Chapter 6 Companion site for Basic Medical Endocrinology, 4th Edition Author: Dr. Goodman

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.1 The gastrointestinal tract. A. The stomach and its functional segments. The lining of the body or corpus contains the acid secreting oxyntic mucosa. The antrum and pylorus control access to the initial portion of the intestine, the duodenum. B. The accessory digestive organs, the liver and pancreas. Bile contains excretory products and the sterols and phospholipids that emulsify ingested fats and facilitate their digestion and absorption. C. The intestines. The duodenum is about 30 cm long and leads into the jejunum (about 2.5 meters long), which in turn leads into the ileum (about 3.8 meters long). The large intestine, the colon, is comprised of the ascending, transverse, and descending portions. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.2 Gastric glands. Hormone secreting cells in the epithelial lining of the stomach and intestinal tract are present in deep invaginations of the mucosal surface scattered among cells of various functions. A. Schematic representation of an oxyntic pit. Note that the acid-producing parietal cells, the enzyme-producing chief cells, and the mucus-producing cells and the differentiating cells that renew the mucosal surface are all “open” to the lumen and come in direct contact with the luminal contents. The ECL (enterochromaffin-like) cells, the somatostatin-secreting D cells, and the ghrelin producing cells are “closed” and have no direct contact with luminal contents. B. Schematic representation of the antral pit. Note that parietal cells are absent, and that the somatostatin producing D cells, the gastrin-producing G cells, and the enterochromaffin cells are “open” and come in contact with the luminal contents. A similar arrangement of cells is seen in the crypts of the mucosae of the small and large intestines. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.3 Schematic representation of the enteric nervous system and its connections to sympathetic and parasympathetic neurons. Interneurons and cell bodies of sensory and motor neurons of the enteric nervous system are found in the submucosal plexus and in the myenteric plexus, which lies between the layers of longitudinal and circular smooth muscle. Signals are transmitted both laterally through the layers of the wall and along the length of the GI tract. Enteric neurons communicate with sensory and motor vagal fibers and with sympathetic postganglionic fibers, which also directly innervate blood vessels, intestinal smooth muscle and mucosal secretory cells. (Redrawn from Johnson, L.R. (2003) Essential Medical Physiology, 3rd ed., 469. Elsevier, Academic Press, San Diego.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.4 Vago-vagal reflexes. Sensory signals arising directly from vagal chemo- or mechanoreceptors or transmitted to vagal afferents from enteric neurons pass up the vagus nerve trunks to neurons in the nucleus of the solitary tract, which communicate with efferent neurons in the dorsal motor nucleus and the nucleus ambiguous (vagal integrating centers). Efferent signals travel down the vagal trunks to activate or inhibit secretion or contraction directly or indirectly by way of the enteric nervous system. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.5 Progastrin, procholecystokinin (CCK), and their posttranslational processing. Amino acids are represented in the single-letter amino acid code. Identical amino acid residues in corresponding positions in both hormones are shown in red, and are found largely in the carboxyl terminus. Posttranslational processing removes the 8 amino acids from the carboxyl terminal of progastrin and 11 amino acids from proCCK. The C-terminal glycine is then cleaved, leaving behind its amino group as an amide on the new C-terminal phenylalanine. Amidation is critical for bioactivity of both hormones. Subsequent cleavage by hormone convertases (blue arrows) produces the most prevalent forms of gastrin and CCK. A = alanine, C = cysteine, D = aspartic acid, E = glutamic acid, F = phenylalanine, G = glycine, H = histidine, I = isoleucine, K = lysine, L = leucine, M = methionine, N = asparagine, P = proline, Q = glutamine, R = arginine, S = serine, T = threonine, V = valine, W = tryptophan, Y = tyrosine. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.6 Stimulation of gastric acid secretion. Histamine secreted by enterochromaffin-like (ECL) cells is the principal stimulus for acid (H+) secretion by parietal cells, which receive direct cholinergic (Ach) neural input and endocrine input from gastrin. The vagus provides stimulatory input to ECL cells with the postganglionic neurotransmitter PACAP (pituitary adenyl cyclase activating peptide), and to the gastrin producing G cells with the postganglionic neurotransmitter GRP (gastrin releasing peptide). G cells also secrete gastrin in response to direct stimulation by peptides and amino acids in the antral lumen. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.7 Cellular actions of gastrin, acetylcholine, and histamine on the parietal cell. Convergence of signaling pathways results in synergistic stimulation of hydrochloride acid. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.8 Actions of gastrin and PACAP in ECL cells. Both gastrin and PACAP stimulate G-protein-coupled receptors to activate the IP3 (inositol trisphosphate)/DAG (diacylglycerol phosphate) pathway and increase intracellular Ca2+. IP3 stimulates release of Ca2+ from the endoplasmic reticulum (ER), and DAG-dependent activation of protein kinase C (PKC) results in phosphorylation and activation of membrane calcium channels. Increased Ca2+ triggers release of preformed histamine from storage granules and induces expression of histidine decarboxylase (HDC), the enzyme that catalyzes histamine formation, and expression of at least two proteins, chromagranin (CGA) and vesicular monoamine transporter type 2 (VMAT-2). Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.9 Direct and indirect feedback regulation of gastrin secretion. Gastrin secretion is positively regulated by luminal nutrients and gastrin releasing peptide (GRP), and is negatively regulated by somatostatin (SST). Gastrin reaches D cells in both the antral and oxyntic mucosae by paracrine or endocrine pathways and stimulates them to secrete SST. Increased luminal H+ concentrations stimulate antral and duodenal D cells to secrete SST. Increased H+ concentrations in the duodenum and luminal nutrients in the intestine increase secretion of enteric hormones, which stimulate D cells in the gastric and duodenal mucosae to secrete SST. Increased luminal H+ concentrations are sensed by neuronal chemoreceptors and initiate vago–vagal reflexes, which result in decreased release of GRP and decreased cholinergic inhibition of D cells. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.10 Effects of somatostatin (SST) and control of its secretion in the gastric mucosa. D cells in the oxyntic mucosa have no access to the luminal contents and are stimulated to secrete SST by hormones secreted by endocrine cells downstream in the GI tract, and inhibited by vagal cholinergic nerves. SST secreted by these cells acts mainly as a paracrine factor. D cells in the antral mucosa are stimulated by increases in H+ concentrations and circulating enteric hormones, and are inhibited by vagal cholinergic neurons. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.11 Effects of ingestion of a standardized liquid meal (arrow) on plasma concentrations of cholecystokinin, gall bladder contraction, and pancreatic chymotrypsin secretion in normal subjects. (Redrawn from data of Liddle, R.A., Goldfine, I.D., Rosen, M.S., Taplitz, R.A., and Williams, J.A. (1985) Cholecystokinin activity in human plasma. Molecular forms, responses to feeding and relationship to gall bladder contraction. J. Clin. Invest. 75: 1144–1152; and Owyang, C., Louie, D.S., and Tatum, D. (1986) Feedback regulation of pancreatic enzyme secretion. Suppression of cholecyctokinin release by trypsin. J. Clin. Invest. 77: 2042–2047.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.12 Actions of CCK on pancreatic secretion and bile flow. Major direct actions are indicated by solid blue arrows. Effects of questionable physiological significance are indicated by the dotted blue arrows. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.13 Regulation of CCK secretion. Red arrows indicate inhibitory influences. LCRF = Luminal Cholecystokinin Releasing Factors. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.14 The secretin/glucagon family of peptides. Amino acids are represented by the single letter amino acid code. Residues colored red are identical with those in corresponding positions in secretin. Residues colored cyan or green are identical with those in corresponding positions in at least three family members. Beyond residue 30, in the C terminal region, sequence divergence is almost complete. In most of these peptides the carboxyl terminal amino acid is amidated. A = alanine, C = cysteine, D = aspartic acid, E = glutamic acid, F = phenylalanine, G = glycine, H = histidine, I = isoleucine, K = lysine, L = leucine, M = methionine, N = asparagine, P = proline, Q = glutamine, R = arginine, S = serine, T = threonine, V = valine, W = tryptophan, Y = tyrosine. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.15 Actions of secretin on bicarbonate secretion by pancreatic and bile duct epithelial cells. Stars indicate processes that are stimulated by secretin through increased cyclic AMP formation and protein kinase A-dependent phosphorylation (see text for explanation). Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.16 Synergistic effects of secretin and CCK on bicarbonate secretion. Secretin alone, CCK alone or secretin and CCK in combination were infused intravenously in six normal human subjects. Bicarbonate output was assessed in samples of duodenal fluids collected through a naso-gastric tube. (Redrawn from data of Refeld, J.F. (2004) Best Practice and Research in Clinical Endocrinology and Metabolism 18: 569–586.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.17 Schematic representation of the actions of secretin and feedback regulation of its secretion. Solid arrows indicate stimulation; dashed arrows indicate inhibition. LSRF = luminal secretin releasing factors. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.18 The incretin effect. Infusion of a solution of 500 mg.of glucose intrajejunally produces a smaller increase in plasma glucose concentration than infusion of the same amount of glucose intravenously (upper panel), but the jejunal infusion elicits a much greater increase (55-fold vs. 12-fold) in insulin secretion. (Reproduced from McIntyre, N., Holdsworth, C.D., and Turner, D.S. (1965) Intestinal factors n the control of insulin secretion. J. Clin. Endocrinol. Metab. 25: 1317.