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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5241-5246
Copyright © 2005 by The Endocrine Society

A Role for Pancreatic Polypeptide in the Regulation of Gastric Emptying and Short-Term Metabolic Control

P. T. Schmidt, E. Näslund, P. Grybäck, H. Jacobsson, J. J. Holst, L. Hilsted and P. M. Hellström

Department of Gastroenterology and Hepatology (P.T.S., P.M.H.), Division of Surgery (E.N.), Danderyd Hospital, and Department of Nuclear Medicine (P.G., H.J.), Karolinska University Hospital, Karolinska Institute, SE-171 76 Stockholm, Sweden; and Departments of Medical Physiology (J.J.H.) and Clinical Chemistry (L.H.), National University Hospital, University of Copenhagen, 2200 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Dr. Peter Thelin Schmidt, Department of Gastroenterology and Hepatology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. E-mail: peter.thelin.schmidt{at}medks.ki.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Previous studies using pancreatic polypeptide (PP) infusions in humans have failed to show an effect on gastric emptying, glucose metabolism, and insulin secretion. This might be due to the use of nonhuman sequences of the peptide.

Objective: The objective of this study was to use synthetic human PP to study gastric emptying rates of a solid meal and postprandial hormone secretion and glucose disposal as well as the gastric emptying rate of water.

Design: This was a single-blind study.

Setting: The study was performed at a university hospital.

Participants: Fourteen healthy adult subjects were studied.

Interventions: Infusion of saline or PP at 0.75 or 2.25 pmol/kg·min was given to eight subjects (gastric emptying of solid food), and infusion of saline or PP at 2.25 pmol/kg·min was given to six subjects (gastric emptying of water).

Main Outcome Measures: The main outcome measures were gastric emptying of solids (scintigraphy), hunger ratings (visual analog scale), and plasma concentrations of PP, insulin, glucagon, somatostatin, glucagon-like peptide 1, glucose, and gastric emptying of plain water (scintigraphy).

Results: PP prolonged the lag phase and the half-time of emptying of the solid meal. The change in hunger rating, satiety, desire to eat after the meal, or prospective consumption was not affected. The postprandial rise in plasma glucose was prolonged by PP. The postprandial rise in insulin was also delayed by PP. PP had no significant effect on the emptying of water.

Conclusions: PP inhibits gastric emptying of solid food and delays the postprandial rise in plasma glucose and insulin. PP is suggested to have a physiological role in the pancreatic postprandial counterregulation of gastric emptying and insulin secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PANCREATIC POLYPEPTIDE (PP) family of regulatory peptides consists of the two hormones, PP and peptide YY, and the neurotransmitter, neuropeptide Y. PP is produced by endocrine F cells located in the periphery of the pancreatic islets (1, 2) and is secreted in response to food intake by a vagal cholinergic mechanism (3, 4).

The physiological role of PP still remains to be defined. PP was first isolated from chickens and cows (5, 6), and most human studies conducted in the 1970s and 1980s were performed with bovine PP (7, 8). However, the use of species-specific PP seems to be of importance due to the large interspecies variations in amino acid sequence (9, 10, 11, 12). The C-terminal part of PP, which is identical for most species, seems to be most important for the biological activity, but the N-terminal part, with species variations, is also required for receptor recognition (13). Thus, bovine PP has a clearly smaller effect on gastric acid secretion in rats that an equimolar dose of rat PP (14). Homologs from other species may have 50- to 100-fold lower affinity for the human receptor (11).

In 1981, Adrian et al. (15) studied gastric emptying in humans using iv infusion of bovine PP, but failed to show an effect, whereas gastric emptying in rats was shown to be inhibited by administration of native PP (16).

We, therefore, hypothesized that an effect of PP on gastric emptying in humans might have been overlooked due to the previous use of a nonhuman form of PP and chose to study the effect of synthetic human PP on gastric emptying of a solid meal, plasma glucose, and secretion of gastropancreatic hormones in healthy subjects. Because PP has been claimed to exert effects on satiety and food intake (17), visual analog scales (VAS) for appetite ratings were included.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

For gastric emptying of solid food, eight healthy human volunteers (four men and four women; age, 26.8 ± 1.3 yr; body mass index, 23.6 ± 0.9 kg/m2), and for gastric emptying of water, six healthy volunteers (two men and four women; age, 35.4 ± 2.5 yr; body mass index, 23.7 ± 0.9 kg/m2) were studied. The ethics and radiation protection committees of Karolinska University Hospital (Solna, Sweden) approved the study, and informed consent was obtained from each subject.

