Chapter 10: Enteric Hormones

Enteric hormones orchestrate appetite, food-seeking behaviors, intake, physical and chemical digestion, and the absorption of the nutrients, intricately linking the brain, the intestines, and multiple endocrine organs to sustain the energy balance of an organism. In 1902, William Maddox Bayliss and Ernest Henry Starling demonstrated that the gastrointestinal (GI) system is the body’s largest endocrine organ. Their work with secretin establishes roles of the GI system beyond digestion and nutrition and includes systemic signaling between regions of the GI system and the central nervous system (CNS) to coordinate appetite, satiety, digestion, and absorption.

Work by John Sidney Edkins in 1902 led to discovery of “gastric secretin,” now known as gastrin. Secretin and gastrin were thought to be the primary chemical mediators of digestion until the 1920s, when cholecystokinin (CCK) was added to the list. Until the 1970s, these three mediators remained the central dogma of GI hormonal signaling. The 1970s, however, yielded an explosion in GI hormone research and the discovery of over 100 additional hormones. The GI system produces exclusively peptide hormones.

Enteric hormones are of great evolutionary importance. Many human enteric hormones can be isolated in similar forms from other species and arise from common precursor tissue-specific mechanisms, known as prohormone processing, yielding a variety of end products from a common precursor. These “alternative splicing” mechanisms create unique mediators with specific functions. Precursor hormones and their derivatives are referred to as a hormone family. These enteric hormone “families” include the gastrin, secretin, and somatostatin (SST) families, among others (Table 10-1). These examples represent conservation of precursors over centuries of species’ evolution. Despite the unique chemistry derived from the tissue-specific processing, similar signaling may occur at receptor sites within/between these families.

In addition to roles in nutrient digestion, absorption, and satiety, many of the GI hormones, including CCK, gastrin, and glucagonlike-peptide (GLP-1), provide a “trophic” signal to organs of the GI system. This trophic effect helps maintain tissue in the GI tract; however, if pathologic concentrations are present, trophism can lead to overproduction of tissue, such as hypertrophied gastric mucosa in gastrinomas.

Enteric hormone regulation involves negative feedback loops, presence of products of digestion, direct hormonal signaling, and neurotransmission. One example of a negative feedback loop involves reduction of gastrin secretion in the stomach due to low pH encountered in the small intestine. Partially digested proteins yield polypeptides, which, when sensed in the small intestine, stimulate secretion of several hormones, including the incretins. Additional mechanisms for regulation of GI hormones include a hormonal “off” signal; for example, secretion of SRIH from the pancreas and other cells halts secretion of several secondary hormones including CCK, gastrin, and secretin. The CNS plays a significant role in the regulation of the GI system, and vice versa. Neuropeptides such as vasoactive intestinal peptide (VIP), substance P, and CCK are used by the brain to regulate GI system activity, including, but not limited to, motility, secretion, and secondary signaling mechanisms of primary hormones.

The “brain-gut axis” consists of the CNS, the GI system, and enteric nervous system (composed of the myenteric and submucosal plexuses). Mediators of communication are neuropeptides that act directly via neuralinputs or circulate systemically to interact with distant targets. Recent studies of the brainstem and nearby nuclei (paraventricular nucleus, supraoptic nucleus, and arcuate nucleus) demonstrate the existence of a modified blood-brain barrier allowing GI hormones such as glucagon-like peptide-1 (GLP-1) to affect the CNS directly impacting hunger, satiety, and vagal nerve signaling.¹ Additionally, the CNS affects the enteric nervous system in many ways. A common example is the anxious individual who develops abdominal pain and loose stools during emotional stress. The study of brain-gut interactions is relatively new and continues to reveal new and exciting pathways in endocrine physiology.

Physiology

The process of physical and chemical digestion and nutrient absorption of carbohydrates involves energy-dependent complex interplay among several anatomical structures, including the CNS, multiple endocrine organs, the liver, and intestines as well as the microanatomy including the enteroendocrine cells, brush border enzymes, namely the disaccharidases, and transporters. Embedded in the apical membrane of enterocytes lining the duodenal villi are brush border enzymes and nutrient transporters. The enzymes are often embedded via protein anchors permitting easier access to luminal contents. The brush border enzymes are highly specific for their unique ligand, be it a disaccharide, tripeptide, or a proenzyme requiring conversion to its active form. Enzymatic activity occurs in proximity to specific transmembrane protein transporters, also embedded in the apical membrane. These transporters are also highly specific for their ligand and may use active transport, secondary active transport, or facilitated diffusion to bring nutrients into the cell. Together, enzymes and transporters digest and efficiently absorb nutrition. Each macronutrient is described in greater depth in the following text, reviewing its unique brush border enzymes and absorption systems.

Phases of Digestion

Digestion occurs in multiple steps to slowly and methodically breaking down food both chemically and physically. The highly regulated process ensures adequate absorption of nutrition. Breakdown in any one of several areas causes pathology and subsequent malnutrition. Digestion can be viewed in “phases” that have distinct physiological characteristics. These stages, as elucidated here, include the cephalic phase (anticipatory priming of the GI system), gastric phase (acid secretion), and completion with the intestinal phase (inhibition of acid secretion with increased intestinal, pancreatic, and biliary secretion).

