Gastrointestinal hormones and apudomas Interest and developments in gastrointestinal hormones "exploded" since gastrin was isolated by Gregory et al1 in 1964. Progress in radioim- Avram M. Cooperman, M.D. munoassay and chromatography had been re- sponsible for the "unleashing" of peptides Department of General Surgery whose nomenclature and properties are scarcely defined before newer peptides are identified and reported. It sometimes seems that there are more peptides than chemical effects attributed to them. Coupled with advances in the chemistry of peptides has been their identification in several clinical syndromes. These syndromes are now more easily recognized than previously because of increasing awareness and the availability of specific therapy (e.g., cimetidine for Zollinger- Ellison syndrome). Basic information about these hormones has been summarized in three recent reviews.2-4 In this paper, the three identified hormones (gas- trin, secretin, and cholecystokinin-pancreo- zymin) are discussed, and also several of the candidate hormones (peptides that await fur- ther clarification before classification as hor- mones), their sites of origin, mechanism of ac- tion, and relation to clinical syndromes. 83 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 84 Cleveland Clinic Quarterly Vol. 44, No. 3 ' Cells of origin involve cyclic AMP, cyclic GMP, and 7 8 Many peptides and hormones may adenylcyclase. ' The association be- share a common cell of origin. This tween cyclic nucleotides and gastroin- testinal hormones was suggested by concept was popularized by Pearse et 9 al5*6 who noted the structural and Sutherland and Rail in 1958. A small chemical similarities of these cells. heat-stable compound found in cellu- Anatomically, the cells are similar to lar membranes capable of stimulating ganglion cells of the neural crest. glycogenolysis was isolated. This was These cells also share chemical simi- 3',5'-cyclic AMP, and it is likely the larities (demonstrated by histochemi- cellular or "second" messenger (the cal techniques). Five of these proper- circulating hormone is the first mes- ties are high fluorogenic amine con- senger). An important component in tent, amine precursor uptake, amino this system is adenylcyclase, an en- acid decarboxylase, side-chain car- zyme that catalyzes the conversion of boxyl groups, and specific immuno- adenosine triphosphate (ATP) to chemical properties. These common cyclic AMP and pyrophosphate. characteristics have led to the acro- Some hormones can penetrate the nym APUD cells for amine precursor cell membrane directly (steroids, es- uptake and decarboxylase cells. The trogens, androgens), but most pep- current list of these cells includes at tides cannot. For these hormones a least 24 specific cells in the stomach, specific binding site is present on the thyroid, islets of Langerhans (pan- cell. Little is known about the sites or creas), duodenum and small intes- numbers of receptors except they are tine, large intestine and anterior pi- numerous (600 to 1000 beta-adrener- tuitary . gic receptors may exist on each tur- key erythrocyte).7 The binding site Early investigations showed the or- and affinity for receptors are spe- igin of APUD cells to be from the cific. Little is understood about the neural crest. These cells have been coupling between hormone and re- shown to migrate to the foregut, mid- ceptor, although phospholipids may gut, and hindgut. If this hypothesis is participate. Cations as Mg+ and Ca++ correct, the origins date back 500 mil- may influence adenylcyclase activity lion years in lower vertebrates. Not as well. Abnormalities in adenylcy- all peptide secreting cells are APUD clase are more than theoretical as dis- cells. Those from the parathyroid eases associated with defects in this and most cells of the anterior pitui- system. These include cholera, tary are not included in this classifica- pseudo-hypoparathyroidism, neph- tion. These totipotential cells may be- rogenic diabetes insipidus, and glyco- come overactive and by hyperplasia, gen storage disease. neoplasia, or dedifferentiation se- crete one or more peptides and cause While enzymatic action of adenyl- a variety of syndromes. cyclase can activate ATP to cyclic AMP, this is the first of the intracellu- lar steps necessary before a cellular Mechanism of action enzymatic function can be produced. The mechanism of action for most Cyclic AMP activates a specific pro- hormones in man has not been de- tein kinase which has two subunits, fined. The most popular hypotheses regulatory and catalytic. It is postu- Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. Summer 1977 Gastrointestinal hormones and apudomas 85 lated that a joined subunit is inactive ter two molecules await chemical and but cyclic AMP dissociates these biological definition. units, liberating a free catalytic com- Most circulating gastrin in man is ponent, the activated enzyme. There produced in the antrum. Less is pro- are many effects of