Study protocol

Both gastric emptying studies (solid food and water) were performed in a randomized cross-over fashion on separate days, at least 1 wk apart. The subjects were studied after an overnight fast at 0800 h, and an indwelling catheter was placed in each antecubital vein.

Gastric emptying of solid food. Simultaneously with the intake of a 99mTc-labeled omelet (see below), an iv infusion of either PP (0.75 or 2.25 pmol/kg·min (Neosystem, Strasbourg, France) dissolved in 0.9% saline containing 0.1% albumin (albumin, Kabi, Stockholm, Sweden; 200 mg/ml), subjected to sterile filtration, and stored at –20 C until use) or saline was started and continued for 180 min.

Gastric emptying of water. An infusion of PP (4.5 pmol/kg·min) or saline was given 15 min before intake of water (330 ml radioactively labeled water). Thereafter, the infusion of PP (2.25 pmol/kg·min) or saline was continued for 120 min after water intake.

Scintigraphic gastric emptying. The scintigraphic gastric emptying test of a solid meal has been described in detail previously (18), and the present technique differs only in that water, and not fruit punch, was served with the meal. In short, subjects fasted overnight were studied after ingesting a 1300-kJ omelet with 12–15 MBq 99mTc-labeled macroaggregated albumin (Pulmonate, Amersham Biosciences, Little Chalfont, UK). Anterior and posterior 1-min acquisitions were obtained with the subject in a standing position. Acquisitions were obtained every 5 min during the first 50 min, thereafter every 10 min during 70 min, and finally at 180 min.

The following parameters were calculated: 1) lag phase, defined as the time period from the termination of meal until 90% of radioactivity remained in the stomach; 2) gastric emptying rate, defined as the percentage of radioactivity disappearing per minute during the linear slope after termination of the lag phase; and 3) half-emptying time (T50), defined as the time for 50% emptying of gastric radioactivity after termination of the meal.

The scintigraphic gastric emptying test of water has been described in detail previously (19). In short, subjects fasted overnight were studied after drinking 330 ml tap water (20 C) mixed with 99mTc-labeled diethylenetriamine pentaacetate (Tc-DTPA) within 1 min. Immediately thereafter, dynamic anterior and posterior 1-min acquisitions were initiated during a 45-min period, with two brakes from 13–17 and 33–38 min. The radioactive content of the drink was 10 MBq.

The following parameters were calculated: 1) gastric emptying rate, defined as the percentage of radioactivity disappearing per minute during the linear slope after termination of the lag phase; and 2) the T50, defined as the time for 50% emptying of gastric radioactivity after intake of the drink.

Appetite ratings

VAS, 100 mm long, were used for rating of hunger, satiety, desire to eat, and prospective consumption in the study of solid gastric emptying. VAS were filled in 10 min before the meal and 10, 30, 60, 120, and 180 min after the meal.

Blood samples and RIAs

The blood samples were collected in prechilled heparinized tubes for analysis of PP, insulin, glucagon, somatostatin, glucagon-like peptide-1 (GLP-1) and glucose 20 and 10 min before intake of the 99mTc-labeled omelet and then at the same time intervals as the scintigraphic acquisitions. The samples were centrifuged at 4 C for 10 min at 2000 x g. Plasma was collected and stored at –20 C for analysis in one series.

Plasma levels of PP, glucagon, somatostatin, and GLP-1 were all measured by highly specific RIAs: PP using antibody 146 (20), somatostatin using R37 (21), glucagon using antibody 4305 (22), and GLP-1 using antibody 89390 (23). Plasma levels of insulin and glucose were measured according to the manufacturer’s instructions on an IMx instrument (Abbott Laboratories, Inc., Chicago, IL) using the Abbott IMx insulin assay and on the Modular P (Roche, Burgdorf, Switzerland) using the Roche glucose assay (hexokinase/glucose-6-phosphate dehydrogenase enzymatic reactions).

Data analysis

All results are presented as the mean ± SEM, and differences resulting in P < 0.05 were considered statistically significant. The gastric lag phase, T50, hunger, satiety, desire to eat, and prospective consumption were all statistically evaluated by ANOVA for repeated measures, followed by Dunnett’s test. Liquid gastric emptying T50 were evaluated by Student’s t test.

