DOCSLIB.ORG

PYY-Tag Transgenic Mice Displaying Abnormal H؉-K؉)Atpase Activity and Gastric Mucosal) Barrier Impairment Umberto Laforenza, Giulia Gastaldi, Guido Rindi, Andrew B

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PYY-Tag Transgenic Mice Displaying Abnormal H؉-K؉)Atpase Activity and Gastric Mucosal) Barrier Impairment Umberto Laforenza, Giulia Gastaldi, Guido Rindi, Andrew B 0023-6837/03/8301-047$03.00/0 LABORATORY INVESTIGATION Vol. 83, No. 1, p. 47, 2003 Copyright © 2003 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. PYY-Tag Transgenic Mice Displaying Abnormal H؉-K؉)ATPase Activity and Gastric Mucosal) Barrier Impairment Umberto Laforenza, Giulia Gastaldi, Guido Rindi, Andrew B. Leiter, Emanuela Cova, Annalisa Marchetti, Maria Elena Candusso, Michele Autelli, Maria Novella Orsenigo, and Ulderico Ventura Department of Experimental Medicine (UL, GG, EC, UV), Section of Human Physiology, and Department of Human Pathology (MEC), University of Pavia, and IRCCS Policlinico S. Matteo (AM, MA), Pavia, and Department of Pathology and Laboratory Medicine (GR), University of Parma, Parma, and Department of General Physiology and Biochemistry (MNO), University of Milan, Milan, Italy; and Division of Gastroenterology (ABL), New England Medical Center, Boston, Massachusetts SUMMARY: The mechanism by which the gastrointestinal hormones peptide YY and glucagon inhibit gastric acid secretion is largely unknown. PYY-Tag transgenic mice develop endocrine tumors in the colon that are composed mainly of peptide YY/enteroglucagon-producing L type cells. Therefore we studied the functional activity of such tumors and the gastric functions of PYY-Tag mice. Fasting and fed PYY-Tag transgenic mice and CD1 controls were assayed for circulating levels of peptide YY, glucagon, insulin, and gastrin. The gastric pH was determined and gastric samples were examined for (a) histologic appearance; (b) Kϩ-stimulated p-nitrophenylphosphatase activity and [14C]aminopyrine accumulation of apical and tubulovesicle membranes; (c) adherent mucus determination by Alcian blue recovery; and (d) DNA/RNA/protein epithelial content and in vivo incorporation of [3H]thymidine into DNA. Transgenic mice showed high serum levels of peptide YY and glucagon, increased gastric pH, and a high incidence of gastric ulcers after fasting. p-Nitrophenylphosphatase activity, [14C] aminopyrine accumulation, and proton pump redistribution from cytoplasmic tubulovesicles to apical membranes were significantly lower in the gastric mucosa of transgenic mice compared with the controls. In addition, the adherent mucus was thinner, and [3H]thymidine incorporation into the DNA was decreased. The abnormal and unregulated levels of circulating peptide YY and glucagon led to gastric acid inhibition and an impairment of gastric barrier function as a result of a striking reduction in epithelial proliferation. (Lab Invest 2003, 83:47– 54). astric acid secretion depends on the activity of vention of neural, endocrine, and paracrine mecha- G (Hϩ-Kϩ)ATPase (EC.3.6.1.36) in parietal cells. In nisms (Urushidani and Forte, 1997; Zeng et al, 1997). humans, basal acid production accounts for 0 to 5 Peptide YY (PYY) and enteroglucagon are synthe- mEq HCl per hour (resting mucosa), whereas after a sized by L-type endocrine cells in the distal ileum and meal it reaches 6 to 40 mEq HCl per hour (stimulated colon and have been shown to inhibit several gut ϩ ϩ mucosa). At rest (H -K )ATPase functions are limited functions including acid secretion (Adrian et al, 1985; by its intracytoplasmic position in vesicles, also called Guo et al, 1987a; Holst, 1997; Pappas et al, 1986; tubulovesicles, and by the reduced permeability of Sheikh, 1991; Walsh, 1994). Considering the location tubulovesicles to KCl (Urushidani and Forte, 1997). of L cells in the distal gut, PYY and enteroglucagon The activation of parietal cells by secretagogues in- may participate in the modulation of transit times, duces tubulovesicle fusion with the