Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man

Regulatory Peptides 158 (2009) 57–62

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Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man A.-B. Witte a, P. Grybäck b, J.J. Holst c, L. Hilsted d, P.M. Hellström a, H. Jacobsson b, P.T. Schmidt a,⁎ a

Department of Medicine, Unit of Gastroenterology and Hepatology, Karolinska University Hospital Solna, Karolinska Institutet, 171 76 Stockholm, Sweden Department of Radiology, Unit of Nuclear Medicine, Karolinska University Hospital Solna, Karolinska Institutet, 171 76 Stockholm, Sweden c Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark d Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark b

a r t i c l e

i n f o

Article history: Received 14 February 2009 Received in revised form 3 June 2009 Accepted 23 July 2009 Available online 3 August 2009 Keywords: Peptide YY Gastric emptying Metabolic control Nausea Satiety

a b s t r a c t Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg− 1 min− 1) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1 ± 5.2 (saline) to 87.0 ± 11.5 min (PYY3-36), whereas retention at 120 min was 2.5 ± 1.4% for saline, 10.7 ± 4.4 for PYY1-36 and 15.8 ± 4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5 ± 22.6 mm) and decreased prospective consumption (VAS change 39.5 ± 7.7 mm). In conclusion, PYY3-36's reducing effect upon food intake might be mediated by a decreased gastric emptying rate. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Peptide tyrosine-tyrosine (PYY) is a hormone secreted from opentype endocrine cells in the gut mucosa, prominently in the ileum and colon [1–5]. When nutrients reach this part of the intestine, PYY is secreted and is assumed to inhibit upper gastrointestinal function as part of the ileal and colonic “brake mechanisms” [6–14]. Both in the circulation and in the intestinal endocrine cells, two forms are abundant and biologically active, namely PYY1-36 and its cleavage product PYY3-36 [15–17]. PYY is co-localized with glucagon-like peptide-1 (GLP-1) in enteroendocrine L-cells [18,19] and both are released after a meal. Possible interactions between the two hormones and their respective roles as insulin secretion modulators have been discussed [19,20]. Intravenous administration of PYY3-36 has been shown to reduce energy intake in both rodents and humans [21–23] and the peptide is currently under evaluation as an anti-obesity agent. According to recent studies, subcutaneous injections of PYY1-36 do not trigger

Abbreviations: AUC, area under the curve; GLP-1, glucagon-like peptide-1; PYY, peptide tyrosine-tyrosine; T50, half-emptying time; VAS, visual analogue scale; Ret120, the percent of radioactivity remaining at 120 min. ⁎ Corresponding author. Department of Medicine, Unit of Gastroenterology and Hepatology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. E-mail address: [email protected] (P.T. Schmidt). 0167-0115/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2009.07.013

satiety to the same level as PYY3-36, but both induce increased postprandial insulin response to a comparable degree [24,25]. PYY1-36 has been shown to inhibit gastric emptying of liquids in humans [13,26]. In rats both PYY1-36 and PYY3-36 inhibit gastric emptying, with PYY3-36 being the most potent [27]. The effect of PYY3-36 on gastric emptying in humans has to our knowledge not been described previously, but in rhesus monkeys it inhibits gastric emptying of liquids and reduces food intake [28]. We therefore investigated the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying of a solid meal. Furthermore, effects on appetite and satiety parameters as well as plasma levels of insulin, GLP-1 and glucose were studied.

2. Methods Eight healthy volunteers (4 men, 4 women; age 28 ± 4; body mass index 22 ± 2 kg m− 2) with no previous or present disease and free of medication (determination based on the candidate's history) were included after informed consent. The original design included nine research subjects; however one was excluded because of substantially pathological emptying results during all infusions including saline control. All subjects were recruited by advertisement at the hospital area. The local ethics and radiation protection committees of the Karolinska University Hospital, Sweden, approved the study.