cyclic AMP in- duced in the duodenum and upper cluding contraction of the myocar- jejunum (the antrum contains 5 to 10 dium, relaxation of smooth muscle, times more gastrin than the duo- aggregation of platelets, stimulation denum). The pancreatic islets have of exocrine pancreatic secretion, and little gastrin. Ninety percent of antral perhaps increasing gastric acid secre- mucosal gastrin is G17 and this pre- tion (through one or more mecha- dominates in man. In pernicious ane- nisms). mia and the Zollinger-Ellison syn- In vitro studies have shown that drome G34 is predominant. Walsh13 secretin, glucagon, vasopressin, ste- studied plasma clearance and gastric roids, and vasoactive intestinal poly- secretory activity of G17, G34, and peptide (VIP) increase 3',5'-cyclic G13. G34 was cleared more slowly AMP levels. Gastrin, CCK-PZ, pan- than G17 or G13 and was as potent as creatic polypeptide, and prostaglan- G17 in stimulating gastric acid secre- dins do not increase cyclic AMP sug- tion; G13 was half as potent. Catabo- gesting another mechanism of ac- lism of the molecule is dependent on tion.8 its size. The half life of infused G17 and G34 in dogs was 3" and 15", re- Gastrin spectively. The larger forms are less Most basic and clinical research has readily metabolized. The kidneys been with gastrin. In 1905 Edkins10 play a major role in gastrin catabo- 14,15 presented a paper "On the Chemical lism. Several chemicals as well as Mechanism of Gastric Secretion" in mechanical stimuli release gastrin. which he reported that antral mu- Some of this work is based on animal cosal extracts in anesthetized cats experiments in which the stimulus stimulated gastric acid secretion. He and effect differ from man. In man named the hormone gastrin (for gas- the natural stimulus for gastrin tric secretin). This work was repro- release is food. High protein meals duced and clarified by Komarov11 in and the amino acid glycine are potent 1938. A significant advance was made releasers of gastrin. Fat, carbohy- by Gregory et al1 in 1964 when they drates, and intragastric alcohol are isolated a pure gastrin extract from poor stimulants. hog antral mucosa. This extract was a Mechanical distention of the stom- polypeptide containing 17 amino ach may release gastrin and cause acids in two peptide molecules (gas- acid hypersecretion; this work was in trin I and II). Many refinements and animals and not man. Recently, purifications have followed. There Olbe16 showed that mechanical dis- are at least five gastrin molecules. tention of the antrum caused acid hy- These include minigastrin (G13), lit- persecretion, but the mechanism was tle gastrin (G17), big gastrin (G34), through a pyloro-oxyntic reflux not consisting of at least six molecules, gastrin. big big gastrin and a larger molecule The vagal release of gastrin has 12 (component I of Rehfeld). The lat- been demonstrated by sham feeding Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 86 Cleveland Clinic Quarterly Vol. 44, No. 3 ' in animals and duodenal ulcer pa- stomach and the release of acetylcho- tients. When sham feeding was tested line . Blockage of acetylcholine or his- in normal man there was no gastrin tamine will diminish these effects of release. It is likely that the mecha- gastrin. The increased secretion of nism of acid secretion is direct vagal pepsin by gastrin is secondary to acid stimulation. This variation in behav- secretion. ior may be due to a vagal inhibitor The third effect of pepsin by gas- that is present in normal man but trin on the stomach is trophic.19 This lacking in duodenal ulcer patients. action is confined to the oxyntic area Other hormones and chemicals may of the stomach, duodenum, and pan- release gastrin (calcium, epineph- creas. Cellular integrity and mucosal rine, and calcitonin).17,18 blood flow in hypergastrinemic states Inhibition of gastrin release is pri- are better maintained. Experimen- marily due to gastric acid. Con- tally, when continuous infusions of versely, any disease with decreased gastrin were given, oxyntic mitosis, acid secretion, e.g., pernicious ane- increased DNA and RNA synthesis mia, may be accompanied by in- was noted. In comparison no similar creased levels of serum gastrin. Of effect was seen after histamine infu- increasing importance has been hor- sion. Furthermore, rat stomachs per- monal inhibition of gastrin secretion fused with pentagastrin showed a by other peptides —VIP, glucagon, 100% to 200% increase in incorpora- and secretin. tion of amino acids. Other pharmacologic actions of Actions of gastrin gastrin include stimulation of water The effects of gastrin on the gas- and electrolyte secretion from stom- trointestinal tract in man are phar- ach, pancreas, liver, small intestine; macologic and physiologic. A phar- stimulation of the lower esophageal macologic effect is one that may not sphincter, decrease in gastric empty- be present with ordinary concentra- ing, relaxation of the pyloric sphinc- tions of circulating hormone.