apical plasma gastric and pancreatic secretion, and nutrient absorp- membrane (membrane trafficking) and an increase in tion (Goodlad et al, 1991). Both peptides are released permeability to KCl. The regulation of parietal cell into the circulation in response to meal ingestion, with activity is directly or indirectly achieved by the inter- special reference to fats, and are widely considered as potential enterogastrones. Indeed, at physiologic doses, PYY and enteroglucagon may inhibit gastric DOI: 10.1097/01.LAB.0000048720.34096.D7 acid secretion induced by pentagastrin, meal, and Received October 14, 2002. vagal stimulation (Adrian et al, 1985; Anini et al, 1999; This work was supported by COFIN 99 (9905021792_002 and Guo et al, 1987b; Holst, 1997; Sheikh, 1991; Walsh, 9906218982_002 to GR), by the University of Pavia FAR 2001, and by 1994; Wettergren et al, 1994; Yang, 2002; Zeng et al, the Health Ministry (020 RCR 98/03 to GR). Address reprint requests to: Dr. U. Laforenza, Department of Experimental 1997). Although PYY and enteroglucagon colocalize in Medicine, Section of Human Physiology, University of Pavia, Via Forla- the same endocrine cell type and are usually released nini, 6, I-27100 Pavia, Italy. E-mail: [email protected] simultaneously, under certain conditions, only one Laboratory Investigation • January 2003 • Volume 83 • Number 1 47 Laforenza et al peptide may be selectively released (Anini et al, 1999; suggests that high levels of circulating PYY and glu- Brubaker, 1991; Plaisancié et al, 1996). cagon do not interfere with normal gastric endocrine Recently, transgenic mice expressing the simian cell differentiation. virus 40 large T antigen under the control of the rat PYY gene promoter (PYY-Tag) (Upchurch et al, 1994, 1996) were generated to examine the ontogeny of Gastric Acid Secretion Is Reduced in PYY-Tag Mice PYY-producing cells in the developing mouse pan- Gastric acid secretion analysis revealed that the creas and colon. PYY-Tag transgenic mice develop fasting gastric pH was significantly higher in PYY-Tag well-differentiated endocrine tumors of the proximal transgenic mice than in the controls (3.85 Ϯ 0.5 vs colon mainly composed of L type cells. 2.53 Ϯ 0.14, respectively [mean Ϯ SEM], n ϭ 5; p Յ Our objective was to investigate the functional activity 0.02, Student’s unpaired t test). Under the fed condi- of such tumors, gastric acid secretion, and the mucosal tion, the gastric pH was also significantly higher in barrier in the gastric mucosa of both fasting and fed PYY-Tag transgenic mice than in controls (4.52 Ϯ 0.37 PYY-Tag mice. A preliminary partial account of these vs 2.53 Ϯ 0.46 respectively [mean Ϯ SEM], n ϭ 5; p Յ results has already been published in an abstract form 0.01, Student’s unpaired t test). (Gastaldi et al, 2000; Laforenza et al, 2000). ϩ When assaying the gastric vesicles used for K - Results stimulated p-nitrophenylphosphatase (pNPPase) ac- tivity and aminopyrine uptake measurements (see PYY-Tag Mice Showed High PYY and Glucagon Serum following paragraphs), electron microscopic examina- Levels tion revealed that P1 was multilamellar and multive- sicular with a mean diameter larger than for P3 (P1, Serum PYY levels were significantly higher in fed and 760 Ϯ 32 nm; P3, 173 Ϯ 7.2 nm [mean Ϯ SEM], n ϭ 50 ف fasting transgenic mice and corresponded to 10- and from three different samples). Their appearance and ف 50-fold, respectively, compared with controls (Table 1). morphometry were similar to those previously de- ف Glucagon levels were also significantly higher ( 2-fold) scribed (Forte et al, 1981; Reenstra and Forte, 1990). in transgenic mice compared with controls. PYY, but not The Kϩ-stimulated pNPPase activity in both PYY-Tag glucagon, levels were increased in fasting transgenic and control mice was measured with increasing concen- mice compared with fed transgenic mice. Gastrin was trations of KCl and showed a hyperbolic course up to a significantly higher in fed transgenic mice compared with concentration