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Each subject participated in three scintigraphic gastric emptying studies of a solid meal in a randomized cross-over design on separate days, at least one week apart. The study was single blinded. The protocol for the gastric emptying examinations is described elsewhere [29]. In short, subjects were examined at 0800 h after an overnight fast and subsequent ingestion of a 310-kcal egg omelette with added flour prepared in microwave oven. The energy composition is: 57% fat (milk, margarine), 22% protein (milk, two eggs), and 21% carbohydrate (wheat flour). The omelette was labelled with 12–15 MBq 99m Tc-labeled macro-aggregated albumin (Maasol, GE Healthcare Srl, Milano, Italien). In order to imitate normal meal situations, a nonlabelled 70-kcal soft-drink (fruit punch) was added to the meal as a liquid component. All subjects consumed the entire meal at all occasions, consumption lasted maximally 10 min, and no water or further nutrition was offered during experiments. Anterior and posterior 1-min acquisitions were obtained every 5 min during the first 50 min, thereafter every 10 min during 70 min, and finally at 180 min, all with the subject in standing position. In between acquisitions, the subject maintained a sitting position. A dual-head gamma camera was used for all examinations. The following parameters were studied: 1) lag phase, defined as the time period from meal termination until 90% of the radioactivity remained in the stomach; 2) gastric emptying rate, defined as the percentage of radioactivity disappearing per minute during the linear slope after ending of the lag phase; 3) half-emptying time (T50), defined as the time period from meal termination until 50% of the radioactivity remained in the stomach; and 4) retention at 120 min, Ret120, defined as the percent of radioactivity remaining at 120 min. At the three different study occasions, subjects received intravenous infusions of either 0.8 pmol kg− 1 min− 1 synthetic human PYY136 or PYY3-36 (NeoMPS, Strasbourg, France) dissolved in 0.9% saline containing 0.1% albumin (200 mg/ml, Kabi, Stockholm, Sweden), or saline containing albumin alone, via an indwelling catheter placed in one antecubital vein. Infusions were started simultaneously with the meal intake and continued for 180 min. The doses of PPY1-36 and PYY 3-36 were based on previous studies with these peptides [21,22,25]. Blood samples were collected in prechilled heparinized tubes, via an indwelling catheter placed in the other antecubital vein, 20 and 10 min before intake of the meal, and thereafter at the same time intervals as scintigraphic measurements were taken. Samples were centrifuged at 2000 ×g at 4 °C for 10 min. Plasma was collected and stored at − 20 °C for one series analysis of the following: PYY, insulin, GLP-1 and glucose. Insulin concentrations in plasma were measured against standards of human insulin by radioimmunoassay using guinea pig antiserum code no. 2004 according to the principles of Albano et al. [30]. The tracer was human insulin monoiodinated in position A14 (a gift from NovoNordisk, Bagsvaerd, Denmark). Plasma levels of glucose were measured using the Roche Glucose assay on a Modular P instrument (Roche, Burgdorf, Switzerland) respectively, following manufacturer's instructions. GLP-1 concentrations in plasma were measured by radioimmunoassays after extraction of plasma with 70% ethanol (vol/ vol, final concentration). Carboxy-terminal GLP-1 immunoreactivity was determined using antiserum code no. 89390 which has an absolute requirement for the intact amidated carboxy-terminus of GLP-1 7-36 amide and cross-reacts less than 0.01% with carboxyterminally truncated fragments and 89% with GLP-1 9-36 amide, the primary metabolite of dipeptidyl-peptidase IV mediated degradation. The sum of the two components (total GLP-1 concentration) reflects the rate of secretion of the L-cell. Sensitivity was below 1 pmol L− 1, and intra-assay coefficient of variation below 5%. Radioimmunoassay of PYY in plasma was performed using antiserum code no. 8413 (Euro-Diagnostica, Malmoe, Sweden), as described [31]. The antiserum cross-reacts 100% with human PYY 136 and PYY 3-36. Synthetic human PYY 1-36 (Peninsula, Merseyside, UK) was used for standards and porcine 125I–PYY (code no. IM259)

