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"Gut-feeling" or evidence-based approaches in the evaluation and treatment of human short-bowel syndrome.

Short bowel syndrome is the malabsorptive state that often follows extensive resection of the small intestine. Long-term survival without parenteral nutrition depends on the process of intestinal adaptation, through which the remaining small bowel gradually increases its absorptive capacity. The process of intestinal adaptation is almost exclusively luminal nutrient dependent. To date the clinical management of short bowel patients is mostly based on a 'trial and error' regimen because human data and randomised trials using trophic substances are lacking due to the small number of patients annually present in pediatric surgical centres. We evaluate here the currently available as well as some more recently developed methods of measuring intestinal absorption and adaptation in short bowel patients. New techniques such as measurements of (1) intestinal permeability and carbohydrate absorption using the sugar absorption test, (2) gastrointestinal hormone production of gastrin, cholecystokinin and peptide YY, (3) transmural potential difference of the gastrointestinal tract using electrophysiology and (4) mucosal enzyme expression of lactase and sucrase-isomaltase using immunohistochemistry were evaluated. These new techniques are promising in monitoring the process of adaptation of the remaining intestine and evaluating the effect of therapeutic interventions in patients with short bowel syndrome.

Adaptation, Physiological↗

Effects of neuromedin B, gastrin-releasing peptide-10 and their fragment peptides on secretion of gastrointestinal and pancreatic hormones in dogs.

The effects of neuromedin B (NMB), gastrin-releasing peptide (GRP)-10 and their C-terminal fragment peptides on the pancreatic and gastrointestinal hormone release were studied in dogs. Intravenous bolus injections of NMB and GRP-10 (4.5 nmol/kg) into conscious dogs elicited a sharp and statistically significant rise in plasma gastrin and insulin levels, but only GRP-10 brought on a significant rise in the plasma glucagon and enteroglucagon levels. The degree of stimulation of gastrin and insulin secretion by NMB and GRP-10 was dose-dependent. With a dose of 4.5 nmol/kg, the minimum size of C-terminal fragment peptides of NMB and GRP-10 to stimulate gastrin secretion was NMB and GRP-10, respectively. Both NMB and GRP-10 (0.1-100 nmol/l) stimulated insulin release from the isolated canine pancreas. The glucagon release was stimulated by 10 and 100 nmol/l GRP-10 and was not stimulated by the same doses of NMB. The somatostatin release was not influenced by either peptide. It is concluded that 1) NMB and GRP-10 can stimulate gastrin and pancreatic hormone secretion, and the latter effect may be mainly due to a direct action on the islet cells; 2) the stimulatory effect of GRP-10 is stronger than that of NMB. The difference in the minimal active fragment between NMB and GRP-10 suggests that the amino acid of position 3 - NMB (Leu) and GRP-10 (His) - may play an important role in their biological activity.

Amino Acid Sequence↗

[Fasting serum gastrin, motilin and secretin in treated and untreated hyperthyroidism].

To study the gastrointestinal hormones involved in hyperthyroidism and the interrelationship with the thyroid hormones, the preprandial serum concentrations of gastrin, motilin and secretin were measured by radioimmunoassay in 33 normal subjects and in 104 patients before and after treatment. The following results were obtained. 1) Serum gastrin concentrations in hyperthyroid patients were significantly higher than that of the control, and when the patients reached euthyroidism or hypothyroidism after treatment, the gastrin concentrations in the serum decreased to the normal level. There was a positive correlation between thyroid hormones and serum gastrin. 2) The changes in serum motilin concentrations in hyperthyroidism before and after treatment did not show any significant differences from that of the control. There was a slightly negative relationship between motilin and gastrin and also between T4 and motilin. 3) The mean serum secretin level rose significantly in hypothyroid patients after treatment for hyperthyroidism, but there was no individual correlation between serum secretin and thyroid hormone.

Adult↗

Delayed gastric emptying and intestinal hormones following pancreatoduodenectomy.

