The enteric hormones, listed in Table 10-2, have multiple sites of action, both within the GI tract and the CNS, linking hunger and satiety with the biochemical and hormonal processes of digestion (Figure 10-1). Within the GI system, these hormones are secreted by specialized neuroendocrine cells (Figure 10-2).
Table 10-2.Enteric Hormones ||Download (.pdf) Table 10-2. Enteric Hormones
|Hormone ||Cell Type ||Gene Locus ||Receptor |
|Secretin ||S cell of duodenum and jejunum ||SCT gene, 11p15.5 ||Gs protein receptor |
|SRIH ||Pancreatic δ cells, stomach D cells, and intestines ||3q28 ||Five subtypes of tissue-specific Gi receptors |
|Ghrelin ||P/D1-cell stomach, pancreatic ε cells ||3p25.3 ||GHS-R, a Gq protein receptor |
|CCK ||I cell ||3p22.1 ||Gs and Gq protein receptor |
|Gastrin ||G and I cell in stomach and duodenum ||GAS gene, 17q21 ||CCK2 receptor, a Gq protein |
|PP ||PP cells ||17q21.31 ||Neuropeptide Y type 4 receptor |
|VIP ||VIP cell ||6q24 ||Gs protein receptor |
|GLP-1 ||L-cell ileum and colon ||Glucagon gene, 2q36-37 ||Gs protein receptor |
|GIP ||K-cell duodenum and jejunum ||17q21.3 ||Gs protein receptor |
|Amylin ||β-cell pancreas ||12p12.1 ||Calcitonin-type receptor bound to RAMP1, 2, or 3 |
Enteric hormones affecting satiety.
Antral mucosa with neuroendocrine cells, hematoxylin and eosin (H&E) staining, 20X magnification.
Made by the duodenal S cells as well as the hypothalamus, secretin is the product of the SCT gene located at 11p15.5 and is initially made in the form of a 120-amino acid prohormone, which is then cleaved into a mature peptide of 27 amino acids.3 Secretin has significant homology with glucagon, VIP, and GIP, and has multiple actions throughout the body. Secretin binds to the aminoterminal end of a class B G-protein–coupled receptor, stimulating Gs coupling and the generation of cyclic adenosine monophosphate (cAMP). The secretin receptor, as part of the class B family, shares homology with the receptors for VIP, glucagon, GLP, GIP, growth hormone (GH)–releasing hormone (GHRH), and pituitary adenylate cyclase–activating peptide (PACAP), among others.4 Secretin release is stimulated by an acidic pH (ie, 2-4.5) in the duodenum and protein interaction with intestinal mucosa. Secretin release is inhibited by H2 antagonists.
Within the gut, secretin inhibits gastric acid secretion while stimulating bicarbonate production by the pancreatic centroacinar cells and intercalated ducts to regulate duodenal pH. Secretin enhances CCK and also stimulates insulin release in response to a glucose load. In response to secretin, pepsin is released from chief cells, and the secretion of glucagon, SRIH, and pancreatic polypeptide (PP) increases. The effects of secretin on gastrin are twofold. In normal situations, secretin decreases gastrin release; however, in a patient who has a gastrinoma, secretin paradoxically increases gastrin release.5
The role of secretin beyond the gut is one of osmoregulation through actions at the hypothalamus, pituitary, and kidney. Hyperosmolality stimulates secretin release from the posterior pituitary as well as from the hypothalamus, enhancing vasopressin release. Both secretin and its receptor are found in the paraventricular and supraoptic nuclei of the hypothalamus, where secretin induces c-fos gene expression to increase hypothalamic release of vasopressin in response to changes in osmolality. Additionally, secretin is able to regulate renal water reabsorption independent of vasopressin.6
Secretin deficiency has been purported to predispose patients to gastric ulceration during Helicobacter infection. Deficiency is thought to make an individual vulnerable to gastric acid erosion of mucosa during the infection.7
Somatostatin (SST), also known as somatotropin-releasing inhibitory hormone (SRIH), is a peptide hormone that exists in two bioactive forms: one consisting of 14 amino acids and another of 28 amino acids. The 14-amino acid form is primarily found in the brain and binds SRIH receptors 1-5. SRIH 28, in contrast, is a gut hormone, found particularly in the colon, and has tight affinity for SRIH receptor type 5 and less for receptor types 1, 2, and 3.8 SRIH receptor type 1 is found in the cerebral cortex and amygdala, as well as the GI tract. SRIH receptor type 2 occurs in cerebral cortex and in the pituitary and adrenal glands. SRIH receptor type 3 is located primarily in the cerebellum and pituitary gland. SRIH receptor type 4 is found in the brain, heart, and the islets of Langerhans. SRIH receptor type 5 is found primarily in the hypothalamus and pituitary gland.9 SRIH isoforms are produced from the SRIH gene as the 116-amino acid preprosomatostatin, which is then cleaved to the 92-amino acid prosomatostatin, which is then cleaved to SRIH-14 and SRIH-28. Specific secretion sites are the stomach, intestines, and pancreatic δ cells, as well as the periventricular nucleus of the hypothalamus. SRIH acts via an α-adrenergic G-protein–coupled (Gαi) receptor to inhibit adenylyl cyclase and activate potassium and calcium channels.