was purchased from Amersham Biosciences, Buckinghamshire UK). The detection limit of the assay was below 2 pmol L− 1 and 50% inhibition was obtained with 40 pmol L− 1 PYY. Recovery of PYY added to plasma in concentrations between 5 and 50 pmol L− 1 deviated less than 15% from expected values. Intra-assay coefficient of variation was below 5%. The antiserum showed no cross-reaction with human NPY or human pancreatic polypeptide in concentrations up to 500 pmol L− 1. No peptide inhibitor was used in the study. The appetite ratings for hunger, satiety, desire to eat, and prospective consumption were scored 10 min before the meal and 10, 30, 60, 120, and 180 min after the meal, using a 100 mm visual analogue scale (VAS). Three of the first four subjects reported nausea during infusion of PYY336. We therefore included rating of nausea in the last four subjects, also using a 100 mm VAS. 2.1. Statistical analysis Mean ± S.E.M. were calculated for all data. Changes in appetite scores were calculated as the difference between min −10 (directly before meal intake) and min 180. Statistical evaluation of the emptying curve and plasma patterns of insulin, glucose, PYY and GLP-1 was performed with repeated measures ANOVA followed by the Bonferroni test. Gastric emptying parameters as lag phase, T50, gastric emptying rate and Ret120 were studied by ANOVA and all VAS measurements by the Friedman's test followed by Dunn's test were used. Differences resulting in P b 0.05 were considered statistically significant. 3. Results 3.1. Plasma concentration of PYY The basal PYY level was 32.2 ± 8.0 pmol L− 1. Stable plasma concentrations of 200–270 pmol L− 1 were obtained within 30 min of continuous infusions of PYY1-36 and PYY3-36. Maximal concentration for PYY1-36 was 265.8 ± 58.3 pmol L− 1 at 50 min and for PYY336 276.4 ± 58.7 pmol L− 1 at 180 min. No significant change in PYY levels was observed during saline infusion and the meal in itself thus had no significant effect on PYY levels (Fig. 1). 3.2. Gastric emptying The gastric emptying patterns are shown in Figs. 2 and 3. Both PYY1-36 and PYY3-36 significantly affected the gastric emptying progress compared to saline (Fig. 2). PYY3-36 slowed emptying rate (from 0.99 ± 0.09 to 0.60 ± 0.05% min− 1) and prolonged halfemptying time (from 63.1 ± 5.2 to 87.0 ± 11.5 min), whereas the lag phase was unaffected (Fig. 3). PYY1-36 did not have any significant effect on gastric emptying rate, half-emptying time or the lag phase,

Fig. 1. Mean±SEM plasma concentrations of peptide YY (PYY) during IV infusion of saline (●), 0.8 pmol kg− 1 min− 1 PYY1-36 (■) or PYY3-36 (□) in eight healthy human volunteers. The infusion began at −10 min and continued for 190 min. ⁎ show time points with significant differences between saline and PYY1-36 and # between saline and PYY3-36.

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before infusion start, VAS for nausea as measured in the 4 following subjects increased significantly for PYY3-36 (maximum at 120 min with VAS score of 50.3 ± 15.9 mm). PYY1-36 did not induce nausea in any subject (Fig. 5). 3.5. Plasma concentrations of glucose, insulin and GLP-1

Fig. 2. Mean radioactivity remaining in the stomach after intake of a solid meal, during IV infusion of saline (●), 0.8 pmol kg− 1 min− 1 PYY1-36 (■) or PYY3-36 (□) in eight healthy human volunteers. Values are corrected for physical decay. ⁎ show time points with significant differences between saline and PYY1-36 and # between saline and PYY3-36.

but both PYY1-36 and PYY3-36 had higher retention at 120 min (Fig. 3). The same pattern was observed in the research subject who was excluded from analysis because of slow emptying during saline infusion. Thus, in this subject Ret120 was 93.6% for PYY1-36, 98.0% for PYY3-36 and 71.6% with saline. 3.3. Appetite ratings Neither PYY1-36 nor PYY3-36 had significant effects on the ratings for desire to eat, hunger and satiety. The rating of prospective consumption decreased significantly upon infusion of PYY3-36 but not PYY1-36 (change in VAS score between −10 and 180 min was 9.5±13.2 mm for PYY1-36, 39.5± 7.7 mm for PYY3-36 and 4.1 ±12.5 for saline) (Fig. 4). 3.4. Nausea Of the first 4 studied subjects, 3 spontaneously reported nausea at one of the study occasions, which subsequently could be identified as the occasion of PYY3-36 infusion. Compared to VAS ratings at 10 min