BACKGROUND/AIMS: Delayed gastric emptying (DGE) is frequently reported in patients following pancreatoduodenectomy (PD). The present study tested the hypothesis that gastrointestinal hormones known to effect gastric emptying contribute to DGE in patients after PD. METHODS: Patients with (delayed, n = 9) or without clinical signs of DGE (non-delayed, n = 22) after PD were investigated. Plasma concentrations of motilin, glucagon-like peptide-1 (GLP-1), neurotensin, and peptide YY (PYY) and the gastric emptying rate (GER), assessed by the paracetamol absorption method were measured after a liquid meal on postoperative day 11. RESULTS: Days with a nasogastric tube (p < 0.01), days until solid food was tolerated (p < 0.05), and hospital stay (p < 0.001) were increased in delayed compared to non-delayed patients. The total and incremental integrated peptide responses of motilin and GLP-1 were similar, but the responses of neurotensin and PYY were reduced, in delayed compared to non-delayed patients, whether considered on clinical grounds or by measured GER (p < 0.05-0.005). CONCLUSION: Neurotensin and PYY slow the rate of gastric emptying in humans. Therefore, our findings suggest that reduced hormone responses were the consequence of DGE arising from delayed delivery of nutrients to the distal intestine where the endocrine cells secrete neurotensin and PYY reside.

Acetaminophen↗

Colonic cyclic AMP metabolism following chronic ethanol consumption in the rat: effect of hormonal secretagogues.

The colonic cyclic AMP system is known to be involved in intestinal secretion and can be stimulated by a variety of gastrointestinal hormones including prostaglandins. We have investigated the effect of chronic ethanol ingestion on the activity of the key enzymes in cyclic AMP metabolism--adenylate cyclase and cyclic AMP phosphodiesterase--in the colonic mucosa of the rat. Chronic ethanol consumption by feeding a nutritionally adequate liquid diet enhanced basal colonic adenylate cyclase activity significantly by 168% (p less than 0.01), but had no effect on colonic low Km cyclic AMP phosphodiesterase activity. In addition, various hormonal secretagogues were used to stimulate colonic adenylate cyclase. Colonic adenylate cyclase exhibited a significantly greater sensitivity and efficacy to prostaglandins and vasoactive intestinal peptide after chronic ethanol ingestion. Since increased intestinal cyclic AMP production due to an increased activity of intestinal adenylate cyclase is known to promote intestinal secretion of water and electrolytes, the frequently observed diarrhea in alcoholics may be explained at least in part by an enhanced production of colonic cyclic AMP.

3',5'-Cyclic-AMP Phosphodiesterases↗

[Hormonal changes and cellular proliferation following partial resection of the pancreas].

This study is an attempt to elucidate the histomorphologic changes in the different portions of the gastrointestinal tract, occurring after partial resection of the pancreas with occlusion of the canal of the pancreas that remains. Experiments were carried out on dogs. A number of gastrointestinal hormones were determined by radioimmunoassay. Serious hormonal disturbances after operative intervention on the pancreas were found. The hormonal derangements following pancreatic surgery were attributed to histomorphologic changes in the digestive system.

Animals↗

Bombesin: action on gut hormones and calcium in man.

Bombesin, a peptide with widespread biological actions, has been demonstrated in human tissues by immunological methods. To investigate its effect in man, synthetic bombesin was infused at low doses in six male volunteers. Bombesin at 2.4 pmol kg-1 min-1 produced significant rises in plasma insulin, glucagon, pancreatic polypeptide, gastrin, cholecystokinin, motilin, glucose-dependent insulinotropic polypeptide, neurotensin, enteroglucagon, vasoactive intestinal polypeptide, and serum calcium. In contrast, bombesin caused a profound fall in parathyroid hormone levels and reduced plasma glucose concentrations. A late rise in plasma calcitonin was also observed. Bombesin had no significant effect on the pituitary hormones, TSH, GH, PRL, or cortisol. No hormonal changes or alterations in calcium were noted during saline infusions. Bombesin has a marked stimulatory effect on gastrointestinal hormones, which is unique and opposite to the effect of somatostatin, a potent inhibitor of gut hormone release. Bombesin also influences calcium-regulating hormones, either directly or through its action on gut hormones. The bombesin concentrations achieved with the dosages used were low enough to indicate a possible physiological role for the endogenous peptide.

Adult↗

Effect of vasoactive intestinal polypeptide on basal and cholecystokinin-induced gallbladder pressure.