Plasma profiles of glucose, insulin, glucagon, somatostatin, and GLP-1 were statistically evaluated with Friedman’s test regarding the time until postprandial peak value and area under the curve (AUC), respectively.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma concentrations of PP

Omelet intake. In the saline group, meal ingestion caused a significant increase in PP concentrations (from a basal level of 10.1 ± 1.9 to a maximal concentration of 94.6 ± 9.3 pmol/liter at 90 min). Infusion of PP increased PP to maximal concentrations at 90 min (of 132.9 ± 10.8 and 299.9 ± 23.7 pmol/liter, during infusion of 0.75 and 2.25 pmol/kg·min, respectively; Fig. 1Go).



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  		FIG. 1. Mean ± SEM plasma concentrations of PP during iv infusion of saline ({blacksquare}) or 0.75 (•) or 2.25 ({square}) pmol/kg·min PP in eight healthy human volunteers (P < 0.01 vs. saline) during a meal.

 
Water intake. In the saline group, a small increase in PP concentrations to a maximum of 48.3 ± 23.4 pmol/liter occurred. During PP infusion, a rapid increase was seen, and the maximum concentration after 50 min was 429.7 ± 27.4 pmol/liter (Fig. 2Go).



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  		FIG. 2. Mean ± SEM plasma concentrations of PP during iv infusion of saline ({blacksquare}) or 2.25 pmol/kg·min PP ({square}) in six healthy human volunteers (P < 0.01 vs. saline) after intake of water.

 
Gastric emptying

The gastric emptying curves for solid food are shown in Fig. 3Go. PP inhibited the lag phase in a dose-dependent manner (26.3 ± 3.3, 38.1 ± 4.7, and 41.1 ± 4.9 min, for saline, 0.75 pmol/kg·min PP (P < 0.05), or 2.25 pmol/kg·min PP(P < 0.01), respectively; Fig. 4Go), and the high dose also prolonged the half-emptying time (88.7 ± 8.2, 94.0 ± 8.9, and 106.7 ± 11.3 min for saline, 0.75 pmol/kg·min PP, or 2.25 pmol/kg·min PP, respectively; P < 0.05; Fig. 4Go).



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  		FIG. 3. Mean radioactivity remaining in the stomach after intake of a solid meal during iv infusion of saline ({blacksquare}) or 0.75 (•) or 2.25 ({square}) pmol/kg·min PP in eight healthy human volunteers.

 


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  		FIG. 4. Gastric lag time and half-emptying time of a solid meal during iv infusion of saline or 0.75 or 2.25 pmol/kg·min PP. Values are the mean ± SEM. *, P < 0.05; **, P < 0.01.

 
The gastric emptying curve for water is shown in Fig 5Go. PP had no significant effect on the liquid T50 (P = 0.55). In three subjects, gastric emptying was faster during the PP infusion compared with saline, whereas in the three other subjects, emptying was faster during saline infusion.



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  		FIG. 5. Mean radioactivity remaining in the stomach after intake of radioactively labeled water during iv infusion of saline ({blacksquare}) or 2.25 pmol/kg·min PP ({square}) in six healthy human volunteers. The two hiatuses were made to enable the volunteers to carry out the investigation in a standing position.

 
Satiety

The hunger ratings, calculated as changes from basal values until 180 min, were unaffected by infusion of PP (39.7 ± 8.3, 31.3 ± 8.2, and 32.9 ± 7.1 for saline, 0.75 pmol/kg·min PP, or 2.25 pmol/kg·min PP, respectively). Similar nonsignificant results were also found for ratings of satiety, desire to eat, and prospective consumption (Fig. 6Go).



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  		FIG. 6. VAS rating for hunger, desire to eat, satiety, and prospective consumption after intake of a 1300-kJ omelet during iv infusion of saline ({blacksquare}) or 0.75 (•) or 2.25 ({square}) pmol/kg·min PP in eight healthy human volunteers.

 
Plasma glucose, insulin glucagon, somatostatin, and GLP-1

Solid meal. Meal ingestion during saline infusion caused a significant increase in plasma glucose (from 5.0 ± 0.1 to 6.2 ± 0.3 mmol/liter) and insulin secretion (from 52.9 ± 5.5 to 233.3 ± 63.5 pmol/liter). The glucose concentration stayed high for a longer time during infusion of PP at the high dose (2.25 pmol/kg·min) compared with saline and the low dose of PP (0.75 pmol/kg·min). The AUC for plasma glucose from 30–60 min was significantly higher during the high dose of PP compared with the low dose and saline (142.1 ± 6.2, 141.8 ± 6.6, and 166.4 ± 9.6 mmol/min·liter for control, 0.75 pmol/kg·min PP, or 2.25 pmol/kg·min PP, respectively; P < 0.05; Fig. 7Go). The insulin concentration reached its maximum later with the highest dose of PP compared with saline (24.3 ± 6.5, 22.9 ± 4.2, and 40.0 ± 9.0 min for control, 0.75 pmol/kg·min PP, or 2.25 pmol/kg·min PP, respectively; P < 0.05; Fig. 7Go).