The concentration curves of glucose, insulin and GLP-1 are shown in Fig. 6. During saline infusion, glucose increased in relation to the meal from pre-meal levels of 5.1± 0.2 to maximally 6.1 ± 0.4 mmol L− 1 and insulin from 75.7 ± 9.7 to maximally 170.5 ± 8.1 pmol L− 1, 30 min after food intake. Both PYY1-36 and PYY3-36 had significant effects on the postprandial rise in insulin compared to saline (Fig. 6). The AUC for the whole time period was not affected for insulin or glucose during infusion of saline and any of the two PYY forms (AUC for saline 41.8± 19.7 nmol min, 35.1 ± 16.0 for PYY1-36 and 34.7 ± 15.6 for PYY3-36). However, the AUC30–60 for insulin was decreased by PYY3-36, but not PYY1-36 (AUC30–60 9.3± 4.9 nmol min for saline, 7.4 ± 3.8 for PYY1-36 and 6.8 ± 3.4 for PYY3-36). The basal level of GLP-1 was 14.0 ± 1.6 pmol L− 1. Neither the meal nor infusion of the two PYY forms had any significant effect on the plasma levels of GLP-1 (Fig. 6). 4. Discussion Our data showing a differential inhibitory effect on gastric emptying of the two isoforms of PYY confirms the findings from animal studies that PYY1-36 and PYY3-36 inhibit gastric emptying [27,28,32]. In rats PYY3-36 is more than 10 times as potent as PYY1-36 in prolonging gastric emptying [27]. The same might be the case in humans. We found a significant effect of both PYY1-36 and PYY3-36, with PYY3-36 having the most outspoken effect. Probably due to limit in power we only found significant effect of PYY3-36 on half emptying time and gastric emptying rate, whereas both peptides increased retention at 120 min. The difference in efficacy between PYY1-36 and PYY3-36 is possibly due to differences in receptor binding profiles. PYY1-36 mainly targets Y1, Y2 and Y5 receptors, whereas PYY3-36 is Y2 receptor selective [33].

Fig. 3. Mean± SEM gastric lag-phase time, gastric emptying rate, half-emptying time (T50) and retention at 120 min Ret120 of a solid meal during IV infusion of saline, 0.8 pmol kg− 1 min− 1 PYY1-36 or PYY3-36 in eight healthy human volunteers; ⁎ P b 0.05 and ⁎⁎ P b 0.01.

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Fig. 4. VAS rating 100 mm (actual values) for desire to eat, hunger, satiety and prospective consumption, performed after intake of a solid meal during IV infusion of saline (●), 0.8 pmol kg− 1 min− 1 PYY1-36 (■) or PYY3-36 (□) in eight healthy human volunteers.

Since PYY3-36 selectively works through the Y2 receptor and is more potent in inhibiting gastric emptying than PYY1-36 one would expect that PYY3-36 had a higher affinity for the Y2 receptor than PYY1-36. However, the two peptides have similar affinity for the Y2 receptor [34] and a possible explanation is that PYY1-36 and PYY3-36 both inhibit gastric emptying through Y2 receptors, but that the effect of PYY1-36 is counterbalanced by its stimulatory effects through Y1 or Y5 receptors. Chen et al. [35] found evidence for a central nervous system mediated inhibitory effect through Y2 receptors, but stimulatory effect through Y1 receptors. The dose of PYY1-36 and PYY3-36 we used increased plasma PYY levels to 200–270 pmol L− 1, which is in the supra-physiological range. Although PYY levels increase after food intake the plasma concentration rarely rises above 60 pmol L− 1. Degen et al. [36] studied different meal sizes up to 1500 kcal and obtained maximal plasma levels of approximately 44 pmol L− 1, Le Roux et al. [23] gave 3000 kcal and found maximal levels of 40 pmol L− 1, and Adrian et al. [37] obtained plasma levels of 54 pmol L− 1 after a 4500 kcal meal.

Fig. 5. VAS rating for nausea after intake of a solid meal during IV infusion of saline (●), 0.8 pmol kg− 1 min− 1 PYY1-36 (■) or PYY3-36 (□) in four healthy human volunteers; P b 0.05 for PYY3-36 vs. saline.