of 10 mM KCl (not shown). In PYY-Tag and both controls and fasting mice (Table 1). No change was control mice, pNPPase activity gradually decreased at observed in insulin serum levels among any of the animal concentrations of 10 to 50 mM KCl. Vmax values were groups considered. significantly lower in the homogenate and P1 fractions of fed transgenic mice compared with controls. In fasting Gastric Endocrine Cells Are Unchanged in PYY-Tag Mice transgenic mice, Vmax value was significantly reduced only in the P1 fraction (Fig. 1). Kmax values remained Gastric endocrine cells of PYY-Tag mice were investi- unchanged (not shown). gated by Grimelius’ silver and vesicular monoamine The meal-induced proton pump redistribution from transporter 2 (VMAT2) immunohistochemistry to assess cytoplasmic tubulovesicles to the apical plasma mem- histamine-producing enterochromaffin-like cells and by brane was investigated by analyzing the ratio of the immunohistochemistry with specific antisera to deter- total Kϩ-stimulated pNPPase activity in P1 to the total mine ghrelin, gastrin, somatostatin, and the rare PYY activity in P3 (P1/P3 ratio) according to Reenstra and cells. The qualitative assessment of size, shape, and Forte (1990). The total pNPPase activity in P1 and P3 number of argyrophil cells and of VMAT2-, ghrelin-, was obtained by multiplying the pNPPase specific gastrin-, somatostatin-, and PYY-immunoreactive activity (␮mol/mg protein · hour) per milligram of total cells showed no apparent change as compared with protein recovered in each fraction. The P1/P3 ratio nontransgenic CD1 mice, except in correspondence was similar in fasting mice but significantly lower in fed of mucosal ulceration (not shown). This observation transgenic mice (Fig. 2). The time course of [14C] Table 1. Serum Gastrointestinal Hormone (PYY, Glucagon, Insulin, and Gastrin) Concentrations in Normal (CD1) and PYY-Tag Transgenic Mice Under Fasting and Fed Conditions Fasting CD1 Fasting Transgenic Fed CD1 Fed Transgenic PYY (pg/ml) 42 Ϯ 7 2130a Ϯ 235 250b Ϯ 94 2699a,c Ϯ 285 Glucagon (pg/ml) 1102 Ϯ 219 1870a Ϯ 105 1015 Ϯ 224 2396a Ϯ 254 Insulin (␮UI/ml) 1.87 Ϯ 0.1 1.78 Ϯ 0.04 1.96 Ϯ 0.1 2.07 Ϯ 0.2 Gastrin (pg/ml) 124 Ϯ 30 118 Ϯ 7 111 Ϯ 34 264d Ϯ 40 Values are mean Ϯ SEM of at least eight different blood samples each from a different mouse.
Load more

Recommended publications
  • Hemodynamic and Renal Effects of Atrial Natriurectic Peptide in Normal
    European Journal of Clinical Investigation The Journal of the European Society for Clinical Investigation Editors-in-Chief R. Arnold, M. Brandis, M. Kern Editorial Board 0. L. M. Bijvoet, A. B. Boneu, G. B. Bolli, J. Brodehl, P. van Brummelen, U. Fölsch, E. Harms, R. D. Hesch, D. R. Higgs, K. Hierholzer, U. Keller, G. Klöppel, K. Kühn, S. Lamberts, H. Löffler, S. Matern, F. R. Matthias, K. H. Meyer z. Büschenfelde, S. Moncada, K. J. Netter, C. Nissen, G. Paumgartner, B. A. Peskar, L. B. A. van de Putte, M. J. Rennie, C. Reiger, E. O. Riecken, H. -D. Roher, H. H. Ropers, P. Schauder, G. Schernthaner, H. Scholz, K. Schrör, V. Schusdziarra, M. Sheppard, K. Sikora, M. V. Singer, E. Steiness, B. E. Strauer, K. Unsicker, G. Utermann, P. Verroust, P. v. Wiehert, R. Ziegler, R. Zinkernagel Volume 18,1988 Published for the European Society for Clinical Investigation by Blackwell Scientific Publications, Oxford London Edinburgh Boston Palo Alto Melbourne Published by Blackwell Scientific Publications Ltd, Osney Mead, Oxford OX2 OEL, U.K. © 1988 Blackwell Scientific Publications Ltd. Authorization of photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Blackwell Scientific Publications Ltd for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the base fee of $3-00 per copy is paid directly to CCC, 27 Congress Street, Salem, MA 01970, U.S.A. Special requests should be addressed to the Editor. 0014-2972/88 $3 00. The use of registered names, trade marks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulation and therefore free for general use.
