Gastrointestinal peptides, including hormones, neurocrines, and paracrines, regulate the functions of the gastrointestinal tract. These functions include contraction and relaxation of the smooth muscle wall and the sphincters; secretion of enzymes for digestion; secretion of fluid and electrolytes; and trophic (growth) effects on the tissues of the gastrointestinal tract. In addition, some gastrointestinal peptides regulate the secretion of other gastrointestinal peptides; for example, somatostatin inhibits secretion of all the gastrointestinal hormones.
Characteristics of Gastrointestinal Peptides
The gastrointestinal peptides are classified as hormones, paracrines, or neurocrines. The designation is based on whether the peptide is released from an endocrine cell or from a neuron of the gastrointestinal tract and the route the peptide takes to reach its target cell (Fig. 8-4).
Figure 8–4 Classification of gastrointestinal peptides as hormones, paracrines, or neurocrines. GI, Gastrointestinal; R, receptor.
Hormones are peptides released from endocrine cells of the gastrointestinal tract. They are secreted into the portal circulation, pass through the liver, and enter the systemic circulation. The systemic circulation then delivers the hormone to target cells with receptors for that hormone. The target cells may be located in the gastrointestinal tract itself (e.g., gastrin acts on the parietal cells of the stomach to cause acid secretion), or the target cells may be located elsewhere in the body (e.g., gastric inhibitory peptide acts on the beta [β] cells of the pancreas to cause insulin secretion). Endocrine cells of the gastrointestinal mucosa are not concentrated in glands but are single cells or groups of cells dispersed over large areas. Four gastrointestinal peptides are classified as hormones: gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (or gastric inhibitory peptide, GIP).
Paracrines, like hormones, are peptides secreted by endocrine cells of the gastrointestinal tract. In contrast to hormones, however, paracrines act locally within the same tissue that secretes them. Paracrine substances reach their target cells by diffusing short distances through interstitial fluid, or they are carried short distances in capillaries. Thus, for a substance to have a paracrine action, the site of secretion must be only a short distance from the site of action. The major gastrointestinal peptide with a known paracrine function is somatostatin, which has inhibitory actions throughout the gastrointestinal tract. (Histamine, another gastrointestinal paracrine, is not a peptide.)
Neurocrines are substances that are synthesized in neurons of the gastrointestinal tract and released following an action potential. After release, the neurocrine diffuses across the synapse and acts on its target cell. Neurocrine substances of the gastrointestinal tract include ACh, norepinephrine, vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP) or bombesin, enkephalins, neuropeptide Y, and substance P. The sources and actions of these substances are summarized in Table 8-1.
Several criteria must be met for a substance to qualify as a gastrointestinal hormone: (1) The substance must be secreted in response to a physiologic stimulus and be carried in the bloodstream to a distant site, where it produces a physiologic action; (2) its function must be independent of any neural activity; and (3) it must have been isolated, purified, chemically identified, and synthesized. After applying these stringent criteria, only the following four substances qualify as gastrointestinal hormones: gastrin, CCK, secretin, and GIP. In addition, several candidate hormones, including motilin, pancreatic polypeptide, and enteroglucagon, meet some, but not all, of the criteria.
Table 8-2 describes the four “official” gastrointestinal hormones with respect to hormone family, site of secretion, stimuli producing secretion, and physiologic actions. Use Table 8-2 as a reference for discussions later in the chapter about motility, secretion, and absorption.
Table 8–2 Summary of Gastrointestinal Hormones
GRP, Gastrin-releasing peptide.
The functions of gastrin are coordinated to promote hydrogen ion (H+) secretion by the gastric parietal cells. Gastrin, a 17-amino acid straight chain peptide, is secreted by G (gastrin) cells in the antrum of the stomach. The 17-amino acid form of gastrin, which is called G17 or “little” gastrin, is the form of gastrin secreted in response to a meal. A 34-amino acid form of gastrin, which is called G34 or “big”gastrin, is secreted during the interdigestive period (between meals). Thus, during the interdigestive period, most of the serum gastrin is in the G34 form, which is secreted at low basal levels. When a meal is ingested, G17 is secreted. G34 is not a dimer of G17, nor is G17 formed from G34. Rather, each form of gastrin has its own biosynthetic pathway, beginning with its own precursor, a progastrin molecule.