It seems that 310 kcal are on the border of giving a significant rise in plasma PYY. In our study 300 kcal was not enough to obtain a significant increase in the saline infusion experiments (placebo to PYY). Morinigo et al. [38] did not find a significant increase in PYY after a 398 kcal liquid meal, whereas Degen et al [36] did find a small but significant increase after a 500 kcal meal. However in two studies it has been shown that significant increase in PPY levels can be obtained with approximately 300 kcal depending on the amount of fibres or the viscosity of the test meal [39,40]. In view of the food-induced secretion of PYY and the colocalization and co-release with GLP-1 [19], one could expect a physiological role of PYY in the balance between gastric emptying, insulin output and blood glucose levels. PYY1-36 has previously been observed to inhibit stimulated insulin secretion in dogs [41,42], mice [43] and rats [44,45], and a direct effect on pancreatic islets is likely [46]. Human studies have so far failed to prove a similar effect for PYY1-36 on either circulating [47] or glucose-stimulated insulin levels [48], a higher postprandial insulin response has, however, been reported [25]. With regard to PYY3-36, increased postprandial glucose and insulin response [25], but no effect on fasting levels [25,49,50] could be observed. Instead, the hormone has been proposed to be involved in the regulation of insulin sensitivity [44]. We could not confirm any of the glucose homeostasis related correlations for PYY, neither for the full-length nor the truncated form of the hormone, although a small inhibition of insulin secretion was observed for both PYY1-36 and PYY3-36. PYY3-36 is known to cause nausea in some individuals [22,25]. Using the same dose as in this study, 0.8 pmol kg− 1 min− 1, but without a concomitant meal, Sloth et al. [25] found that five of nine subjects had to discontinue the infusion due to nausea, abdominal discomfort and heat flushes. In the study by Degen et al. [22] the subjects had not been eating for 4 h when the infusion was started and a meal was not given until 1 h after infusion start. In that study, one out of sixteen individuals had to discontinue at the dosage of 0.8 pmol kg− 1 min− 1, four experienced nausea, one vomiting, six abdominal discomfort and four fullness. None of the subjects in our study reported abdominal discomfort or heat

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It thus seems that PYY1-36 has only minor effect on appetite scores, whereas PYY3-36 seems to reduce appetite if infused for a period before a meal. In our design with initiation of PYY infusion simultaneously with food intake the likelihood of finding significant effects on appetite scores is thus low. In conclusion, the ability of PYY3-36 to reduce food intake might be mediated by a decreased gastric emptying rate and nausea. A role of PYY3-36 or PYY1-36 in short-term metabolic control could not be confirmed. Acknowledgements The work was supported by grants from the Swedish Research Council, the Prof. Nanna Svartz Fund, the NovoNordisk Foundation, the Bengt Ihre Foundation, The Danish Medical Research Council, DanORC, and the Karolinska Institute Faculty Foundation. References

Fig. 6. Mean ± SEM plasma concentrations of glucose, insulin, and glucagon-like peptide-1 (GLP-1) during IV infusion of saline (●), 0.8 pmol kg− 1 min− 1 PYY1-36 (■) or PYY3-36 (□) in eight healthy human volunteers during a solid meal. ⁎ show time points with significant differences between saline and PYY1-36 and # between saline and PYY3-36.

flushes and none had to discontinue the infusion. The degree of side effects might thus be worse if PYY3-36 is infused in the fasting state compared to the fed state. One could speculate whether the effect on gastric emptying and food intake by PYY3-36 is independent of nausea or whether nausea is actually causing decreased emptying rate and energy intake. At doses not causing nausea PYY3-36 does reduce energy intake, shown both with intravenous infusion [22] and subcutaneous administration [25]. Whether these lower doses also decrease gastric emptying is not known and the impact of nausea on the inhibitory effect of PYY3-36 on gastric emptying is thus unknown. PYY1-36 did not have any effect on the appetite parameters, and the only appetite parameter affected by PYY3-36 was prospective consumption. Sloth et al. also did not find any effect on appetite or hunger, but a significant lowered rating of perceived ability to eat for PYY3-36 [25]. Batterham et al. [21] reported on VAS scores for hunger that were reduced by PYY3-36. Degen et al. [22] also found a reduced hunger score before meal intake, but not during or directly after the meal. In the studies by Degen and Batterham, PYY was infused for a longer period before meal intake.

