, which may thereby lead to the previously observed alterations in gastric activity.

The effect of pancreatic polypeptide on hepatocyte insulin receptor concentration

The effect of pancreatic polypeptide on hepatocyte insulin receptor concentration

Alterations in hepatocyte insulin binding in chronic pancreatitis: Effects of pancreatic polypeptide

Hepatic insulin resistance has previously been demonstrated in chronic pancreatitis, and has been shown to be ameliorated by pancreatic polypeptide administration. Insulin binding was investigated in chronic pancreatitis induced by infusion of oleic acid into the pancreatic duct of rats. Acute pancreatitis was induced in 12 200 to 225 g 8-week-old male Sprague-Dawley rats by intubation of the main bile duct at its junction with the duodenum through a small midline abdominal incision, and infusion of 99% oleic acid 0.015 mL/min for 4 minutes, with an additional 4 minutes dwell-time after infusion. Sham-operated animals served as controls. After 6 weeks, chronic pancreatitic and sham-operated animals received either intraperitoneal bovine pancreatic polypeptide or saline vehicle for 5 days. Intraduodenal glucose tolerance tests (GTT) were performed in fasted animals, after which tissues were procured. Insulin receptors were isolated from solubilized hepatocyte and rectus abdominus membranes and competitive-binding studies were performed by incubation with 125I-insulin. Dissociation coefficients (Kd) and maximum binding capacities (Bmax) for high-affinity receptors were derived from Scatchard analyses. Bmax and Kd in muscle were not altered in animals with chronic pancreatitis. In liver, Bmax was significantly less in rats with chronic pancreatitis given saline than in sham-operated rats given saline (17.0 +/- 6.3 versus 47.6 +/- 13.1 fmol/mg protein; data are mean +/- SEM). Pancreatic polypeptide administration increased hepatic Bmax in rats with chronic pancreatitis (to 47.2 +/- 9.8 fmol/mg protein), but had no significant effect in sham-operated rats. Receptor affinity was not significantly different in rats with chronic pancreatitis or rats who underwent sham operations and was unaltered by the administration of pancreatic polypeptide. The integrated plasma glucose response during the GTT was reduced by pancreatic polypeptide administration in rats with chronic pancreatitis (29.5 +/- 15.0 mg/dL per minute versus 69.0 +/- 21.8 in chronic pancreatitis without pancreatic polypeptide), but was not significantly altered in sham-operated animals. Diminished expression of high-affinity receptors on the hepatocyte membrane may contribute to hepatic insulin resistance in chronic pancreatitis. In this model, pancreatic polypeptide improved glucose tolerance and increased receptor capacity to the level observed in livers from nonpancreatitic animals.

Pancreatic polypeptide and splanchnic blood flow in anesthetized rats

The aim of the study was to evaluate the effects of pancreatic polypeptide (PP) on splanchnic blood flow in anesthetized rats. For this purpose, either PP dissolved in saline (225, 450, or 900 pmol/kg body weight/h) or saline alone was infused at a rate of 2 ml/h for 30 min. Immediately after the infusion the blood flow to the whole pancreas, islets, duodenum, and colon was measured with a microsphere technique. The highest dose of PP caused a small decrease in mean arterial blood pressure. The two lowest doses decreased duodenal blood flow, but did not affect the blood perfusion to the other investigated organs. The highest dose of PP decreased the blood flow to the pancreas, islets, and duodenum, did not affect colonic blood flow. No change in the fraction of whole pancreatic blood flow diverted through the islets could be seen after PP administration. It is concluded that administration of high doses of PP induces a general splanchnic vasoconstriction.

Stimulation of gastric secretion and enhanced gastric mucosal damage following central administration of pancreatic polypeptide (PP) in rats.