SRIH has multiple actions that are site-specific (Table 10-3). In the pituitary gland, it inhibits release of GH as well as thyrotropin (TSH). Its action on GH antagonizes the actions of GHRH; while GHRH stimulates GH release, SRIH affects the timing and amplitude of GH pulses, dampening and inhibiting pulsatility.
Table 10-3.Actions of Somatostatin ||Download (.pdf) Table 10-3. Actions of Somatostatin
|Inhibits insulin, glucagon, GLP, gastrin, ghrelin, CCK, VIP, and secretin |
|Inhibits secretion of gastric acid, pepsin, pancreatic enzymes, bile, and intestinal fluids |
|Decreases gastric emptying |
|Inhibits gallbladder contraction |
|Decreases intestinal motility |
|Causes splanchnic vasoconstriction |
|Inhibits release of GHRH, thyrotropin-releasing hormone, and corticotropin-releasing hormone |
|Affects memory through hippocampal receptor |
SRIH has many GI effects. It specifically suppresses the release of gastrin, CCK, secretin, motilin, VIP, GIP, and glucagon. In suppressing these hormones, SRIH slows gastric emptying rate, decreases smooth muscle contraction and blood flow within the intestine, and suppresses insulin and exocrine pancreatic secretion.
While native SRIH has a very brief half-life, SRIH analogs have prolonged efficacy and have proven useful in the management of carcinoid syndrome, acromegaly, and hypoglycemia. Current synthetic forms include octreotide and lanreotide. Octreotide, which has three substituted amino acids to prolong its half-life, binds SRIH receptor type 2 in the pituitary and adrenals and type 5 in the hypothalamus and pituitary, but binds poorly to types 1 and 4 in the amygdala, GI tract, and pancreas. Lanreotide has similar binding affinities. Consequently, octreotide and lanreotide are useful in decreasing GH and TSH secretion from pituitary tumors. A newer analog, pasireotide, has high affinity for SRIH receptor type 5 in the pituitary and hypothalamus, which is expressed by some ACTH-secreting tumors. As the pancreas only has SRIH receptor type 2, while the pituitary has types 1, 2, 3, and 5, synthetic analogs can be chosen based on tumor location to modify hormone response. A major side effect of SRIH analogs is gallstones, and glucosedysregulation and cardiac conduction abnormalities may also occur.
The excess of SRIH may be seen in somatostatinomas, insulin deficiency states, and diabetic gastroenteropathy. Characteristics of SRIH excess include hyperglycemia, pancreatitis, steatorrhea, dyspepsia, gallstones, jaundice, or hypochlorhydria. The most common manifestation of a somatostatinoma is jaundice or abdominal pain secondary to mass effects.
Ghrelin is a 28-amino acid polypeptide product of a gene in the region of chromosome 3q25-26. The initial product is a 117-amino acid peptide referred to as pre-proghrelin. It is secreted in its final form by the oxyntic cells in the stomach, intestines, pancreas, kidney, hypothalamus, and pituitary. Ghrelin stimulates GH release and increases appetite/hunger and eating behaviors (ie, orexigenic hormone) (Figure 10-4). GH secretion and food intake appear to be dependent on a unique property of the ghrelin molecule, namely, the acylation of its third serine residue, an octanoylation necessary for ghrelin to bind the GH secretagogue receptor (GHS-R). GHS-R is a Gqα-protein–coupled receptor that exists in two forms: GHS-R1a is found in the CNS and peripheral tissues, while GHS-R1b is a truncated form of the receptor found in a variety of tissues.
