Impaired release of peptide YY in patients with proctocolectomy and ileal pouch-anal anastomosis.

BACKGROUND: Peptide YY (PYY) is a gut hormone produced by endocrine cells in the distal small bowel, colon, and rectum. PYY inhibits upper gastrointestinal secretory and motor functions. The aim of this study was to determine whether basal and postprandial plasma PYY levels in patients with proctocolectomy and ileal pouch-anal anastomosis (IPAA) are reduced and to determine the relationship between plasma PYY and plasma cholecystokinin (CCK) levels. METHODS: Plasma concentrations of PYY and CCK were measured before and after ingestion of a standardized breakfast in 14 IPAA patients and in 12 healthy control subjects. RESULTS: Basal PYY was slightly lower in the IPAA patients than in the controls (8.3 +/- 0.3 versus 9.3 +/- 1.1 pM; not significant). Ingestion of the meal induced a small but significant increase of PYY to a maximum of 10.9 +/- 0.9 pM in patients. Integrated postprandial PYY was markedly reduced in patients when compared with the controls (1725 +/- 66 pM*180min versus 3194 +/- 480 pM*180 min; P < 0.005). Plasma PYY concentrations were inversely correlated with plasma CCK concentrations in the 2nd and 3rd h after the meal (r = -0.86; P = 0.0001). CONCLUSION: PYY release in response to meal ingestion is markedly reduced but not completely absent in patients with proctocolectomy and ileal pouch-anal anastomosis. The inverse relationship between circulating PYY and CCK in the late postprandial phase is compatible with a negative feedback regulation of CCK release by endogenous PYY.     

Effects of bolus doses of fat on small intestinal structure and on release of gastrin, cholecystokinin, peptide tyrosine-tyrosine, and enteroglucagon.

To investigate the enterotrophic effects of bolus doses of long chain triglycerides, two groups of eight female Wistar rats were fed identical diets with 48.2% total calories as the essential fatty acid rich oil Efamol. To one group the oil was given in twice daily bolus doses by gavage, while for the other group the oil was mixed with the remainder of the feed and thus consumed over 24 hours. The animals were killed after 20 to 22 days. Bolus dosing significantly increased parameters of mucosal mass along the length of the small intestine in association with an increase in two hour accumulation of vincristine arrested metaphases in small intestinal crypts. In a second experiment, four replicate studies were carried out, each involving two groups of 12 rats respectively fed as described above. After 21 days one animal from each group was killed every two hours, providing regular plasma samples over 24 hours for measurement of gastrin, cholecystokinin, peptide tyrosine-tyrosine and enteroglucagon. Bolus dosing markedly enhanced release of peptide tyrosine-tyrosine and enteroglucagon, but not of gastrin or cholecystokinin. Thus, the enhanced enterotrophic effects of bolus doses of long chain triglycerides could be mediated by release of a distally located gut peptide, perhaps enteroglucagon.     

Effect of neurotensin on gut mucosal growth in rats with jejunal and ileal Thiry-Vella fistulas.

Neurotensin (NT) stimulates growth of normal and atrophic small bowel mucosa; the mechanisms for this trophic effect of NT are not completely known. The purpose of this study was to (a) determine whether the trophic effect of NT is mediated by mechanisms involving luminal or nonluminal factors and (b) determine whether NT exerts a differential trophic effect on either jejunal or ileal mucosa. Twenty-eight male Sprague-Dawley rats underwent construction of either a jejunal or ileal Thiry-Vella fistula (TVF). After a 1-week recovery period, rats were further subdivided into groups to receive either saline (control) or NT (300 micrograms/kg). Rats were killed on day 6, and TVF as well as corresponding segments of intact jejunum or ileum were removed. Mucosa was scraped, weighed, and analyzed for DNA and protein content. In addition, representative sections of full-thickness bowel from each group were examined histologically. In the jejunal TVF group, NT increased mucosal growth measurements in both the TVF and the intact jejunum. However, in the ileal TVF group, NT stimulated proliferation of intact ileal mucosa only; it had no effect on ileal mucosa in the TVF. These results suggest that NT exerts a systemic effect independent of luminal factors on the proliferation of proximal gut mucosa in addition to an indirect effect produced by stimulation of endogenous luminal secretions. In contrast, an indirect mechanism appears to be the predominant action of NT on growth of distal gut mucosa.     