The minimum fragment necessary for biologic activity of gastrin is the C-terminal tetrapeptide (Fig. 8-5). (The C-terminal phenylalanine contains an NH2 group, which simply means that it is phenylalamide.) Although the C-terminal tetrapeptide is the minimum fragment necessary for activity, it still is only one sixth as active as the entire gastrin molecule.
Figure 8–5 Structures of human gastrin and porcine cholecystokinin (CCK). The blue-shaded boxes show the fragments necessary for minimal biologic activity. The green-shaded box shows the portion of the CCK molecule that is identical to gastrin. Glp, Pyroglutamyl residue.
Secretion of gastrin. In response to eating a meal, gastrin is secreted from G cells located in the antrum of the stomach. The physiologic stimuli that initiate gastrin secretion all are related to ingestion of food. These stimuli include the products of protein digestion (e.g., small peptides and amino acids), distention of the stomach by food, and vagal stimulation. Among the products of protein digestion, the amino acids phenylalanine and tryptophan are the most potent stimuli for gastrin secretion. Local vagal reflexes also stimulate gastrin secretion. In these local reflexes, the neurocrine released from vagal nerve endings onto the G cells is gastrin-releasing peptide (GRP), or bombesin. In addition to these positive stimuli, gastrin secretion is inhibited by a low pH of the gastric contents and by somatostatin.
Actions of gastrin. Gastrin has two major actions: (1) It stimulates H+ secretion by gastric parietal cells, and (2) it stimulates growth of the gastric mucosa, a trophic effect. The physiologic actions of gastrin are nicely illustrated in conditions of gastrin excess or deficiency. For example, in persons with gastrin-secreting tumors (Zollinger-Ellison syndrome), H+ secretion is increased and the trophic effect of gastrin causes the gastric mucosa to hypertrophy. Conversely, in persons whose gastric antrum is resected (which removes the source of gastrin, the G cells), H+ secretion is decreased and the gastric mucosa atrophies.
Zollinger-Ellison syndrome is caused by a gastrin-secreting tumor or gastrinoma, usually in the non–β-cell pancreas. The signs and symptoms of Zollinger-Ellison syndrome all are attributable to high circulating levels of gastrin: increased H+ secretion by parietal cells, hypertrophy of the gastric mucosa (the trophic effect of gastrin), and duodenal ulcers caused by the unrelenting secretion of H+. The increased H+ secretion also results in acidification of the intestinal lumen, which inactivates pancreatic lipase, an enzyme necessary for fat digestion. As a result, dietary fats are not adequately digested or absorbed, and fat is excreted in the stool (steatorrhea).Treatment of Zollinger-Ellison syndrome includes administration of H2 receptor–blocking drugs (e.g., cimetidine); administration of inhibitors of the H+pump (e.g., omeprazole); removal of the tumor; or, as the last resort, gastric resection, which removes gastrin’s target tissue.
The functions of cholecystokinin (CCK) are coordinated to promote fat digestion and absorption. CCK is a 33-amino acid peptide, which is structurally related to gastrin and a member of the “gastrin-CCK family” (see Fig. 8-5). The C-terminal five amino acids (CCK-5) are identical to those of gastrin and include the tetrapeptide that is minimally necessary for gastrin activity. Thus, CCK has some gastrin activity. CCKA receptors are selective for CCK, while CCKB receptors are equally sensitive to CCK and gastrin. The minimum fragment of CCK necessary for its biologic activity is the C-terminal heptapeptide (seven amino acids [CCK-7]).
CCK is secreted by the I cells of the duodenal and jejunal mucosa in response to two types of physiologic stimuli: (1) monoglycerides and fatty acids (but not triglycerides) and (2) small peptides and amino acids. These stimuli alert the I cells to the presence of a meal containing fat and protein, which must be digested and absorbed. CCK will then ensure that appropriate pancreatic enzymes and bile salts are secreted to aid in this digestion and absorption.
There are five major actions of CCK, and each contributes to the overall process of fat, protein, and carbohydrate digestion and absorption.