The present study was carried out to investigate the central effects of pancreatic polypeptide on gastric secretion and gastric ulcer formation in conscious rats. Intracisternal injection of rat pancreatic polypeptide (62.5, 250, and 1000 ng/rat) into pylorus-ligated rats resulted in a dose-dependent stimulation of gastric acid and pepsin secretion. In contrast, intraperitoneal injection of even higher doses of pancreatic polypeptide (250, 1000, and 2500 ng/rat) failed to increase gastric secretion. This stimulatory effect of centrally administered pancreatic polypeptide was completely blocked by vagotomy and by pretreatment with atropine. Intracisternal injection of PP (500-2000 ng/rat) dose-dependently increased the severity of gastric lesions induced by 2-deoxy-D-glucose or indomethacin. In contrast, intraperitoneal injection of PP failed to increase the severity of the gastric lesions induced by 2-deoxy-D-glucose or indomethacin. These results indicate that pancreatic polypeptide is capable of acting centrally in the brain to stimulate gastric acid and pepsin secretion through a vagal, muscarinic pathway and in so doing exerts an ulcerogenic action on the gastric mucosa.

Effects of pancreatic polypeptide on insulin action in exocrine secretion of isolated rat pancreas.

1. Effects of pancreatic polypeptide (PP) on insulin action in pancreatic exocrine secretion was investigated by using an isolated rat pancreas that was perfused with Krebs-Henseleit solution containing 2.5 mM glucose, 0.1% bovine serum albumin and 3% Dextran T-70 at a vascular flow rate of 1.2 ml min-1. 2. Cholecystokinin-8 (CCK-8) at a concentration of 14 pM stimulated basal flow rate and amylase output of the isolated pancreas. Twenty-five millimolar glucose not only increased the basal flow rate and amylase output but also potentiated the CCK-stimulated flow rate and amylase output. 3. Porcine insulin, administered intra-arterially at a concentration of 100 nM, also increased the basal flow rate and amylase output, and also potentiated the CCK-stimulated flow rate and amylase output. 4. Rat PP, given intra-arterially at a concentration of 10 pM, completely abolished the potentiation effects of both the 25 mM glucose and the exogenous insulin on the CCK-stimulated flow rate and amylase output. Rat PP also inhibited the flow rate and amylase output increased by either 25 mM glucose alone or exogenous insulin alone. However, rat PP did not change the flow rate and amylase output stimulated by CCK-8 alone. 5. These results indicate that insulin is an important stimulatory hormone of pancreatic exocrine secretion, and that PP exerts the inhibitory role in pancreatic exocrine secretion by modulating the insulin action.

The effect of pancreatic polypeptide on glucose disposal after surgical alterations of the pancreas.

Surgical alterations of the pancreas result in anatomic changes that can affect postoperative glucose metabolism. Pancreas transplantation results in reduction of beta-cell mass, systemic release of insulin, and denervation. The authors hypothesized that such alterations affect peripheral glucose disposal to induce an "insensitivity" to endogenously (systemically) released insulin. Additionally, they hypothesized that surgically induced deficiency of the postprandial hormone, pancreatic polypeptide, might contribute to altered glucose disposal. The authors studied two surgical models in dogs known to be devoid of pancreatic polypeptide--70% proximal pancreatectomy (PPx) and PPx plus distal pancreas autotransplantation (PAT/B). Oral glucose challenge and euglycemic hyperinsulinemic clamp studies were performed before and after a 16-day "pulsed" infusion of pancreatic polypeptide. Both surgical procedures resulted in elevations in the integrated glucose response after oral glucose, which was not affected by pancreatic polypeptide infusion. Euglycemic clamp studies showed decreased hepatic glucose output (Ra) and overall glucose disposal (Rd) in the fasted state for both surgical groups. The transplant animals demonstrated significant decreases in Rd during the hyperinsulinemic challenge (3.2 +/- 0.01 versus 5.7 +/- 0.01 mg/kg/minute at 60 to 120 minutes for PAT/B versus control). After 16 days of pancreatic polypeptide infusion, however, basal Ra, as well as basal and 60- to 120-minute Rd values, were returned to control values in the transplant group. The authors conclude that pancreas transplantation results in altered glucose disposal, possibly due to an altered effectiveness of systemically released insulin. They conclude that pancreatic polypeptide is an important modulator of peripheral insulin action. Therefore, the role of pancreatic polypeptide must be taken into account when evaluating postoperative glucose metabolism in canine models of pancreas transplantation.