    [Show full text]
  • Discovery, Characterization, and Clinical Development of the Glucagon-Like Peptides
    Discovery, characterization, and clinical development of the glucagon-like peptides Daniel J. Drucker, … , Joel F. Habener, Jens Juul Holst J Clin Invest. 2017;127(12):4217-4227. https://doi.org/10.1172/JCI97233. Harrington Prize Essay Endocrinology Gastroenterology The discovery, characterization, and clinical development of glucagon-like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance. Find the latest version: https://jci.me/97233/pdf The Journal of Clinical Investigation HARRINGTON PRIZE ESSAY Discovery, characterization, and clinical development of the glucagon-like peptides Daniel J. Drucker,1 Joel F. Habener,2 and Jens Juul Holst3 1Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 2Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA. 3Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. sequences of cloned recombinant cDNA copies of messenger RNAs.
    [Show full text]
  • 1 to the Stomach Inhibits Gut-Brain Signalling by the Satiety Hormone Cholecystokinin (CCK)
    Targeted Expression of Plasminogen Activator Inhibitor (PAI)-1 to the Stomach Inhibits Gut-Brain Signalling by the Satiety Hormone Cholecystokinin (CCK) Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy By Joanne Gamble October 2013 I For Lily, you are the sunshine in my life…. II Table of Contents Figures and tables VII Acknowledgements XI Publications XIII Abstract XIV Chapter 1 ................................................................................................................................ 1 1.1 Overview ........................................................................................................................... 2 1.2 The Gastrointestinal Tract and Digestive Function ...................................................... 4 1.2.1 Distribution, Structure and Biology of Enteroendocrine (EEC) Cells ........................ 5 1.2.2 Luminal Sensing ......................................................................................................... 6 1.3 Energy Homeostasis ......................................................................................................... 7 1.3.1 Gut Hormones ........................................................................................................... 10 1.3.1.1 The Gastrin Family ............................................................................................ 11 1.3.2 PP-fold Family .........................................................................................................
    [Show full text]
  • Defects in Α-Cell Function in Patients with Diabetes Due to Chronic
    Diabetes Care 1 Lena Mumme,1 Thomas G.K. Breuer,1 Defects in -Cell Function in CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL a Stephan Rohrer,1 Nina Schenker,1 Patients With Diabetes Due to Bjorn¨ A. Menge,1 Jens J. Holst,2 Michael A. Nauck,1 and Juris J. Meier1 Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals https://doi.org/10.2337/dc17-0792 OBJECTIVE Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose adminis- tration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypo- glycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to b-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. 1Diabetes Division, Department of Medicine I, CONCLUSIONS St.
    [Show full text]
  • Hormonal Control of Glucose Homoeostasis in Ruminants
    PYOC.Nutr. SOC.(1983), 42, 149 '49 Hormonal control of glucose homoeostasis in ruminants By G. H. MCDOWELL,Dairy Research Unit, Department of Animal Husbandry, University of Syndey, Camden, NSW, 2570, Australia Little, if any, glucose is absorbed from the alimentary tract of the grazing ruminant and it appears that significant absorption of glucose only occurs in ruminants consuming relatively large amounts of grain (Bergman, 1973; Lindsay, 1978). In spite of this, ruminants have an absolute requirement for glucose which is similar to that of nonruminants. Certainly glucose is an essential metabolite for the brain as there is no oxidation of ketones in the brain of the ruminant (Lindsay, 1980). Moreover, glucose is required for turnover and synthesis of fat, as a precursor of muscle glycogen and in pregnant and lactating ruminants, glucose is an essential metabolite. Indeed the glucose requirements of late-pregnant and lactating ruminants increase dramatically beyond that required for maintenance (Bergman, 1973, see also Table 2, p. 164). It is not surprising that volatile fatty acids derived from rumen fermentation of carbohydrate provide some 70% of the energy requirements of the ruminant (Bergman, 1973). Even so, gluconeogenesis and the maintenance of glucose homoeostasis are critical processes in view of the absolute requirements for glucose. Unlike the situation in monogastric species, gluconeogenesis is maximal after feed ingestion and decreases during food restriction. The major factor influencing the rate of gluconeogenesis is the availability of substrates (Lindsay, 1978). In fed ruminants the principal precursors are propionate and amino acids, with lactate and glycerol making minor contributions to glucose production.