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.19 Effects of different dietary nutrients in secretion of incretin hormones. Eight healthy volunteers were fed 375-calorie meals consisting of only glucose, protein, or fat. Venous blood was sampled at the indicated times. A. Glucose and fat promptly increased plasma concentrations of GIP (glucose-dependent insulinotropic peptide), but proteins had no effect on GIP secretion. B. Glucose and protein promptly increased plasma levels of GLP-1 (glucagon-like peptide 1), but the response to the fatty meal was delayed. Note the difference in the scales for plasma concentrations of GIP and GLP in panels A and B, and note also that peak plasma concentrations of both hormones were achieved in 30 minutes after the glucose meal. C. Plasma concentrations of insulin were increased only after the glucose meal, which also increased plasma insulin concentrations (Panel D). Plasma glucose and insulin concentrations were unchanged after ingesting protein or fat, despite increased secretion of GIP and GLP-1, illustrating the glucose dependence of the incretin effect. (Redrawn from the data of Elliot, R.M., Morgan, L.M., Tredger, L.A., Deacon, S., Wright, J., Marks, V. (1993) Glucagon-like peptide-1 (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: Acute post-prandial and 24-h secretion patterns. J. Endocrinol. 138: 162.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.20 Post-translational processing of proglucagon. Black arrows indicate dibasic sites of cleavage by hormone convertases. The green arrow points to a monobasic cleavage site. The cross-hatched area represents the hexapeptide N-terminal extension found in the immature glucagon-like peptide 1 (GLP-1). The final products of pancreatic alpha cells and intestinal L cells are determined by the presence of different convertases in the two cell types. GRPP = Glicentin-related pancreatic peptide; GLP-2 = glucagon-like peptide-2. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.21 Effects of glucagon-like peptide-1 (GLP-1) infusion on gastric emptying and acid secretion following ingestion of a standardized liquid meal in nine healthy male volunteers. Subjects were given a constant infusion of either saline or 1.2 pmol of GLP-1/kg/minute beginning 30 minutes before eating and continuing through the subsequent 4 hours (green bar). The arrow indicates the time of meal ingestion. (Redrawn from the data of Nauck, M.A., Niedereichholz, U., Ettler, R., Holst, J.J., Orskov, C., Ritzel, R., Schmiegel, W.H. (1997) Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. Endocrinol. Metab. 273: E981–E988.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

The ileal brake. (GLP-1 = glucagon-like peptide-1) FIGURE 6.22 The ileal brake. (GLP-1 = glucagon-like peptide-1) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.23 Amino acid sequences of the PPY (PPfold) family of peptides using the single letter amino acid code. Residues shown in red are identical in corresponding positions in all three peptides. Residues shown in cyan or green are identical with those in corresponding positions in two family members. A = alanine, C = cysteine, D = aspartic acid, E = glutamic acid, F = phenylalanine, G = glycine, H = histidine, I = isoleucine, K = lysine, L = leucine, M = methionine, N = asparagine, P = proline, Q = glutamine, R = arginine, S = serine, T = threonine, V = valine, W = tryptophan, Y = tyrosine. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.24 The effects of isocaloric test meals of carbohydrate, protein, and fat on plasma concentrations of neurotensin in healthy young adult subjects. (Redrawn from Rosell, S. and Rökaeus, Ä. (1979) The effect of ingestion of amino acids, glucose and fat on circulating neurotensin-like immunoreactivity (NTLI) in man. Acta. Physiol. Scand. 107: 263–267.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.25 The motilin ghrelin family. A. Post-translational processing of prepromotilin and preproghrelin. Cleavage of proghrelin releases ghrelin from the N terminus and a second peptide called obestatin, which may have biological activity. B. Amino acid sequences of motilin and ghrelin represented with the single amino acid code. Insertion of a gap between residues 15 and 16 in motilin optimizes the correspondence to the sequence of ghrelin and probably represents the loss of a codon. The octanoate held in ester linkage with the serine at position 3 of ghrelin is essential for activity. Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.26 Effects of motilin on gastric muscle tone. An intragastric balloon was placed in the stomachs of normal fasted volunteers and filled with air. Changes in gastric muscle tone were detected as changes in balloon volume: Increased muscle tone decreases balloon volume. Infusion of atropine, which blocks acetylcholine receptors, resulted in expansion of the balloon, indicating a decrease in tone. Infusion of motilin alone (not shown) or during the continued infusion of atropine increased gastric tone as indicated by decreased volume of the balloon. This effect of motilin is not mediated by parasympathetic stimulation of gastric muscle. (Redrawn from the data of Cuomo, R., Vandaele, P., Coulie, B., Peeters, T., Depoortere, I., Janssens, J., and Tack, J. (2006) Influence of motilin on gastric fundus tone and on meal-induced satiety in man: Role of cholinergic pathways. Am. J. Gastroenterol. 101: 804–811.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.

Copyright © 2009 by Academic Press. All rights reserved. FIGURE 6.27 Average plasma ghrelin concentrations during a 24-h period in 10 human subjects consuming breakfast (B), lunch (L), and dinner (D) at the times indicated (0800, 1200, and 1730, respectively). (From Cummings, D.E., Purnell, J.Q., Frayo, R.S., Schmidova, K., Wisse, B.E., and Weigle, D.S. (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50: 1714–1719.) Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman Copyright © 2009 by Academic Press. All rights reserved.