Effect of jejunal infusion of bile acids on small bowel transit and fasting jejunal motility in man.

The effect of jejunal infusion of glycochenodeoxycholic acid and glycocholic acid on small bowel transit time, fasting jejunal motility and serum bile acid concentrations was investigated in groups of five to six healthy subjects. Glycochenodeoxycholic acid at a concentration of 15 mmol/l (total amount: 5 mmol) and glycocholic acid 15 mmol/l (total amount: 5 mmol), both with lecithin 2.5 mmol/l, delayed (p less than 0.02) small bowel transit when compared with a bile acid free infusion [158.3 (12.5) min v 111.7 (17.6) min and 103.3 (21.8) min v 70.0 (14.9) min], inhibited (p less than 0.01 and p less than 0.05 respectively) the percentage duration of pressure activity of phase 2 [13.1 (1.8)% v 28.1 (3.4)% and 29.2 (5.5)% v 34.9 (3.9)%], but did not change duration of migrating motor complex, or of its phases. Glycochenodeoxycholic acid 10 mmol/l (total amount: 3.3 mmol), either with or without lecithin, did not delay small bowel transit significantly [145.0 (13.2) min v 115.0 (19.5) and 90.0 (11.7) min v 84.0 (8.3)]. When bile acids were infused, serum bile acid curves were similar to those obtained after a liquid meal and the peak serum bile acid concentration occurred 33.7 (6.6) min before (p less than 0.001) completion of small bowel transit. These observations suggest a role for endogenous bile acids in the regulation of small gut motility.     

Stimulatory actions of insulin-like growth factor-I and transforming growth factor-alpha on intestinal neurotensin and peptide YY.

Proliferation of the gastrointestinal mucosa is stimulated by the growth factors, insulin-like growth factor-I (IGF-I) and transforming growth factor-alpha (TGF-alpha), or the closely related epidermal growth factor (EGF), as well as the gastrointestinal hormones, gastrin, neurotensin (NT), and peptide YY (PYY). The stimulatory actions of these growth factors or gastrointestinal hormones on the gastrointestinal mucosa may be direct or mediated in part by gastrointestinal peptides or the growth factors, respectively. The purpose of these studies therefore was to examine the effects of IGF-I and TGF-alpha on stomach gastrin and intestinal NT and PYY gene expression [i.e. messenger RNA (mRNA), peptide levels] and secretion. Mice were given recombinant human IGF-I (3, 6 mg/kg BW/day x 14 days). Transgenic mice with the rat TGF-alpha gene linked to a metallothionein promoter were used as a model of chronic TGF-alpha excess. IGF-I and TGF-alpha did not affect gastrin gene expression. Steady-state intestinal NT and PYY mRNA and peptide levels were elevated in a dose-related manner by IGF. TGF-alpha also increased intestinal expression of NT and PYY peptide, but not mRNA levels. Basal serum levels of PYY were elevated by IGF-I and TGF-alpha. IGF-I and TGF-alpha did not increase intestinal chromogranin A (CGA) gene expression, a marker of endocrine cells, or the density of PYY-containing cells in the colon, indicating that the elevations in intestinal gut peptide gene expression by IGF-I and TGF-alpha are not due simply to an increased number of enteroendocrine cells. IV infusion of EGF also stimulated release of PYY in the dog. Together, these findings indicate that IGF-I and TGF-alpha may cause secretion of gut hormones and exert a major upregulatory influence on the regulation of intestinal peptide hormone homeostasis.     