Pancreatic Polypeptide and Peptide YY Inhibit the Denervated Canine Pancreas

Pancreatic polypeptide and peptide YY are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests secondarily mediated mechanism(s) of action. To determine the role of extrinsic neural and intrinsic cholinergic elements on this inhibitory effect, a total of nine dogs underwent two-stage extrapancreatic denervation and creation of a chronic pancreatic fistula. After recovery, pancreatic polypeptide or peptide YY (400 pmol/kg/h) was administered during the intermediate hour of a 3-hour secretion (125 ng/kg/h)/cholecystokinin (50 ng/kg/h) infusion. Exocrine secretion pancreatic polypeptide or peptide YY hours was compared with that of the first and third hours. The studies were then repeated during infusion of atropine (10 micrograms/kg/h). Despite extrinsic denervation, pancreatic polypeptide and peptide YY significantly inhibited secretin/cholecystokinin-induced pancreatic output. Although less profound, significant inhibition persisted in the presence of an atropine background. Pancreatic polypeptide or peptide YY infusion also decreased the exocrine response to meal stimulation. We conclude that the inhibitory effects of pancreatic polypeptide and peptide YY are not mediated by extrapancreatic, and possibly not by intrapancreatic cholinergic, neural pathways.

Effect of pancreatic polypeptide, thyrotropin-releasing hormone, and glucagon on plasma amino acid uptake by human pancreas

The effects of pancreatic polypeptide, thyrotropin-releasing hormone, and glucagon on plasma amino acid uptake by the exocrine pancreas were studied in 12 healthy volunteers aged 22–31 years. Pancreatic amino acid uptake was determined by measuring free plasma amino acid concentration before and during pancreatic stimulation with cerulein (50 ng/kg · h). The administration of this peptide caused a significant decrease (by 14%–20%) in plasma amino acid concentration. Pancreatic polypeptide and thyrotropin-releasing hormone, given at respective doses of 195 pmol/kg · h and 2 μg/kg · h, significantly prevented this decrease by 79.3% and 55.8%, respectively. Glucagon, administered at a dose of 7.5 μg/kg · h, significantly augmented (by 68.8%) the decreasing effect of cerulein on plasma amino acid concentration. In 2 patients with severe exocrine pancreatic insufficiency, cerulein had no effect on the concentration of plasma amino acids, whereas the addition of glucagon caused a marked decrease. The results indicate that pancreatic polypeptide and thyrotropin-releasing hormone are able to inhibit plasma amino acid uptake by pancreatic acinar cells; this inhibitory effect could be a mechanism by which these peptides decrease pancreatic enzyme secretion. Glucagon does not seem to affect pancreatic amino acid uptake, at least not under the experimental conditions of this study. The decrease in plasma amino acid concentration following glucagon administration was likely the result of the stimulation of amino acid uptake by extrapancreatic tissues by this peptide.

The Effect of Pancreatic Polypeptide and Peptide YY on Pancreatic Blood Flow and Pancreatic Exocrine Secretion in the Anesthetized Dog

Pancreatic polypeptide (PP) and peptide YY (PYY) are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests intermediate mechanisms of action. To examine the role of pancreatic blood flow in these inhibitory effects, xenon-133 gas clearance was used to measure pancreatic blood flow while simultaneously measuring pancreatic exocrine secretion. PP or PYY (400 pmol/kg/h) was administered during the intermediate hour of a 3-h secretin (125 ng/kg/h)/cholecystokinin octapeptide (CCK-8) (50 ng/kg/h) infusion. Exocrine secretion and pancreatic blood flow during the PP or PYY hours were compared with that observed in the first and third hours of the secretin/CCK-8 infusion. PP and PYY significantly inhibited secretin/CCK-8-induced pancreatic exocrine secretion. In addition, PYY (but not PP) significantly reduced pancreatic blood flow during secretin/CCK-8 stimulation. Nevertheless, there was no correlation between pancreatic blood flow and bicarbonate or protein outputs. It is concluded that changes in pancreatic blood flow do not mediate the inhibitory effects of PP or PYY on the exocrine pancreas.

