Supraphysiological doses of intravenous PYY 3-36 cause nausea,but no additional reduction in food intake

Abstract

Abstract

Background

Peptide YY (PYY_3-36) infused to levels within the physiological range reduces appetite and food intake in humans without nausea. However, PYY_3-36 has previously been shown to cause nausea at higher doses.

Methods

We studied the relationship of PYY_3-36, nausea and food intake in six volunteers, using three different PYY_3-36 preparations infused to achieve supraphysiological PYY plasma levels.

Results

Supraphysiological levels of PYY caused nausea in five subjects (P < 0.05). Although PYY_3-36 increased satiety (P < 0.05) and reduced food intake (P < 0.05), no greater enhancement of satiety or inhibition of food intake was observed compared with previous reports.

Conclusions

This study cautions against the use of supraphysiological doses of PYY_3-36 as it may increase nausea with no benefit in food reduction.

Introduction

Peptide YY (PYY) is a 36 amino acid peptide present in L-cells throughout the gastrointestinal tract. ¹ Postprandially, PYY is released into the circulation with peak plasma levels appearing in the second hour. ^1,2 Concentrations of PYY are proportional to the calorie content of the meal. ^1,2 PYY_3-36 is the major form both within in the gut mucosa and the circulation. ^1,2 Several gastrointestinal diseases associated with loss of appetite are associated with chronically elevated fasting plasma PYY levels. ² PYY also reduces gastric emptying and delays gastrointestinal transit. ² These actions may decrease nutrient load and increase absorption time in acute small intestinal disease.

PYY_3-36 reduces appetite and food intake in lean and obese humans. ¹ In this and other studies, no nausea was observed when exogenous PYY_3-36 was infused intravenously to reach plasma concentrations similar to that found after a large meal. ^1,2 Phase 1 trials are currently evaluating PYY_3-36 as an obesity treatment. PYY_3-36 has, however, previously been shown to cause nausea at higher doses. ³

Methods

We studied the relationship of PYY_3-36, nausea and food intake in six healthy males aged 25.8 ± 2.4 y (mean ± SD) with a body mass index (BMI) of 22.8 ± 1.5 kg/m², using three different PYY_3-36 preparations (2 different synthetic preparations from Bachem, UK and one from PolyPeptide Laboratories, Germany). The study aimed to achieve supraphysiological PYY plasma levels at least twofold higher than previously attained. ¹ All peptides were prepared as previously described. ¹ The double-blind randomized placebo-controlled four-way crossover study utilized an established protocol of a 90 min 1 pmol/kg/min PYY_3-36 infusion, followed by an ad libitum buffet lunch 120 min after the infusion ended. ¹ There was a minimum of three days between studies. Every 30 min venous blood samples were collected and 100 mm visual analogue scales (VAS) for hunger, satiety and nausea completed by participants. ¹ Written informed consent was obtained (LREC 2003/6616) and PYY immunoreactivity was measured using an established in-house radioimmunoassay. ^1,2

PYY concentration was evaluated by analysis of the final (steady state) concentration. Both peak and end-infusion VAS for nausea and other domains were used for analysis. All data-sets were evaluated to ensure normal distribution with the Kolmogorov-Smirnov test. Parametric statistical analysis was used throughout (Sigmastat v2.0 SPSS Science, Chicago, IL, USA). Statistical comparison between the four interventions were made using ANOVA, and where the F-statistic was significant, differences to control were determined by Holm-Sidak post hoc analysis. Pearson correlation was used to evaluate whether the subjective sensation of ‘nausea’ was related to ‘fullness’ or ‘hunger’ using the pooled data from each of the infusions with three batches of PYY. Pearson correlations were also determined between the end-infusion nausea, fullness and hunger and the subsequent calorie intake. Area under the curve (AUC) was calculated using the trapezoid rule. P < 0.05 was considered statistically significant.