Contraction of the gallbladder with simultaneous relaxation of the sphincter of Oddi ejects bile from the gallbladder into the lumen of the small intestine. Bile is needed for emulsification and solubilization of dietary lipids.
Secretion of pancreatic enzymes. Pancreatic lipases digest ingested lipids to fatty acids, monoglycerides, and cholesterol, all of which can be absorbed. Pancreatic amylase digests carbohydrates, and pancreatic proteases digest protein.
Secretion of bicarbonate (HCO3−) from the pancreas. This is not a major effect of CCK, but it potentiates the effects of secretin on HCO3− secretion.
Growth of the exocrine pancreas and gallbladder. Because the major target organs for CCK are the exocrine pancreas and the gallbladder, it is logical that CCK also has trophic effects on these organs.
Inhibition of gastric emptying. CCK inhibits or slows gastric emptying and increases gastric emptying time. This action is critical for the processes of fat digestion and absorption, which require a considerable amount of time. CCK slows the delivery of chyme (partially digested food) from the stomach to the small intestine, ensuring adequate time for the subsequent digestive and absorptive steps.
Secretin, a 27-amino acid peptide, is structurally homologous to glucagon and is a member of the secretin-glucagon family (Fig. 8-6). Fourteen of the 27 amino acids of secretin are identical and in the same position as those of glucagon. In contrast to gastrin and CCK, which have active fragments, all 27 amino acids of secretin are required for its biologic activity. For activity, the entire secretin molecule must fold into its tertiary structure, an α helix.
Figure 8–6 Structures of secretin, glucose-dependent insulinotropic peptide (GIP), and glucagon. The blue-shaded fragments (amino acids) show the portions of GIP and glucagon that are homologous with secretin.
Secretin is secreted by the S cells (secretin cells) of the duodenum in response to H+ and fatty acids in the lumen of the small intestine. Thus, secretion of secretin is initiated when the acidic gastric contents (pH < 4.5) arrive in the small intestine.
The function of secretin is to promote the secretion of pancreatic and biliary HCO3−, which then neutralizes H+ in the lumen of the small intestine. Neutralization of H+ is essential for fat digestion; pancreatic lipases have pH optimums between 6 and 8, and they are inactivated or denatured when the pH is less than 3. Secretin also inhibits the effects of gastrin on the parietal cells (H+ secretion and growth).
Glucose-Dependent Insulinotropic Peptide
Glucose-dependent insulinotropic peptide (GIP), a 42-amino acid peptide, is also a member of the secretin-glucagon family (see Fig. 8-6). GIP has 9 amino acids in common with secretin and 16 amino acids in common with glucagon. Because of this homology, pharmacologic levels of GIP produce most of the actions of secretin.
GIP is secreted by K cells of the duodenal and jejunal mucosa. It is the only gastrointestinal hormone that is secreted in response to all three types of nutrients: glucose, amino acids, and fatty acids.
The major physiologic action of GIP is stimulation of insulin secretion by the pancreatic β cells; because of this action, it is classified as an incretin (i.e., a gastrointestinal hormone that promotes the secretion of insulin). This action explains the observation that an oral glucose load is utilized by cells more rapidly than an equivalent intravenous glucose load. Oral glucose stimulates GIP secretion, which stimulates insulin secretion (in addition to the direct stimulatory action of absorbed glucose on the β cells). Glucose given intravenously stimulates insulin secretion only by the direct action on the β cells. The other actions of GIP are inhibition of gastric H+ secretion and inhibition of gastric emptying.
Candidate, or putative, hormones also are secreted by the gastrointestinal tract. They are considered to be candidate hormones because they fail to meet one or more of the criteria necessary to be classified as “official” gastrointestinal hormones.
Motilin, a 22-amino acid peptide, is not a member of the gastrin-CCK family or the secretin-glucagon family. It is secreted from the upper duodenum during fasting states. Motilin is believed to increase gastrointestinal motility and, specifically, to initiate the interdigestive myoelectric complexes that occur at 90-minute intervals.
Pancreatic polypeptide is a 36-amino acid peptide secreted by the pancreas in response to ingestion of carbohydrates, proteins, or lipids. Pancreatic polypeptide inhibits pancreatic secretion of HCO3− and enzymes, although its physiologic role is uncertain.