Effects of pancreatic polypeptide on biliary flow and bile acid secretion stimulated by secretin and cholecystokinin in the conscious pig

Fourteen castrated male Large White pigs, weighing 42.5 ± 1.0 kg, were fitted with biliary and duodenal fistulae for biliary secretion studies. Furthermore, catheters were placed in a carotid artery for blood sampling and in a jugular vein for peptide infusion. Bile was automatically restituted to the animals and continuously sampled for analysis on experimental days. Following an 8 day recovery period, infusion studies were performed after an overnight fast. After a 30 min basal period, sustained biliary flow and bile acid output were obtained and maintained throughout the assay with secretin (36 pmol/kg/h) and CCK-8 (600 pmol/kg/h) infusion. Then, 200, 400, 600, 800 or 1200 pmol/kg/h of porcine pancreatic polypeptide (PP) were infused for 60 min. Secretin plus CCK infusion was continued for 1 h after PP infusion was stopped. Each dose of PP was given on a separate day. Biliary flow was not affected by PP except for the dose of 400 pmol/kg/h. On the contrary, bile acid concentration and output decreased with the lowest dose of PP (200 pmol/kg/h). As soon as the first dose of PP was infused, bile acid concentration and output fell to about 60% of values obtained with secretin plus CCK. Plasma levels of PP were below or similar to postprandial values for 200, 400 and 600 pmol/kg/h and they were significantly larger with 800 and 1200 pmol/kg/h. Bile acid concentration and output did not return to values obtained with secretin plus CCK infusion after cessation of PP infusion. In conclusion, porcine PP given in physiological doses to the pig decreases bile acid output whereas biliary flow remains unaffected.

Effects of pancreatic polypeptide on the pancreatic exocrine secretion stimulated by secretin and cholecystokinin in the conscious pig

Fourteen castrated male Large White pigs, weighing 42.5 ± 1.0 kg, were fitted with pancreatic and duodenal fistulae for pancreatic secretion studies. Moreover, catheters were placed in a carotid artery for blood sampling and in a jugular vein for peptide infusion. Pancreatic juice was automatically restituted to the animals and continously sampled for analysis on experimental days. Following an 8-day recovery period, perfusion studies were performed after an overnight fast. After a 30-min basal period, sustained pancreatic flow and protein output were obtained and maintained throughout the assay with secretin (36 pmol/kg/h) and CCK-8 (600 pmol/kg/h) infusion. Then, 200, 400, 600, 800 or 1200 pmol/kg/h of porcine pancreatic polypeptide (PP) were infused for 60 min. Secretin + CCK infusion was continued for 1 h after PP infusion was stopped. Each dose of PP was given on a separate day. Neither pancreatic flow nor bicarbonate output were affected whatever the dose of infused PP. On the contrary, protein concentration and output decreased with the lowest dose of PP (200 pmol/kg/h) and the diminution was more pronounced with the other doses. With 600 pmol/kg/h as well as with 800 and 1200 pmol/kg/h of PP, pancreatic protein output fell to about 20% of values obtained with secretin + CCK. Plasma levels of PP were below or similar to postprandial values for 200, 400 and 600 pmol/kg/h and they were significantly larger with 800 and 1200 pmol/kg/h. Protein concentration and output returned to values obtained with secretin + CCK infusion after cessation of PP infusion. In conclusion, porcine PP given in physiological doses to the pig decreases pancreatic protein output whereas pancreatic flow remains unaffected.

Effect of pancreatic polypeptide on the motility of the guinea-pig small intestine in vitro

The effect of porcine pancreatic polypeptide (PP) on the motor activity of the longitudinal and circular muscles of the guinea-pig isolated small intestine was investigated. PP (0.2–20 nM) inhibited cholinergic contractions of the longitudinal muscle in response to electrical field stimulation, the maximal effect being a 30% reduction of the contraction amplitude. Carbachol-induced contractions of the longitudinal muscle were not affected by PP (10 nM). PP (0.3–30 nM) also inhibited reflex contractions of the circular muscle elicited by balloon distension and recorded orally to the site of distension; the maximal effect was a 80% reduction of the reflex contraction. In contrast, carbachol-induced contractions of the circular muscle remained unaltered by PP (10 nM). It was further found that PP (10 and 100 nM) enhanced the threshold intraluminal pressure at which peristaltic waves were triggered. All these effects of PP appeared to be transient. Taken together, these data indicate that PP does not act on intestinal smooth muscle but can modulate the activity of certain enteric neurones which are involved in the regulation of intestinal motility.