Studies were conducted in vivo to examine the pressure response of the opossum gallbladder to vasoactive intestinal polypeptide (VIP) alone and in combination with cholecystokinin (CCK). The following observations were made (1) VIP alone produced dose-related decreases in basal gallbladder pressure; (2) VIP eliminated spontaneous contractile activity when present; (3) VIP significantly antagonized the expected pressure response to CCK infusion. These observations lend further support to our proposal that the regulation of gallbladder motor function depends upon the actions and interactions of the gastrointestinal hormones on gallbladder smooth muscle.

Animals↗

Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers.

The effect of an infusion of two doses of peptide YY (PYY), a novel putative gastrointestinal hormone, has been assessed on mouth to caecum intestinal transit time and on the rate of gastric emptying after ingestion of an inert 200 ml liquid meal thought unlikely to interrupt fasting gastrointestinal motility patterns. A low dose of PYY was chosen to give plasma concentrations within the range seen postprandially in healthy subjects, while the high dose mimicked the raised levels seen in several malabsorptive conditions. During infusion of PYY at 0.18 pmol/kg/min plasma concentrations rose from a basal of 8 +/- 2 pmol/l to 38 +/- 5 pmol/l and at 0.51 pmol/kg/min to 87 +/- 10 pmol/l. Mouth to caecum transit time was delayed from 67 +/- 4 mins on the saline infusion day to 94 +/- 7 mins (p less than 0.01) on the low dose and 192 +/- 9 mins (p less than 0.001) on the high dose infusion day. Time to 50% gastric emptying was prolonged from 37 +/- 8 mins during saline infusion to 63 +/- 10 mins (p less than 0.05) during low and 130 +/- 12 mins (p less than 0.001) during high dose infusion. Thus the infusion of PYY shows a dose related inhibition of mouth to caecum intestinal transit time and of the rate of gastric emptying and suggests this novel hormonal peptide to be of importance in gastrointestinal physiology.

Dose-Response Relationship, Drug↗

Efffect of vasoactive intestinal polypeptide on gallbladder smooth muscle in vitro.

The effect of vasoactive intestinal polypeptide (VIP) on basal and octapeptide of cholecystokinin (OP-CCK) induced tension was examined with guinea pig gallbladder smooth muscle strips in vitro. VIP alone produced dose-related decreases in resting tension and antagonized spontaneous contractile activity where present. In combination with OP-CCK, VIP decreased the expected contractile respone. The degree of antagonism depended upon the concentrations of OP-CCK and VIP. VIP had no effect on acetylcholine-induced contractions. From these observations, we propose that VIP can affect gallbladder motor activity by decreaseing smooth muscle tone and by antagonizing cholecystokinin. These findings lend further support to our proposal that gallbladder motor function may depend upon the action and interaction of the gastrointestinal hormones.

Animals↗

Vagal and hormonal influences on gastric secretion in duodenal ulcer disease.

Current concepts on the pathophysiology of gastric hypersecretion in duodenal ulcer disease have been presented and the role of vagal nerves and gastrointestinal hormones particularly gastrin has been discussed. Duodenal ulcer patients form a heterogenous group with regard to the gastric acid and pepsin secretion and gastrin release. They may differ from healthy subjects by several wall defined defects including an increased mass of parietal and peptic cells, increased capacity to secrete acid and pepsin, increased vagal drive to the parietal cells, hyperreactivity of antrum, decreased effectiveness of antral and duodenal autoregulatory mechanisms, defective release of secretin, increased gastric emptying and defective removal of gastric acid load from the duodenum. Very little is known what proportion of duodenal ulcer patients suffer from various pathologic disturbences and what are the mechanisms underlying these changes.

Animals↗

[Clinical importance of gut hormones].

The lecture includes materials on gut hormones. Descriptions of the main synthesis places as well as structure and functions of hormones are given. The introduction of radioimmunoassay and immunoenzyme techniques to clinical practice made it possible to reach a success in the field of studying gastrointestinal hormones. Basic gut hormones and their role in the control over functioning digestive system and body as a whole under normal and pathological conditions are given.

Gastrointestinal Hormones↗

Acid releases motilin from human duodenum in vitro.

The effect of hydrochloric acid and sodium hydroxide on motilin release from human duodenal mucosa was studied in vitro. Tissue was incubated in 2 ml chambers continuously perfused with medium and was exposed repeatedly to the stimuli. Motilin released into the medium was determined by a specific radioimmunoassay. Whereas alkalinisation abolished basal motilin release, acidification resulted in a 14-fold increase of peptide secretion. The results indicate that motilin secretion can be stimulated in vitro and that the perfusion system described may be a useful tool in studying the mechanism of gastrointestinal hormone release.