    [Show full text]
  • Gut Hormones
    259 PROCEEDINGS OF THE NUTRITION SOCIETY The Three Hundred and Eighteenth Scktajk Meeting was held in the Medical and Biological Sciences Building, University of Southampton, on 20 and 21 July I978 SYMPOSIUM ON ‘HORMONES AND FOOD UTILIZATION’ Gut hormones By S. R. BLOOM, Department of Medicine and J. M. POLAK,Department of Pathology, The Royal Postgraduate Medical School, Hamwsmith Hospital, Du Cane Road, London W12 oHS History At the end of the last century Pavlov proposed that the control of alimentary function was by nervous reflex. His explanation was intellectually satisfying and a great advance on previous extremely woolly theories. Histologically fine nerve fibres which could be seen running in the gut w& and sectioning the main nerve trunks undoubtedly affected gastrointestinal function. Meanwhile, however, Brown Sequard, attempting to rejuvenate his ageing body, was able to show that extracts of testes greatly increased his prowess in several directions. His findings, published in 1889, caught the public imagination and by the end of the century extracts of numerous organs were available for the purpose of treating real and imagined ailments. Thus when Bayliss & Starling were investigating the influence of the duodenum on the exocrine pancreas, the idea of making duodenal extracts came readily. They were astonished to find that such an extract had all the effects on the exocrine pancreas that had been previously attributed to Pavlov’s nervous reflexes. They proposed that there must be a chemical messenger released from the duodenum which acted via the circulation and proposed the term hormone. Nature of the gut endocrine system Although the first substance to be named hormone, secretin, was from the alimentary tract, progress in the understanding of gut endocrinology was very slow.
    [Show full text]
  • Hedonic Interruption of the Physiological Controls of Eating: Sites and Mechanisms
    Dissertation der Graduate School of Systemic Neurosciences der Ludwig-Maximillians-Universität München Hedonic interruption of the physiological controls of eating: sites and mechanisms ESTE LEIDMAA PhD Thesis 5th of Febuary 2016 Thesis Advisory Committee Professor Osborne Almeida (Supervisor) Professor Christophe Magnan (2nd reviewer) Professor Heidrun Potschka Dr. Susanne E La Fleur (External reviewer) Prof. Harald Luksch (Reviewer from GSN) Date of the thesis defence: 22.06.2016 Pühendusega minu perele Table of Contents Table of Contents ........................................................................................................................... List of Abbreviations ...................................................................................................................... i Abstract ............................................................................................................................................ 5 Chapter 1. General Introduction ...................................................................................................... 7 1.1. Feeding – an essential behaviour .................................................................................... 8 1.1.1. Meeting the energy demands of brain and body ....................................................... 8 1.1.2. Overeating and obesity ............................................................................................. 10 1.1.3. Pathological consequences of obesity .....................................................................