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  		FIG. 7. Mean ± SEM plasma concentrations of glucose and insulin during iv infusion of saline ({blacksquare}) or 0.75 (•) or 2.25 ({square}) pmol/kg·min PP during a meal. *, P < 0.05.

 
Plasma glucagon was marginally influenced by meal ingestion. In the period from 50–180 min postprandially, the AUC tended to be increased during saline infusion compared with both doses of PP (both, P = 0.052; Fig. 8Go).



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  		FIG. 8. Mean ± SEM plasma concentrations of glucagon, somatostatin, and GLP-1 during iv infusion of saline ({blacksquare}) or 0.75 (•) or 2.25 ({square}) pmol/kg·min PP during a meal.

 
Plasma somatostatin and GLP-1 (Fig. 8Go) were not affected by the infusion of PP, but GLP-1 increased in response to meal ingestion.

Water intake. In the studies of gastric emptying of water, there was no difference in insulin and glucose levels between PP and saline infusions (Fig. 9Go).



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  		FIG. 9. Mean ± SEM plasma concentrations of glucose and insulin during iv infusion of saline ({blacksquare}) or 2.25 pmol/kg·min PP ({square}) after intake of water.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A physiological role of PP in the regulation of appetite and food intake has recently been suggested (17, 24, 25). In light of the fast and long-lasting secretion of PP in relation to food intake, a physiological role in the balance among gastric emptying, insulin secretion, and blood glucose is likely. Hence, an endocrine pancreatico-gastric axis, in line with the entero-insular axis (incretin hormones) (26) and the ileal brake phenomenon (27, 28), is postulated to exist.

The question is whether the dose used in our experiment results in physiological or pharmacological plasma levels of PP. Toft-Nielsen et al. (29) studied the effects of a breakfast with an energy content of 2250 kJ. They obtained a plasma level of 250 pmol/liter within 20 min after the meal was begun. In our study the subjects ate an omelet with a low energy content (1298 kJ). With this meal, endogenous PP secretion, as seen in the saline experiments, resulted in a maximal plasma level of 90 pmol/liter. When we gave the highest dose of exogenous PP together with the omelet, we obtained plasma levels of 220–230 pmol/liter within the first 50 min. From 60–120 min, the plasma levels rose to approximately 300 pmol/liter.

The effects of the highest dose of PP (2.25 pmol/kg·min) on the lag time of gastric emptying and the effects on insulin secretion and glucose levels are seen within the first 50 min. Within these initial 50 min, the plasma levels of PP (220–230 pmol/liter) are within the physiological range (250 pmol/liter). Thus, the effects seen in this study are obtained with plasma levels within the physiological range, although after 60 min the plasma levels obtained are slightly supraphysiological.

The effect of PP on gastric emptying of solid food was significant, but minor. One could hypothesize that endogenous PP released due to intake of the omelet was inhibiting gastric emptying submaximally and that an additional increase in plasma PP by exogenous infusion would enhance the inhibitory effect only minimally. To test this hypothesis, we also investigated the effect of PP on gastric emptying of water, where the endogenous release of PP is small. However, PP did not inhibit the emptying of water, and this hypothesis can be rejected. In other words, exogenous PP has a significant, but small, inhibitory effect on gastric emptying of solid food.

Although Adrian et al. (15) failed to shown an effect of infusion of 1 or 2 pmol/kg·min bovine PP in humans, we found a clear inhibitory effect with infusion of almost the same dose of PP using the human sequence. These differences underline the importance of the use of species-specific PP.

Although native PP was used, we did not find any effect of PP on feelings of hunger, satiety, desire to eat, and prospective consumption. A recent study in humans showed that a 90-min infusion of PP at 10 pmol/kg·min given 2 h before a buffet meal reduced appetite and decreased food intake (17). The study design was different from ours, because we infused PP together with a fixed meal and measured appetite during the meal and prospective desire to eat. Our design might not be sensitive enough to detect small effects on appetite, or the concentrations used might have been too low to produce an effect on appetite and food intake.

However, even if not measured, the data obtained by Batterham et al. (17) on appetite reduction are most likely due to a concurrent slowing of gastric emptying, which seems pivotal for reduced appetite and eating. Furthermore, it is known that PP increases after exercise (30, 31, 32). This is in line with the everyday experience that strenuous exercise causes appetite reduction and negative energy balance (33, 34).