Through its binding to the GHS-R1a and subsequent phospholipase activity, as well as by Gs/protein kinase A pathways in some tissues, ghrelin enhances GH secretion, speeds gut motility, and may additionally have bone remodeling and immune function roles in the GI system. Ghrelin is able to cross the blood-brain barrier to decrease energy expenditure and increase caloric intake. The CNS orexigenic actions are mediated by activation of neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus responding to ghrelin/GHS-R binding to release NPY/AgRP.10
Release of ghrelin is regulated by several factors. Its secretion is normally inversely correlated with BMI. Fasting, chronic disease, and states of malnutrition raise ghrelin levels. Conversely, because glucose and insulin suppress ghrelin secretion, eating—especially carbohydrate consumption—suppresses ghrelin release. However, themost significant suppression of ghrelin occurs with high protein intake. Interestingly, humans can decrease ghrelin secretion with the actions of chewing, smelling, or tasting food without actually swallowing calories. The daily significance of ghrelin in the secretion of GH and appetite regulation of healthy individuals remains unclear.
Obesity: Obese individuals have lower fasting ghrelin levels but do not consistently demonstrate postprandial ghrelin suppression compared to normal-weight individuals. Unfortunately, caloric restriction in an obese patient increases ghrelin, as the body senses a state of deprivation despite excess stores. Thus, ghrelin may be important when calorie balances are negative to restore or maintain BMI, which may contribute to weight regain after dieting. Interestingly, sleeve gastrectomy and gastric bypass procedures, but perhaps not gastric banding, are associated with greatly reduced ghrelin levels, which may contribute to postprocedural weight loss.10
Genetic syndromes associated with obesity may provide insight into the role of ghrelin in appetite regulation. Individuals with Prader-Willi syndrome (PWS)—characterized by voracious, unregulated appetite—have fasting ghrelin levels that are three to four times higher than in weight-matched, obese controls without this genetic disorder. Furthermore, the magnitude of postprandial ghrelin secretion decrease is blunted in PWS subjects compared to matched obese controls, suggesting that PWS patients fail to detect the nonfasting state of calorie sufficiency.11 Thus, the typical obese subject has lower ghrelin levels than a weight-matched individual with PWS. While ghrelin would, therefore, seem to have a significant role in appetite/energy balance dysregulation in PWS, this has actually proven very difficult to demonstrate.
Cholecystokinin (CCK) exists as a 33-amino acid peptide with homology to gastrin in the C terminal 5-aminoacid sequence.12 It is secreted from I cells in duodenal and jejunal mucosa, and it facilitates intestinal absorption of fat. CCK stimulates gallbladder contraction for bile release while relaxing the sphincter of Oddi. Secretion of bicarbonate and pancreatic lipase and amylase are also stimulated by CCK. Finally, CCK slows gastric emptying and is trophic for gallbladder and exocrine pancreas cells. The effects of CCK are mediated by the G-protein–coupled CCK1 receptor, which has both Gs and Gq effects, stimulating an increase in cAMP in the gallbladder, pancreas, stomach, central and peripheral nervous systems, and the sphincter of Oddi. CCK appears to be the primary hormone responsible for the sensation of fullness and satiety that occurs during eating. CCK secretion is stimulated by free fatty acids, monoglycerides, small peptides, and amino acids in the small intestine.