Duodenum↗

Peptide YY attenuates transcription factor activity in tumor necrosis factor-alpha-induced pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a disease characterized by inflammation. Nuclear factor (NF)-kappaB, Smad proteins, and the steroid hormone family peroxisome proliferator-activated receptors (PPARs) are involved in regulation of gene transcription during the disease process. Peptide YY (PYY), a gastrointestinal hormone, inhibits NF-kappaB translocation to acinar nuclei in tumor necrosis factor (TNF)-alpha-induced AP. We investigated TNF-alpha induction of Smad proteins, PPARalpha/gamma, and NF-kappaB by TNF-alpha, and hypothesized that PYY would attenuate this effect. STUDY DESIGN: Rat acinar cells were treated with recombinant TNF-alpha (200 ng/mL). PYY (3 to 36) was added at 500 pM at 30 minutes after TNF-alpha treatment until cell harvest at 2 hours. Western blot analysis and intracellular staining of the p65 subunit of NF-kappaB were performed. NF-kappaB, Smad3/4, and PPARalpha/gamma binding activities were determined by protein/DNA array analysis and verified by electrophoretic-mobility shift assay and densitometry. RESULTS: Cellular localization of NF-kappaB p65 showed nuclear staining within 2 hours, with controls stained in the cytoplasm. With PYY, p65 stained in the cytoplasm. Nuclear p65 was increased significantly (p < 0.05) by TNF-alpha at 2 hours and PYY reduced it. Array analysis revealed upregulation of NF-kappaB, PPARalpha/gamma, and Smad3/4 with TNF-alpha. TNF-alpha stimulated NF-kappaB activation sevenfold, and binding was enhanced (p < 0.05). PYY reduced NF-kappaB binding to control levels. PPAR binding increased 51% after TNF-alpha treatment and was reduced to 33% with PYY. Smad3/4 binding was increased (p < 0.05) above controls with TNF-alpha and PYY reduced it by 40%. CONCLUSIONS: TNF-alpha increases early nuclear translocation of the p65 subunit of NF-kappaB in acinar cells. Exposure to TNF-alpha activates transcription factors NF-kappaB, Smad3/4, and PPARalpha/gamma. PYY reduces this activation. Treatment with PYY may have therapeutic potential in improving AP.

Acute Disease↗

The amino acid sequence of chymodenin, a hormone-like peptide from porcine duodenum, is identical to cytochrome C-oxidase, peptide VII.

The amino acid sequence of chymodenin, a hormone-like peptide from porcine duodenum is reported. The molecule is known to rapidly alter the proportions of digestive enzymes secreted by the rabbit pancreas in vivo and in vitro, by selection of the specific intra-pancreatic source from which the preset mixture of digestive enzymes is secreted. The sequence is identical to that of cytochrome C-oxidase peptide VII (cCoVII) from bovine heart, with the exception of a substitution of threonine for alanine at position 6 and a second substitution of alanine for threonine at position 71. Disulfide bridges link positions 29-64 and 39-53. cCoVII-chymodenin has a pentapeptide (-Ala-Glu-Gly-Thr-Phe-) near the carboxy-terminus which is immediately preceded by an -Arg-Arg- sequence in the porcine and bovine sequences of cCoVII. This peptide is identical to a pentapeptide found close to the amino terminus of the hormones gastric inhibitory peptide (GIP) and glucagon-like peptide I. The identity to cCoVII means chymodenin as isolated is itself unlikely to be a gastrointestinal hormone. However, the partial commonality of sequence with the glucagon-secretin family immediately adjacent to a pro-hormone-like activation site, and the specific actions on the exocrine pancreas, means that the molecule probably mimics the natural actions of an as-yet uncharacterized member of the glucagon family, which exerts a unique action on exocrine pancreatic secretion.

Amino Acid Sequence↗

A personal experience with pancreatic and duodenal neuroendocrine tumors.