Enteroglucagon is released from intestinal cells in response to a decrease in blood glucose concentration. It then directs the liver to increase glycogenolysis and gluconeogenesis.
Glucagon-like peptide-1 (GLP-1) is produced from the selective cleavage of proglucagon. It is synthesized and secreted by the L cells of the small intestine. Like GIP, GLP-1 is classified as an incretin,because it binds to receptors on the pancreatic beta cells and stimulates insulin secretion. In complementary actions, it also inhibits glucagon secretion, increases the sensitivity of pancreatic beta cells to secretagogues such as glucose, decreases gastric emptying, and inhibits appetite (i.e., increases satiety). For these reasons, analogues of GLP-1 have been considered as possible treatments for type 2 diabetes mellitus.
As with the gastrointestinal hormones, paracrines are synthesized in endocrine cells of the gastrointestinal tract. The paracrines do not enter the systemic circulation but act locally, reaching their target cells by diffusing over short distances.
Somatostatin is secreted by D cells (both endocrine and paracrine) of the gastrointestinal mucosa in response to decreased luminal pH. In turn, somatostatin inhibits secretion of the other gastrointestinal hormones and inhibitsgastric H+ secretion. In addition to these paracrine functions in the gastrointestinal tract, somatostatin is secreted by the hypothalamus and by the delta (δ) cells of the endocrine pancreas.
Histamine is secreted by endocrine-type cells of the gastrointestinal mucosa, particularly in the H+-secreting region of the stomach. Histamine, along with gastrin and ACh, stimulates H+ secretion by the gastric parietal cells.
Neurocrines are synthesized in cell bodies of gastrointestinal neurons. An action potential in the neuron causes release of the neurocrine, which diffuses across the synapse and interacts with receptors on the postsynaptic cell.
Table 8-1 presents a summary of neurocrines including nonpeptides such as ACh and norepinephrine and peptides such as VIP, GRP, the enkephalins, neuropeptide Y, and substance P. The best-known neurocrines are ACh (released from cholinergic neurons) and norepinephrine (released from adrenergic neurons). The other neurocrines are released from postganglionic noncholinergic parasympathetic neurons (also called peptidergic neurons).
The centers that control appetite and feeding behavior are located in the hypothalamus. A satiety center, which inhibits appetite even in the presence of food, is located in the ventromedial nucleus (VPN) of the hypothalamus and a feeding center is located in the lateral hypothalamic area (LHA). Information feeds into these centers from the arcuate nucleus of the hypothalamus.
The arcuate nucleus has various neurons that project onto the satiety feeding centers. Anorexigenic neurons release pro-opiomelanocortin (POMC) and cause decreased appetite; orexigenic neurons release neuropeptide Y and cause increased appetite. The following substances influence the anorexigenic and orexigenic neurons of the arcuate nucleus and, accordingly, decrease or increase appetite and feeding behavior.
Leptin. Leptin is secreted by fat cells in proportion to the amount of fat stored in adipose tissue. Thus, leptin senses body fat levels, is secreted into the circulation, crosses the blood-brain barrier, and acts on neurons of the arcuate nucleus of the hypothalamus. It stimulates anorexigenic neurons and inhibits orexigenic neurons, thereby decreasing appetite and increasing energy expenditure. Because leptin detects stored body fat, it has chronic (long-term) effects to decrease appetite.
Insulin. Insulin has similar actions to leptin, in that it stimulates anorexigenic neurons and inhibits orexigenic neurons, thus decreasing appetite. In contrast to leptin, insulin levels fluctuate during the day, thus it has acute (short-term) effects to decrease appetite.
GLP-1. As discussed earlier, GLP-1 is synthesized and secreted by intestinal L cells. Among its actions (like leptin and insulin), it decreases appetite.
Ghrelin. Ghrelin is secreted by gastric cells just before ingestion of a meal. It acts oppositely to leptin and insulin to stimulate orexigenic neurons and inhibit anorexigenic neurons, thus increasing appetiteand food intake. Periods of starvation and weight loss strongly stimulate ghrelin secretion.
Peptide YY (PYY). PYY is secreted by intestinal L cells following a meal. It acts to decrease appetite, both through a direct effect on the hypothalamus and by inhibiting ghrelin secretion.