Local effect of neurotensin on canine ileal blood flow, and its release by luminal lipid

This study was performed to determine whether the level of neurotensin in mesenteric venous blood after lipid perfusion is sufficient to establish neurotensin as a mediator of lipid-induced mesenteric vasodilation. In anesthetized dogs, arterial flow to segments of the ileum was recorded, and blood was collected for measurement of neurotensin-like immunoreactivity, and neurotensin and metabolites. Perfusion of the lumen with micellar lipid resulted in an increase in blood blow from 37.7 +/- 4.1 to 44.5 +/- 3.9 ml/min/100 g (p less than 0.01; n = 8); flow to a control segment did not change. Venous plasma neurotensin-like immunoreactivity doubled, and neurotensin also increased (to 11.3 +/- 3.9 fmol/ml; p less than 0.05). Close intra-arterial infusion of neurotensin at 5 pmol/min increased blood flow to 44.3 +/- 3.4 ml/min/100 g (p less than 0.025; n = 5); flow to a control segment did not change. Neurotensin-like immunoreactivity increased to the same extent as with lipid perfusion, and neurotensin increased to 28.6 +/- 6.1 fmol/ml (p less than 0.05). No accumulation of metabolites was detected in either experiment. Thus, infused neurotensin caused increased ileal blood flow at a level in venous plasma comparable to that present after lipid perfusion, suggesting that neurotensin may have a role in the local regulation of ileal blood flow.     

Effects of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon, pancreatic glucagon and peptide YY in the rat

The effect of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon (EG), pancreatic glucagon (PG) and peptide YY (PYY) was studied in the rat alcohol model. Plasma levels of gastrin and PYY were not significantly changed under chronic and/or acute alcohol, while PG was stimulated by acute intraperitoneal ethanol injections in control animals as well as in chronically ethanol-fed rats (8 +/- 1 vs. 28 +/- 6 pmol/l, p less than or equal to 0.05, and 7 +/- 1 vs. 21 +/- 4 pmol/l, p less than or equal to 0.05). EG levels were significantly raised after chronic ethanol feeding (45 +/- 5 vs. 73 +/- 8 pmol/l, p less than or equal to 0.01) and even further elevated if an acute dose of alcohol was given to chronically ethanol-fed rats (73 +/- 8 vs. 168 +/- 29 pmol/l, p less than or equal to 0.05). The immunohistologically evaluated numbers of the respective hormone-producing cells were not significantly changed by alcohol feeding. The ethanol-dependent elevations of EG and PG may contribute, at least in part, to the intestinal hyper-regeneration, motility disturbances and altered glucose metabolism observed after alcohol consumption.     

Fat-induced jejunal inhibition of gastric acid secretion and release of pancreatic glucagon, enteroglucagon, gastric inhibitory polypeptide, and vasoactive intestinal polypeptide in man.

The effect of intrajejunal (i.j.) infusion of fat on meal-stimulated gastric acid secretion and release of pancreatic glucagon (PG), enteroglucagon (EG), gastric inhibitory polypeptide (GIP), and vasoactive intestinal polypeptide (VIP) was studied in seven healthy volunteers. I.j. fat markedly inhibited meal-stimulated acid secretion as compared to a control study with i.j. saline infusion. The acid inhibition was accompanied by augmental plasma concentrations of EG, GIP, and VIP but not of PG, suggesting that EG, GIP, and VIP may be among mediators of fat-induced jejunal inhibition of acid secretion. Concentration-time relationship makes it unlikely that the observed inhibition could be ascribed to any single peptide studied.     

The enteroglucagon response to intrajejunal infusion of glucose, triglycerides, and sodium chloride, and its relation to jejunal inhibition of gastric acid secretion in man.

In a previous communication we demonstrated that pentagastrin-induced gastric acid secretion is strongly and equally inhibited by intrajejunal infusions of hypertonic glucose, hypertonic sodium chloride, and triglycerides. Samples of peripheral venous blood obtained during these experiments were now analysed for insulin, glucose, pancreatic glucagon, and enteroglucagon. Pancreatic glucagon was stimulated weakly only by triglycerides. Enteroglucagon secretion was strongly stimulated by glucose, moderately by triglycerides, and unaltered after sodium chloride. Insulin secretion was stimulated only during the glucose infusion. We concluded that enteroglucagon is not responsible for the jejunal inhibition of gastric acid secretion in man by jejunal administration of hyperosmolal NaCl solution but may participate in the inhbition evoked by jejunal administration of glucose of triglycerides. Furthermore, it is unlikely that enteroglucagon is in itself insulinogenic in man.     

Effect of ileal infusion of glycochenodeoxycholic acid on segmental transit, motility, and flow in the human jejunum and ileum.