CCK excess may manifest as a rare variant of the Zollinger-Ellison syndrome. Presentation has been described with octreotide/streptozotocin-responsive diarrhea, peptic ulcer disease, cholelithiasis, and significant weight loss. While gastrin levels are low, CCK levels can be as high as 1000 times normal.13 CCK deficiency has been described in the context of autoimmune polyglandular syndrome type 1. The deficiency is manifested by weight loss and severe steatorrhea, with nondetectable serum CCK levels.14
Gastrin is the product of the GAS gene on 17q21 and is produced in the G cells of the stomach antrum, the duodenum, and pancreas. The 17-amino acid form is most common (85%), but several other forms do exist, including a 34-amino acid form; both are produced from a 101-amino acid prepropeptide.15 Release of gastrin is stimulated by stomach distension, vagal stimulation via the neurocrine gastrin–releasing peptide, amino acids (particularly tryptophan and leucine), and hypercalcemia. Gastrin secretion can be inhibited by hydrochloric acid in the stomach, SRIH, GIP, secretin, glucagon, and calcitonin. The CCK receptor type 2 (CCK2R), which is a Gq-protein–coupled receptor, binds gastrin, activating JAK2-STAT3, phospholipase C/protein kinase C, MAP kinase, and other pathways, leading to release of histamine from enterochromaffin cells, parietal cell release of gastric acid in response to cAMP, and pepsinogen secretion from chief cells. Parietal cell function is altered by the insertion of K+/H+ ATPase pumps into the apical membrane of the parietal cell. Gastrin aids gastric motility, stimulates fundal growth and parietal cell maturation, and increases antral motility. The lower esophageal sphincter, pyloric sphincter, and ileocecal valve are relaxed by gastrin. Gastrin induces pancreatic secretion and empties the gallbladder.
Gastrin excess can be caused by a gastrinoma, the most common GI tumor seen in the multiple endocrine neoplasia type 1 (MEN1) syndrome. The tumor is usually found in the pancreas, and it can cause peptic ulcer disease, abdominal pain, watery diarrhea, and upper GI bleeding. The Zollinger-Ellison syndrome (Table 10-4) consists of peptic ulcer disease that occurs in the context of a gastrinoma. Weight loss and steatorrhea frequently occur. The diarrhea is due to fat malabsorption, and is not secretory, in contrast to that seem with VIPomas. The diagnosis of a gastrinoma is established by finding a randomly elevated gastrin or, in response to secretin stimulation, a serum gastrin level of greater than 1000 pg/mL in the context of a gastric pH of less than 5. A computerized tomographic (CT) scan or magnetic resonance imaging (MRI) can aid in localization of the tumor.16
Table 10-4.Features of Zollinger-Ellison Syndrome ||Download (.pdf) Table 10-4. Features of Zollinger-Ellison Syndrome
|Associated with gastrinoma |
|Peptic ulcer disease |
|Weight loss |
A sporadic gastrinoma is usually pancreatic in origin. By contrast, a gastrinoma in the context of MEN1 is often duodenal and multiple in location. Metastases are present in 30% to 60% of cases at diagnosis, usually affecting the liver. Therapy of a gastrinoma includes proton pump inhibitors, histamine-2 blockers, surgical resection of the sporadic tumor, or surgical debulking of multifocal tumors.
Though traditionally identified as a CNS hormone, 90% of the body’s monoamine neurotransmitter, serotonin, also known as 5-hydroxytryptamine, is actually located in the enterochromaffin cells of the GI system and has its action primarily through its G-protein–coupled receptors, of which many subtypes exist in brain and intestine. Some are Gsα, acting through increasing adenylate cyclase, while others are Giα, decreasing adenylyl cyclase, or Gqα, acting through phospholipase C. Serotonin is known to affect food-seeking behaviors by decreasing appetite, regulating intestinal motility, and sometimes triggering emesis. It is a vasoconstrictor stored within platelets to aid clot formation and, within the CNS, helps regulate mood, sleep, memory, and learning.
Some patients with MEN1 are found to have serotonin excess as a result of a carcinoid tumor producing the carcinoid syndrome (Table 10-5) for which flushing, diarrhea, and tricuspid valvular disease can be presenting symptoms. Niacin deficiency may be part of the syndrome and cause a pellagra-like rash. The diagnosis of a carcinoid tumor is made by verifying elevations of 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample. Radiolabelled octreotide scanning may localize the tumor more frequently than eitherCT scan or MRI. Therapy can include surgery, octreotide, interferon-α, and antihistamine.7
Table 10-5.Carcinoid Syndrome ||Download (.pdf) Table 10-5. Carcinoid Syndrome
|Associated with MEN1 |
|Diarrhea even during fasting |
|Tricuspid valvular disease |
|Excess serotonin secretion |
|Pellagra due to tryptophan deficiency |