In animal studies conflicting results regarding the effect of PP on food intake have been obtained. In some studies, peripheral administration of PP reduced food intake and body weight (mice and dogs) (35, 36, 37), whereas no effect was found in other studies (mice and rats) (38, 39).

The effect of PP on gastric emptying could be either centrally or peripherally mediated, or a combination. In animal studies, the effects of PP exerted in the gastrointestinal tract are dependent on intact vagal function. Vagotomy abolishes the effect of PP on gastric emptying and acid secretion when given intracisternally or by microinjections into the dorsal vagal complex (14, 40, 41). Y4 receptors are found in the dorsal vagal complex, including the nucleus of the solitary tract, area postrema, and the dorsal motor nucleus of vagus (42, 43), as well as in the gastrointestinal tract (9, 44). PP is not produced in the brain, and the blood-brain barrier excludes circulating peptide hormones from entering the brain. However, the area postrema has an incomplete blood-brain barrier. Whitcomb et al. (45) have shown that radiolabeled PP given iv binds at this site and thus gains access to the nucleus of the solitary tract and dorsal motor nucleus of vagus. Another possibility is that PP affects afferent vagal fibers and thereby inhibits gastric emptying. Asakawa et al. (24) found that the anorexigenic effect of PP in mice partly is mediated by vagal afferent pathways. Whether the effect of PP on gastric emptying in humans is mediated directly in gastric tissue or by a central mechanism mediated through the vagus nerve cannot be determined from this study. However, lesions of the area postrema alter the effects of PP on exocrine pancreatic secretion in rats (46), which opens the possibility of a role of the dorsal vagal complex in the effects of PP on gastric emptying. Our findings suggest that the inhibitory effect of PP on gastric emptying most likely is a direct one and not mediated by other gut hormones, such as GLP-1 or somatostatin.

The postprandial increase in plasma glucose was sustained for a longer time by PP infusion at 2.25 pmol/kg·min, and the insulin rise was delayed. The inhibition of gastric emptying is probably the primary step causing the sustained glucose response that, in turn, delays insulin secretion. PP might have a more direct effect on insulin secretion, but several publications describe either no or only minor effects of PP on the endocrine pancreas in vivo as well as in vitro (7, 47, 48, 49). In the study by Batterham et al. (17), infusion of PP in the fasting state had no effect on insulin secretion, supporting the view that the PP effects observed on glucose and insulin levels are directly dependent on the delayed gastric emptying.

The fact that PP at the concentrations attained after food intake can affect the gastric emptying rate and regulates delivery of nutrients for absorption in the small bowel speaks in favor of a metabolic link between the pancreas and stomach, mediated through endocrine mechanisms. Of the pancreatic hormones released after a meal, insulin does not affect gastric emptying (50), and as shown in our present study, glucagon was only marginally increased and somatostatin not at all. PP, however, displayed significantly increased levels after food intake along with an inhibition of gastric emptying. Thus, our data speak in favor of PP as a candidate for endocrine pancreatico-gastric communication. Even if the slowing of gastric emptying as induced by PP was limited with the doses used in our study of healthy individuals, conditions may be different in disease conditions where circulating PP levels can be greatly increased and its effects greater. In response to a meal, plasma PP concentrations increase in parallel with insulin (51, 52, 53, 54). This is the case in the Arizona Pima Indians, who are at risk to develop hyperinsulinemia and are reported to have higher plasma concentrations of PP especially in response to a meal (51, 55). Thus, it is suggested that high PP levels, as seen in conjunction with hyperinsulinemia, can act as a pancreatic feedback mechanism to delimit the preabsorptive delivery of nutrients when hyperinsulinemia is signaling a positive energy balance.

In conclusion, iv infusion of PP in a dose resulting in physiological plasma levels inhibits gastric emptying of a solid meal and delays the postprandial rise in plasma insulin and prolongs glucose increment. This endocrine pancreatico-gastric response of PP may have impact as a metabolic counterregulation of glucose disposal in relation to meal intake.


   Footnotes
 
This work was supported by grants from the Swedish Research Council, the Prof. Nanna Svartz Fund, the Ruth and Richard Juhlin Fund, and the Bengt Ihre Foundation.

First Published Online July 5, 2005

Abbreviations: AUC, Area under the curve; GLP-1, glucagon-like peptide-1; PP, pancreatic polypeptide; T50, half-emptying time; VAS, visual analog scale(s).

Received October 22, 2004.

Accepted June 28, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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