The hypothesis that the presence of glycochenodeoxycholic acid (GCDC) in the human Ileal bile acid concentrations showed a 54.0 (9.3)% absorption of glycochenodeoxycholic acid by the been tested in healthy volunteers. Mean transit times, flow rates and intraluminal pressures in a 40 cm jejunal segment proximal (n = 6) and a 40 cm ileal segment distal (n = 6) to a GCDC infusion port were measured. During GCDC infusion (60 mumol/min) jejunal and ileal transit were markedly (p less than 0.05) delayed (31.6 (7.7), mean (SEM) v 14.5 (3.8) min and 37.0 (5.7) v 21.0 (3.5) min, respectively), segment volumes increased (141.1 (30.2) v 59.2 (9.9) ml and 173.2 (26.3) v 83.9 (9.5) ml; p less than 0.05), while flow rates did not change significantly (4.6 (0.6) v 4.5 (0.6) ml/min and 4.8 (0.5) v 4.2 (0.3) ml/min, respectively). Ileal pressures (distal to the GCDC infusion port) decreased (p less than 0.05) promptly (1.0 (0.1) min) after the start of GCDC infusion. Inhibition of jejunal motility was more gradual and reached significance (p less than 0.05) only 30 min after beginning of the infusion. Ileal bile acid concentrations showed a 54.0 (9.3)% absorption of glycochenodeoxycholic acid by the 40 cm ileal segment. These observations suggest the existence of an intestinal control mechanism in healthy man, whereby presence of glycochenodeoxycholic acid in the ileum inhibits motility and delays transit in the jejunum and ileum.     

Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility.

In immunohistochemical studies using antisera to peptide YY (PYY), a 36 amino acid polypeptide isolated from porcine duodenum, it was found that PYY-like immunoreactivity occurred mainly in endocrine cells of the gastrointestinal mucosa. PYY-immunoreactive cells were particularly abundant in the distal intestine and have been observed in five species, including man. By radioimmunoassay it was found that, in the rat, the amount of PYY immunoreactivity was about 100-fold higher in the colon than in the duodenum. The chromatographic profiles of PYY immunoreactivity from the rat colon and porcine PYY on a SP-Sephadex ion exchanger were similar. Furthermore, serial dilutions of extracts from the rat colon and porcine PYY had parallel displacement curves in radioimmunoassay. Close intraarterial administration of PYY in cats caused an intestinal vasoconstriction and an inhibition of jejunal and colonic motility. Simultaneously there was a rise in systemic arterial blood pressure. These effects of PYY were also observed after pretreatment with adrenergic blocking agents. It is concluded that PYY is a gastrointestinal peptide that is present mainly in endocrine cells of distal intestine and that has effect on both intestinal motility and the cardiovascular system.     

Effect of peptide YY on gastric acid secretion, gastrin and somatostatin release in the rat

The influence of PYY on stimulated gastric acid secretion and the possible role of gastric somatostatin was measured in rats. PYY, infused intravenously at a dose of 800 pmol/kg/h, reduced pentagastrin (20.8 nmol/kg/h) stimulated gastric acid secretion by 34 +/- 3%, whereas in controls acid secretion remained constant throughout the 90 min observation period. In a second series the effect of PYY on the endogenous gastric somatostatin-like immunoreactivity and gastrin-release was tested in the isolated, vascularly perfused rat stomach. PYY perfused at concentrations of 10 pM to 100 nM did not change either somatostatin or gastrin secretion from the rat stomach in vitro. The study shows that PYY suppressed acid secretion in the rat. Endogenous somatostatin or gastrin is unlikely to mediate the inhibitory effect of PYY on acid production.     