    [Show full text]
  • Purification and Sequence of Rat Oxyntomodulin (Enteroglucagon/Peptide/Intestine/Proglucagon/Radlolmmunoassay) NATHAN L
    Proc. Nati. Acad. Sci. USA Vol. 91, pp. 9362-9366, September 1994 Biochemistry Purification and sequence of rat oxyntomodulin (enteroglucagon/peptide/intestine/proglucagon/radlolmmunoassay) NATHAN L. COLLIE*t, JOHN H. WALSHO, HELEN C. WONG*, JOHN E. SHIVELY§, MIKE T. DAVIS§, TERRY D. LEE§, AND JOSEPH R. REEVE, JR.t *Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90024; *Center for Ulcer Research and Education, Gastroenteric Biology Center, Department of Medicine, Veterans Administration Wadsworth Center, School of Medicine, University of California, Los Angeles, CA 90073; and §Division of Immunology, Beckman Institute of City of Hope Research Institute, Duarte, CA 91010 Communicated by Jared M. Diamond, May 26, 1994 ABSTRACT Structural information about rat enteroglu- glucagon plus two glucagon-like sequences (GLP-1 and -2) cagon, intestinal peptides containing the pancreatic glucagon arranged in tandem. The present study concerns the enter- sequence, has been based previously on cDNA, immunologic, oglucagon portion of proglucagon (i.e., the N-terminal 69 and chromatographic data. Our interests in testing the phys- residues and its potential cleavage fragments). iological actions of synthetic enteroglucagon peptides in rats Our use of the term "enteroglucagon" refers to intestinal required that we identify precisely the forms present in vivo. peptides containing the pancreatic glucagon sequence. Fig. 1 From knowledge of the proglucagon gene sequence, we syn- shows two proposed enteroglucagon forms, proglucagon-(1- thesized an enteroglucagon C-terminal octapeptide common to 69) (glicentin) and proglucagon-(33-69) (OXN; see Fig. 1). both proposed enteroglucagon forms, glicentin and oxynto- The primary structures based on amino acid sequence data of modulin, but sharing no sequence overlap with glucagon.
    [Show full text]
  • Gut Hormones in Adaptation
    Gut: first published as 10.1136/gut.28.Suppl.31 on 1 January 1987. Downloaded from Gut, 1987, 28, SI, 31-35 Gut hormones in adaptation S R BLOOM From the Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London. SUMMARY The presence of a circulating factor affecting gut growth can be surmised from the findings in gut isolated from the main food stream and not under direct nutritional influence. Thus when a Thiry Vella fistula is constructed and the crypt cell production rate counted in the fistula it can be shown to correlate with the degree of resection of the main bowel left in continuity. The only hormones which become raised in a similar pattern are enteroglucagon and peptide tyrosine tyrosine (PYY). Enteroglucagon has been shown to be part of preproglucagon, which contains in addition oxyntomodulin, glucagon like peptide 1 1-37 and 6-36NH2 and glucagon like peptide 2. These form the main candidates for the 'hormone of gut growth'. Peptide tyrosine tyrosine has been tested by direct administration over 12 days, matching the natural rise, but no affect on crypt cell production rate was seen. Glucagon like peptide 1 1-37 was similarly tested and also found to produce no effect. It remains to test the other members of the glucagon family to confirm or refute the hypothesis that one of them is the enigmatic small gut growth factor. It is well recognised that after damage, for example by the control groups. All oral food was excluded from infection, the growth rate of the intestinal mucosa the second group which were only fed intravenously increases rapidly and that after small intestinal and gained slightly more weight than the other two http://gut.bmj.com/ resection the residual intestine hypertrophies.
    [Show full text]
  • Distribution of the Gut Hormones in the Primate Intestinal Tract
    Gut: first published as 10.1136/gut.20.8.653 on 1 August 1979. Downloaded from Gut, 1979, 20, 653-659 Distribution of the gut hormones in the primate intestinal tract M. G. BRYANT AND S. R. BLOOM From the Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London SUMMARY Reliable and specific radioimmunoassays have been developed for the gut hormones secretin, gastrin, cholecystokinin, pancreatic glucagon, VIP, GIP, motilin, and enteroglucagon. Using these assays, the relative pattern of distribution of the gut hormones has been determined using the same bowel extracts for all measurements. VIP occurred in high concentration in all regions of the bowel, whereas secretin, GIP, motilin, and CCK were predominantly localised in the proximal small intestine. Pancreatic glucagon was almost exclusively confined to the pancreas. Like VIP, enteroglucagon also exhibited a wide pattern of distribution but was maximal in the ileum. The acid ethanol extraction method that was used was found to be unsuitable for gastrin. On gel chromatography of the extracts, motilin and VIP eluted as single molecular species in identical position to the pure porcine peptides. CCK, pancreatic glucagon, enteroglucagon and GIP were all multiform. Over the last decade the development of radio- peptide throughout the primate intestinal tract immunoassays for the gut hormones has allowed using the same bowel extracts for all measurements. their quantitative measurement both in plasma and in tissue. Although this has prompted several investi- Methods http://gut.bmj.com/ gations to determine the normal distribution of these hormones in different species (Unger et al., 1961; EXTRACTION Bloom and Bryant, 1973; Reeder et al., 1973; The complete intestinal tract was removed after Rehfeld et al., 1975; Bloom et al., 1975; O'Dorisio brief anaesthesia from four healthy baboons and et al., 1976), no comprehensive study has been three monkeys (Macaca Iris) all of whom had been undertaken in the primate.