BACKGROUND: Since the concept of hormones was proposed in 1901, numerous gastrointestinal hormones and neuroendocrine tumors that can produce these hormones have been identified. The most common tumors are gastrinomas and insulinomas. STUDY DESIGN: During a 35-year experience, there were 82 neuroendocrine tumors, including 37 gastrinomas, 11 insulinomas, 16 nonfunctioning tumors, 11 gastrinomas suspected but not found, 3 tumors arising in lymph nodes, 1 somatostatinoma, 1 glucagonoma, and 2 amphicrine tumors. MEN I syndrome coexisted with three pancreatic gastrinomas, two pancreatic and duodenal gastrinomas, four suspected gastrinomas, one nonfunctioning tumor, two insulinomas, and no duodenal gastrinomas. RESULTS: Of the nine patients with pancreatic gastrinoma without MEN I, three had lymph node, three had liver metastases, and one had both. The mean survival time was 4.8 years. Three patients with pancreatic gastrinoma and MEN I were alive at 2, 17, and 20 years, respectively. Of the 20 patients with duodenal gastrinoma, none had MEN I; 13 had lymph node metastases and 1 had liver metastases. The overall followup was 7.0 years. Ten patients were biochemically cured. Nonfunctioning tumors, with one exception, originated in the pancreas. Of the three gastrinomas potentially arising in lymph nodes, two, and possibly three, were cured by node removal. Eleven patients had an insulinoma. No patient had recurrence of hypoglycemia after removal of an insulinoma. CONCLUSIONS: Patients with duodenal gastrinoma with lymph node metastases were curable, and cures were achieved occasionally after resection of liver metastases. Results of operation were similar for those with and without MEN I. MEN I and metastases were not contraindications to operation; instead, these patients should be operated on aggressively. Gastrinomas not found at operation were likely to be small duodenal gastrinomas. Gastrinomas can arise in a lymph node and can be cured by its removal. Parietal cell vagotomy is recommended after operation for gastrinomas in the event of residual tumor. With the exception of patients with MEN I or microadenomata, insulinomas were treated best by tumor enucleation. Otherwise, Whipple operation or distal pancreatectomy and enucleation of tumor in the remaining pancreas was indicated.

Duodenal Neoplasms↗

Peripheral motilin administration stimulates feeding in fasted rats.

Although the physiologic function of the gastrointestinal hormone motilin remains uncertain, plasma levels of this peptide vary with migrating myoelectric complexes (MMCs) in the small intestine. In the fed state, both MMCs and plasma motilin are suppressed. During fasting, cyclical peaks of motilin in plasma occur at the same time as Phase III of the MMC cycle occurs in the duodenum. This dependence of motilin concentrations in plasma on the feeding state of the animal prompted an investigation of the effects of motilin on feeding behavior. Intraperitoneal injection of motilin into fasted, but not fed, rats stimulated eating in a dose dependent manner. A significant stimulation of feeding was seen at doses of 5 and 10 micrograms/kg. Sated rats did not eat whether injected with motilin or vehicle. The feeding response to motilin was blocked by prior injection of the rats with naloxone, naltrexone, or pentagastrin. The dose response suppression of food intake by naloxone was similar in fasted animals treated with motilin or vehicle. Motilin may function as a hunger hormone during periods of fasting.

Animals↗

Expression of peptide receptors in human endocrine tumours of the pancreas.

BACKGROUND: Gut peptides are known to influence hormone release and growth of endocrine tumours of the pancreas. Although information on somatostatin receptors has been provided recently, little is known on the receptor status of other gastrointestinal hormones in such tumours. AIMS: To analyse the spectrum of gut hormone receptors on endocrine tumours of pancreas. SUBJECTS: Four types of endocrine tumours from eight patientS. METHODS: The receptors for bombesin, secretin, vasoactive intestinal peptide, cholecystokinin, and somatostatin have been visualised and quantified with storage phosphor autoradiography. RESULTS: Bombesin receptors were present in all five gastrinomas and two primary VIPomas. Secretin receptors were expressed in four primary gastrinomas and one primary VIPoma from pancreas. Vasoactive intestinal peptide receptors were identified in four primary gastrinomas and all VIPomas. Furthermore, all VIPomas expressed cholecystokinin-B (gastrin) receptors, whereas, gastrinomas did not contain cholecystokinin-B receptors. The receptors for somatostatin were detected in all gastrinomas and VIPomas. Both somatostatinoma and glucagonoma were negative for all five types of peptide receptors studied. CONCLUSIONS: Besides somatostatin receptors, most of gastrinomas and VIPomas also express receptors for bombesin, secretin, and vasoactive intestinal peptide.

Adenoma, Islet Cell↗