Effect of peptide YY on insulin release stimulated by 2-deoxyglucose and neuropeptides in dogs

Peptide YY (PYY) is a hormone released from gut after a meal. The objective of this study was to determine the effect of PYY on insulin release stimulated by either 2-deoxyglucose (2-DG) or neuropeptides in conscious dogs with gastric and duodenal fistulas. In control experiments dogs received either 2-DG (75 mg/kg i.v. bolus) or atropine (25 micrograms/kg bolus followed by 20 micrograms/kg/h i.v.) plus 2-DG (75 mg/kg i.v.) or bethanechol (80 micrograms/kg/h i.v.) or vasoactive intestinal peptide (VIP, 4 micrograms/kg i.v. bolus) or gastrin-releasing peptide (GRP, 400 pmol/kg/h i.v.) or tetragastrin (G4, 100 micrograms/dog, i.v. bolus). On separate days, PYY was also infused intravenously in combination with one of the above stimulants. Given intravenously, PYY (200, 400 pmol/kg/h) significantly inhibited 2-DG stimulated-insulin secretion in a dose-dependent fashion. This inhibitory effect also existed in the presence of atropine. Peptide YY (400 pmol/kg/h) depressed the insulin levels in response to GRP or G4 but failed to inhibit bethanechol- and VIP-stimulated insulin release. After administration of the above stimulants, PYY did not modify the blood sugar concentrations. These results demonstrated that PYY might inhibit the cephalic phase of insulin release from dogs triggered by 2-DG and by the neuropeptides GRP and G4. Thus, PYY may play a negative feedback regulatory role on insulin release.     

Use of antiserum to neurotensin reveals a physiological role for the peptide in rat prolactin release.

Previous studies have indicated that the brain peptide neurotensin can stimulate prolactin release by direct action on the pituitary gland, whereas its action within the hypothalamus is inhibitory. The inhibitory action is mediated by the release of dopamine into the hypophyseal portal veins, which deliver the neurotransmitter to the anterior pituitary gland to inhibit prolactin release. Our experiments were done to evaluate the physiologic significance of these neurotensin actions by injecting the globulin fraction of highly specific neurotensin antiserum either intravenously or intraventricularly. Injection into the third ventricle of either 1 or 3 microliter of neurotensin antiserum significantly increased plasma prolactin concentrations in (i) ovariectomized and (ii) ovariectomized estrogen- and progesterone-primed rats within 1 hr of injection. The response was more pronounced in the ovariectomized than in the ovariectomized estrogen- and progesterone-treated animals and was dose related. Intraventricular injection of these doses of neurotensin antiserum also evoked elevations in plasma prolactin in intact males, which were significant but smaller in magnitude than those seen in female rats. To evaluate the effect of the antiserum on the pituitary directly, the antiserum was injected intravenously at a dose of 40 microliter, which was sufficient to block the blood pressure-lowering effect of neurotensin. After the intravenous injection of antiserum, a highly significant suppression of plasma prolactin occurred, detectable when first measured at 1 hr after injection in both ovariectomized and ovariectomized estrogen- and progesterone-treated animals; however, the intravenous injection of antiserum had no significant effect on the prolactin release in males. These data indicate the physiological significance of the hypothalamic inhibitory actions of neurotensin on prolactin release, which are probably mediated by its stimulation of dopamine release that in turn, inhibits prolactin secretion by the lactotropes. The direct stimulatory effect of the peptide on prolactin release after its presumed release into portal vessels also appears to be physiologically significant in female but not in male rats.     

Human pancreatic polypeptide, neuropeptide Y and peptide YY reduce the contractile motility by depressing the release of acetylcholine from the myenteric plexus of the guinea pig ileum.

Transmural stimulation (TS; 15 V, 0.5 msec, 1-5 Hz, for 30 sec) caused a contraction in a frequency-dependent manner of the longitudinal muscle with myenteric plexus of the guinea pig ileum. Two-min premedication with human pancreatic polypeptide (HPP, 10(-8) M-10(-6) M), neuropeptide Y (NPY, 10(-8) M-10(-6) M), and peptide YY (PYY, 10(-8) M-10(-6) M) partially, by less than 35%, reduced TS (15 V, 0.5 msec, 10 Hz)-evoked contraction in a dose-dependent manner without affecting the resting tensions. Hexamethonium, phentolamine, prazocine, yohimbine, propranolol, naloxone and theophylline had no effects on the inhibitory actions of these peptides on TS-evoked contractions. TS (15 V, 0.5 msec, 10 Hz)-evoked 3H-ACh release was significantly reduced by 2-min premedication of HPP (10(-6) M), NPY (10(-6) M) and PYY (10(-6) M). The order of potency of these depressant effects on TS-evoked contraction and 3H-ACh release was PYY greater than NPY greater than HPP. It is suggested that the members of PP family have inhibitory effects on the contractile motility by depressing ACh release from myenteric plexus of the guinea pig ileum.     