    [Show full text]
  • (GRP), at a Dose of 5 Pmol/Kg . Min for 30 Min, Have Been 3. Neither Peptide Produced a Discernible Change In
    J. Phy8iol. (1983), 344, pp. 37-48 37 With 6 text-ftgures Printed in Great Britain ENDOCRINE RESPONSES TO EXOGENOUS BOMBESIN AND GASTRIN RELEASING PEPTIDE IN CONSCIOUS CALVES BY S. R. BLOOM*, A. V. EDWARDS AND M. A. GHATEI* From the Department of Medicine, the Royal Postgraduate Medical School, Hammersmith Hospital, London W12*, and the Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG (Received 13 January 1983) SUMMARY 1. The effects ofi.v. infusions ofsynthetic amphibian bombesin and porcine gastrin releasing peptide (GRP), at a dose of 5 pmol/kg . min for 30 min, have been investigated in conscious calves 3-6 weeks after birth. 2. The protocols produced a closely similar rise in the bombesin-like immuno- reactivity of the arterial plasma of 208 + 14 pmol/l (bombesin) and 210 + 32 pmol/l (GRP) which fell exponentially with a half-life ofabout 3 min when the infusions were terminated. 3. Neither peptide produced a discernible change in mean heart rate or aortic blood pressure, or in the mean arterial plasma concentrations of enteroglucagon, gastric inhibitory peptide (GIP), gastrin or cholecystokinin (CCK). 4. GRP, but not bombesin, produced a small but significant rise in the mean plasma somatostatin concentration. 5. Both peptides produced a significant rise in mean plasma pancreatic glucagon and pancreatic polypeptide concentration and proved to be exceptionally potent insulinotropic agents. These responses were associated with a rise in plasma glucose concentration which could not be attributed to a direct action of GRP on the liver. 6. The distribution of bombesin-like immunoreactivity in the gastrointestinal tract was consistent with the findings of other workers who have concluded that it is restricted to nerve terminals.
    [Show full text]
  • Effect of Neuromedin B on Gut Hormone Secretion in the Rat
    Biomedical Research 5 (3) 229-234, 1984 EFFECT OF NEUROMEDIN B ON GUT HORMONE SECRETION IN THE RAT - Mitsuyoshi NAMBA, Mohammad A. GHATEI, Thomas E. ADRIAN, Adolfo J. BACARESE-HAMILTON, Peter K. MULDERRY and Stephen R. BLOOM Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Road, London W12 OHS, U.K. ABSTRACT Neuromedin B is a novel decapeptide which has recently been isolated from porcine spi- nal cord and shows striking sequence homology with bombesin-like peptides at the C-ter- minal region. The effect of synthetic neuromedin B on the secretion of gastrointestinal and pancreatic regulatory peptides has been compared with bombesin in the rat. Insulin, glucagon, enteroglucagon, gastrin, cholecystokinin (CCK) and bombesin were measured in plasma by radioimmunoassays. Neuromedin B (1.0 nmol) had significant stimulatory effects on insulin, enteroglucagon, gastrin and CCK release, similar in pattern but slightly less potent than those ofbombesin (1.0 nmol). Neuromedin B had no significant effect on plasma concentrations of glucagon and bombesin. These results suggest the possibility that neuromedin B could be one of the neural factors which play a regulatory role in the control of the endocrine pancreas and gastrointestinal tract. A variety of putative peptide neurotransmitter with bombesin-like peptides at the C-terminal have been identified by radioimmunoassay and region (Table 1). immunocytochemistry in the gut and pancreas. Although the effect of neuromedin B has not Of these peptides, bombesin-like peptides which hitherto been investigated, it is apparent from was originally isolated from amphibian skin (4), the sequence homology that this peptide may exhibits biological activity on several mamma- well exhibit bombesin-like actions.
    [Show full text]