[1] Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89(5): 1070–7. [2] Greeley Jr GH, Hill FL, Spannagel A, Thompson JC. Distribution of peptide YY in the gastrointestinal tract of the rat, dog, and monkey. Regul Pept 1987;19(5–6): 365–72. [3] Kishimoto S, Kato R, Mukai T, et al. Distribution and endocrine morphology of polypeptide YY (PYY) containing cells in the human gut. Hiroshima J Med Sci 1985;34(1): 155–60. [4] Lundberg JM, Tatemoto K, Terenius L, et al. Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility. Proc Natl Acad Sci U S A 1982;79(14): 4471–5. [5] Roddy DR, Koch TR, Reilly WM, Carney JA, Go VL. Identification and distribution of immunoreactive peptide YY in the human, canine, and murine gastrointestinal tracts: species-related antibody recognition differences. Regul Pept 1987;18(3–4): 201–12. [6] Armstrong DN, Krenz HK, Modlin IM, Ballantyne GH. Bile salt inhibition of motility in the isolated perfused rabbit terminal ileum. Gut 1993;34(4): 483–8. [7] Cuche G, Cuber JC, Malbert CH. Ileal short-chain fatty acids inhibit gastric motility by a humoral pathway. Am J Physiol Gastrointest Liver Physiol 2000;279(5): G925–30. [8] Dumoulin V, Moro F, Barcelo A, Dakka T, Cuber JC. Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum. Endocrinology 1998;139(9): 3780–6. [9] Hoentjen F, Hopman WP, Jansen JB. Effect of circulating peptide YY on gallbladder emptying in humans. Scand J Gastroenterol 2001;36(10): 1086–91. [10] Lin HC, Zhao XT, Wang L, Wong H. Fat-induced ileal brake in the dog depends on peptide YY. Gastroenterology 1996;110(5): 1491–5. [11] Nightingale JM, Kamm MA, van Jr dS, Ghatei MA, Bloom SR, Lennard-Jones JE. Gastrointestinal hormones in short bowel syndrome. Peptide YY may be the ‘colonic brake’ to gastric emptying. Gut 1996;39(2): 267–72. [12] Pironi L, Stanghellini V, Miglioli M, et al. Fat-induced ileal brake in humans: a dosedependent phenomenon correlated to the plasma levels of peptide YY. Gastroenterology 1993;105(3): 733–9. [13] Savage AP, Adrian TE, Carolan G, Chatterjee VK, Bloom SR. Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers. Gut 1987;28(2): 166–70. [14] Spiller RC, Trotman IF, Higgins BE, et al. The ileal brake-inhibition of jejunal motility after ileal fat perfusion in man. Gut 1984;25(4): 365–74. [15] Eberlein GA, Eysselein VE, Schaeffer M, et al. A new molecular form of PYY: structural characterization of human PYY(3-36) and PYY(1-36). Peptides 1989;10(4): 797–803. [16] Grandt D, Schimiczek M, Beglinger C, et al. Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1-36 and PYY 3-36. Regul Pept 1994;51(2): 151–9. [17] Grandt D, Schimiczek M, Struk K, et al. Characterization of two forms of peptide YY, PYY(1-36) and PYY(3-36), in the rabbit. Peptides 1994;15(5): 815–20. [18] Eissele R, Goke R, Willemer S, et al. Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Investig 1992;22(4): 283–91. [19] Ballantyne GH. Peptide YY(1-36) and peptide YY(3-36): Part I. Distribution, release and actions. Obes Surg 2006;16(5): 651–8. [20] Camilleri M. Integrated upper gastrointestinal response to food intake. Gastroenterology 2006;131(2): 640–58. [21] Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002;418(6898): 650–4. [22] Degen L, Oesch S, Casanova M, et al. Effect of peptide YY3-36 on food intake in humans. Gastroenterology 2005;129(5): 1430–6. [23] Le Roux CW, Batterham RL, Aylwin SJ, et al. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 2006;147(1): 3–8. [24] Sloth B, Davidsen L, Holst JJ, Flint A, Astrup A. Effect of subcutaneous injections of PYY1-36 and PYY3-36 on appetite, ad libitum energy intake, and plasma free fatty

62

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32] [33] [34]

[35]

[36]