Modulatory effect of insulin on rat small intestinal motility and peptide release in vitro.

Intact segments of rat ileum were stimulated in vitro by either electrical field stimulation (EFS) or cholinergic stimulation with carbachol, in the presence of absence of varying insulin concentrations (50, 100 and 200 microU/ml), and the contraction in the longitudinal axis was recorded. Insulin had no significant influence on the carbachol contractile dose-response curve nor did it affect the cholinergically mediated 'on-contraction' at onset of the electrical stimulus. The 'off-contraction' occurring at cessation of the electrical stimulus was partly mediated by a cholinergic and partly by a noncholinergic and nonadrenergic mechanism, and decreased over time with repeated stimulation. This decay with time was significantly attenuated by insulin. In the presence of insulin, release of bombesin-like immunoreactivity induced by carbachol or EFS significantly increased. On the other hand, the release of somatostatin-like immunoreactivity was suppressed by 50-70% in the presence of insulin. These results demonstrate that in vitro insulin can modify both the motility responses of isolated segments of rat ileum and the neuropeptide release from such segments.     

Plasma cholecystokinin, plasma peptide YY and gallbladder motility in patients with slow transit constipation: effect of intestinal stimulation

BACKGROUND/AIM: Because cholecystokinin and peptide YY are gut hormones with potent effects on gastrointestinal motility, we determined whether abnormalities of cholecystokinin and peptide YY exist in slow transit constipation. METHODS: Plasma concentrations of these hormones before, during and after intraduodenal infusion of a liquid meal in 21 patients with slow transit constipation were compared with the results in 8 healthy controls. RESULTS: Fasting levels of plasma cholecystokinin (3.1+/-0.2 vs. 2.4+/-0.2 pM; p = 0.02) were higher in patients. Basal plasma peptide YY (11.4+/-1.4 vs. 8.9+/-0.7 pM; p = 0.1) tended to be higher in patients. After the meal (60-90 min), incremental cholecystokinin (p<0.05), but not peptide YY, was significantly higher in patients. During intraduodenal infusion of the meal (0-60 min), incremental plasma cholecystokinin (251+/-20 pM.min) and peptide YY (1,146+/-186 pM. min) in patients were almost similar to control values (262+/-22 and 901+/-166 pM. min). Gallbladder volumes before, during and after the meal were not different between the 2 groups. Gastric emptying of a solid meal was delayed in the majority of patients (12 of 18). Abnormalities of plasma cholecystokinin were observed only in patients with delayed gastric emptying. CONCLUSION: Plasma levels of cholecystokinin are elevated in the fasting state and decrease more slowly after stimulation, but maximum release in response to intestinal nutrients is not altered in patients with slow transit constipation. The abnormality seems to be confined to a subgroup of patients with delayed gastric emptying.     

Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans

The level of somatostatin-28, a bioactive peptide derived from pro-somatostatin in gastrointestinal epithelial cells, increases in human plasma after food intake. To determine if an equivalent response occurs with individual components of a mixed meal, somatostatin-28 and prosomatostatin, somatostatin-14, and somatostatin-13, in combination, were measured in healthy men before and after intake of (a) a mixed meal (715 kcal), (b) carbohydrate (100 g equivalent glucose), (c) protein (22 and 45 g), and (d) fat (25 and 50 g). After the mixed meal, somatostatin-28 levels doubled within 120 min and gradually declined by 4 h. With carbohydrate, somatostatin-28 levels were unaltered. After 22 and 45 g of protein, somatostatin-28 increased equivalently within 60 min, representing 30% of the amount with the mixed meal. With 25 g fat, a somatostatin-28 increase similar to that with the meal was seen; this response was doubled with 50 g fat. No changes in prosomatostatin, somatostatin-14, or somatostatin-13 were observed with the mixed meal or with the separate macronutrients. The authors conclude that fat is the major stimulus for somatostatin-28 secretion in humans and hypothesize that somatostatin-28 is an inhibitor of the endocrine and exocrine pancreas during nutrient absorption.