Results

Table 1 shows the results for plasma PYY concentrations achieved at the end of the infusion, nausea as indicated on the VAS at baseline, at the end of the infusion, when the meal was served and the calories consumed. Nausea sensations at the end of the infusion were markedly increased in volunteers given all preparations of PYY_3-36 (P < 0.05) with the exception of one subject who did not experience any nausea during the study. Perception of nausea returned to baseline 30 min after the end of the infusion and remained at these levels for another 90 min until the meal was served. Satiety was increased by all the preparations compared with saline (P < 0.05). All three preparations of PYY_3-36 reduced food intake compared with saline (P < 0.05). Peak nausea was present at the end-infusion point. No correlation was found between peak nausea levels and fullness (P = 0.5). End of infusion nausea did correlate negatively with hunger (R = 0.6, P = 0.02), but there was no correlation between nausea (end of infusion) and hunger pre-meal (120 min after infusion was stopped) R = 0.1, P = 0.7. AUC demonstrated similar results with no correlations between AUC nausea and AUC fullness or calorie intake (P = 0.2 and P = 0.4, respectively). A significant correlation was found with AUC nausea and AUC hunger (R = 0.5, P = 0.02).

Table 1

Data on six subjects following infusion of saline or one of three preparations of PYY_3-36, the plasma PYY concentrations achieved at the end of the infusion, the nausea visual analogue scale (VAS) scores in mm for baseline, at the end of the infusion and when the meal was served and calories consumed

	Plasma PYY end of infusion pmol/L (SEM)	VAS nausea baseline mm (SEM)	VAS nausea end of infusion mm (SEM)	VAS nausea at meal mm (SEM)	Calories kcal (SEM)
Saline	13 ± 4.9	10.8 ± 2.2	10.8 ± 2.2	10.2 ± 6.1	1206 ± 32
Bachem A	146 ± 37*	9.7 ± 2.1	50.7 ± 10.3*	8.7 ± 2.0	984 ± 67*
Bachem B	94 ± 17*	10.8 ± 3.4	39.5 ± 10.5*	12.2 ± 1.9	957 ± 79*
Polypeptide	90 ± 26*	9.0 ± 2.8	39.3 ± 12.2*	8.5 ± 2.1	970 ± 79*

*P < 0.05 from saline day (ANOVA, with Holm-Sidak post hoc analysis)

Three separate batches of PYY_3-36 were used to avoid the remote possibility that any contaminating factor could have caused the observed nausea. All three batches of PYY_3-36 were associated with nausea when infused, suggesting this is a specific response.

Discussion

Previous studies have demonstrated a dose-dependent reduction in food intake following infusion of graded doses of PYY_3-36. ¹ In these studies, PYY_3-36 infusion doses up to 0.8 pmol/kg/min were not associated with nausea. ¹ The mechanism by which higher levels of PYY_3-36 cause nausea is unclear. It has been suggested that hunger, satiety and nausea are points on the same physiological spectrum. ⁴ Certainly, nausea is associated with high dose exogenous infusion of a number of anorectic gut hormones, including cholecystokinin, ⁴ GLP-1, ⁵ exenatide ⁶ and oxyntomodulin. ⁷

The present study, when compared with the previous reports, found no greater enhancement of satiety or inhibition of food intake at supraphysiological plasma PYY levels. ¹ Our results therefore suggest that two PYY threshold levels may exist. Exceeding the first of these thresholds may reduce food intake without nausea, while exceeding the second, higher threshold may cause nausea without further reduction in food intake. Our study found that the subjective feeling of nausea was short-lived and lasted for no more than 30 min. PYY_3-36 significantly reduced food intake after nausea levels had returned to baseline. Though the mechanisms regulating nausea and appetite are complex, these results suggest that the effects of PYY_3-36 on appetite may be independent of its nauseous effects. Normal postprandial release of PYY at physiological levels may reduce food intake without nausea, while the nausea response at high level may be a specific adaptation to particular pathophysiological states, for e.g. tropical sprue, where nausea might reduce further stress on the gastrointestinal tract.

Obese individuals report decreased postprandial satiety and consume more calories. ¹ PYY_3-36 may be an appropriate therapy for obesity because obese humans have lower fasting plasma PYY, an attenuated postprandial PYY response and are sensitive to the anorectic effects of PYY_3-36. ¹ The present study, however, suggests that supraphysiological doses of PYY_3-36 do not further reduce food intake, but do cause nausea. Any therapeutic use of PYY_3-36 will need to take this into account in order to reduce unwanted side-effects.