A.-B. Witte et al. / Regulatory Peptides 158 (2009) 57–62 acid concentration in obese males. Am J Physiol Endocrinol Metabol Gastrointest Physiol 2007;293(2): E604–9. Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metabol Gastrointest Physiol 2007;292(4): E1062–8. Allen JM, Fitzpatrick ML, Yeats JC, Darcy K, Adrian TE, Bloom SR. Effects of peptide YY and neuropeptide Y on gastric emptying in man. Digestion 1984;30(4): 255–62. Chelikani PK, Haver AC, Reidelberger RD. Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats. Am J Physiol Regul Integr Comp Physiol 2004;287(5): R1064–70. Moran TH, Smedh U, Kinzig KP, Scott KA, Knipp S, Ladenheim EE. Peptide YY(3-36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am J Physiol Regul Integr Comp Physiol 2005;288(2): R384–8. Gryback P, Hermansson G, Lyrenas E, Beckman KW, Jacobsson H, Hellstrom PM. Nationwide standardisation and evaluation of scintigraphic gastric emptying: reference values and comparisons between subgroups in a multicentre trial. Eur J Nucl Med 2000;27(6): 647–55. Albano JD, Ekins RP, Maritz G, Turner RC. A sensitive, precise radioimmunoassay of serum insulin relying on charcoal separation of bound and free hormone moieties. Acta Endocrinol (Copenh) 1972;70(3): 487–509. Schmidt PT, Ljung T, Hartmann B, Hare KJ, Holst JJ, Hellstrom PM. Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY. Eur J Gastroenterol Hepatol 2005;17(2): 207–12. Chelikani PK, Haver AC, Reidelberger RD. Intravenous infusion of peptide YY(336) potently inhibits food intake in rats. Endocrinology 2005;146(2): 879–88. Wynne K, Stanley S, Bloom S. The gut and regulation of body weight. J Clin Endocrinol Metab 2004;89(6): 2576–82. Keire DA, Mannon P, Kobayashi M, Walsh JH, Solomon TE, Reeve Jr JR. Primary structures of PYY, [Pro(34)]PYY, and PYY-(3-36) confer different conformations and receptor selectivity. Am J Physiol Gastrointest Liver Physiol 2000;279(1): G126–31. Chen CH, Stephens Jr RL, Rogers RC. PYY and NPY: control of gastric motility via action on Y1 and Y2 receptors in the DVC. Neurogastroenterol Motil 1997;9(2): 109–16. Degen L, Drewe J, Piccoli F, et al. Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men. Am J Physiol Regul Integr Comp Physiol 2007;292(4): R1391–9.

[37] Adrian TE, Long RG, Fuessl HS, Bloom SR. Plasma peptide YY (PYY) in dumping syndrome. Dig Dis Sci 1985;30(12): 1145–8. [38] Morinigo R, Moize V, Musri M, et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2006;91(5): 1735–40. [39] Weickert MO, Spranger J, Holst JJ, Otto B, Koebnick C, Möhlig M, Pfeiffer AF. Wheat-fibre-induced changes of postprandial peptide YY and ghrelin responses are not associated with acute alterations of satiety. Br J Nutr 2006;96(5): 795–8. [40] Juvonen KR, Purhonen AK, Salmenkallio-Marttila M, Lähteenmäki L, Laaksonen DE, Herzig KH, Uusitupa MI, Poutanen KS, Karhunen LJ. Viscosity of oat branenriched beverages influences gastrointestinal hormonal responses in healthy humans. J Nutr 2009;139(3): 461–6. [41] Greeley Jr GH, Lluis F, Gomez G, Ishizuka J, Holland B, Thompson JC. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs. Am J Physiol 1988;254(4 Pt 1): E513–7. [42] Pappas TN, Debas HT, Goto Y, Taylor IL. Peptide YY inhibits meal-stimulated pancreatic and gastric secretion. Am J Physiol 1985;248(1 Pt 1): G118–23. [43] Bottcher G, Ahren B, Lundquist I, Sundler F. Peptide YY: intrapancreatic localization and effects on insulin and glucagon secretion in the mouse. Pancreas 1989;4(3): 282–8. [44] Aponte GW, Fink AS, Meyer JH, Tatemoto K, Taylor IL. Regional distribution and release of peptide YY with fatty acids of different chain length. Am J Physiol 1985;249(6 Pt 1): G745–50. [45] Szecowka J, Tatemoto K, Rajamaki G, Efendic S. Effects of PYY and PP on endocrine pancreas. Acta Physiol Scand 1983;119(2): 123–6. [46] Boey D, Sainsbury A, Herzog H. The role of peptide YY in regulating glucose homeostasis. Peptides 2007;28(2): 390–5. [47] Adrian TE, Sagor GR, Savage AP, Bacarese-Hamilton AJ, Hall GM, Bloom SR. Peptide YY kinetics and effects on blood pressure and circulating pancreatic and gastrointestinal hormones and metabolites in man. J Clin Endocrinol Metab 1986;63(4): 803–7. [48] Ahren B, Larsson H. Peptide YY does not inhibit glucose-stimulated insulin secretion in humans. Eur J Endocrinol 1996;134(3): 362–5. [49] Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349(10): 941–8. [50] Neary NM, Small CJ, Druce MR, et al. Peptide YY3-36 and glucagon-like peptide17-36 inhibit food intake additively. Endocrinology 2005;146(12): 5120–7.