Cephalic phase

The cephalic phase of digestion is the “priming” phase in anticipation of the delivery of nutrition to the GI tract, probably evolved as a consequence of human’s eating patterns that are less like the grazing seen in other species and occur in more discrete meals.¹ It is the discrete nature of these meals that mandates the GI system to be “primed” to digest and absorb efficiently. The cephalic phase is orchestrated by the vagus nerve (hence “cephalic”) and its mediating neurotransmitter, acetylcholine (Ach). Additional mediators include secretin and ghrelin. By contrast, leptin and amylin inhibit appetite. Stimulation of appetite occurs with the thought, sight, and/or smell of food, and it is sufficient to induce neural firing and priming of the GI system. In 1902, Pavlov famously proved the effect of conditioning responses in dogs; however, he was less appreciated for actually having proven the cephalic phase of digestion by proving dogs salivate in anticipation of food. Vagal stimulation mediates the breakdown and absorption of nutrition. Beginning in the mouth, Ach stimulation increases salivation and enzyme production while the stomach produces increasing levels of acid and gastrin. The endocrine pancreas begins to elevate basal insulin levels while its exocrine portion begins production and secretion of its digestive enzymes as well as bicarbonate. The liver and gallbladder increase bile production and delivery to the small intestine lumen under the influence of Ach. Intestinal motility also begins to increase. Many of the subsequent hormones listed in this chapter also are increased in response to intestinal stimulation, adipocyte stimulation, and gastric stimulation by the vagus nerve. The cephalic phase increases the efficiency of the digestive process.²

Gastric phase

The gastric phase of digestion is initiated when the masticated, partially digested bolus of food enters the stomach. The goal of the gastric phase of digestion is to increase the stomach’s acidity to advance chemical digestion while physical digestion dramatically increases. Partially digested nutrients and distension of the stomach stimulate gastric G cells by way of direct stimulation as well as by vagovagal reflex arcs. The majority of hydrochloric acid secretion and gastrin secretion occurs during this phase.

Intestinal phase

Entrance of the chyme (partially digested food) into the small intestine is a highly regulated process and marks the beginning of the intestinal phase of digestion. The bulk of chemical digestion begins in the duodenum with enzymes that are exquisitely sensitive to pH, osmolality, and other parameters. With entry of the chyme into the duodenum, mucosal production of secretin, gastric inhibitory polypeptide (GIP), and CCK help slow motility to allow time for digestion and absorption while also inhibiting the stomach’s production of acid. Pancreatic secretion is also stimulated for release of additional digestive enzymes.

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).

Secretin

Physiology

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 G_s 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

Pathophysiology

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

Physiology

(Figure 10-3)

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 (G_αi) 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.

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.

Pathophysiology

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

Physiology

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 G_qα-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 G_s/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.

Pathophysiology

1. 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

2. 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

Physiology

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 G_s and G_q 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.

Pathophysiology

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

Physiology

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 G_q-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.

Pathophysiology

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

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.

Serotonin

Physiology

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 G_sα, acting through increasing adenylate cyclase, while others are G_iα, decreasing adenylyl cyclase, or G_qα, 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.

Pathophysiology

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

Physiology

Vasoactive intestinal polypeptide (VIP) is a 28-amino acid peptide with multiple actions in the central and peripheral nervous systems, GI system, immune system, heart, lungs, and genitourinary system. It has vasodilatory, smooth muscle relaxation, and immunomodulating activities.¹⁷ VIP acts via G_s protein receptors known as VPAC1 and VPAC2. These receptors are tissue-specific and mediate VIP effects through adenylyl cyclase activation. In the GI system, VIP is a dominant inhibitory neurotransmitter, where it relaxes the lower esophageal sphincter, the sphincter of Oddi, and the anal sphincter. It inhibits gastric acid production and increases pancreatic enzyme and intestinal chloride secretion. VIP is best known in the context of the VIPoma (Table 10-6) that produces a secretory diarrhea. The incidence of VIPoma is 0.05 to 0.5 per million people. Peak ages of VIPoma presentation are 2 to 4 years and 30 to 50 years. Patients with MEN1 represent 5% of patients with VIPoma.

In the brain, VIP is believed to have roles in circadian rhythms, memory, neurodevelopment, and neuroprotection. Immune function is modulated by VIP through its roles in T-cell differentiation and migration; receptor agonists to VPAC1 and VPAC2 and antagonists have been suggested for treatment of autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis.¹⁸

Pathophysiology

VIPomas are usually malignant, often metastatic tumors that presents with flushing, hypokalemia, achlorhydria, hypovolemia, secretory diarrhea, and metabolic acidosis due to loss of bicarbonate into the stool. The electrolyte abnormalities are often referred to as the WDHA syndrome: “watery diarrhea, hypokalemia, and achlorhydria.” Sodium and potassium concentrations are elevated in stool samples. Diagnosis requires confirmation of VIP levels greater than 75 pg/mL in two blood samples. Localizing the tumor may be difficult, requiring ultrasound, CT scanning, and/or octreotide scanning. In adults, the pancreas is often involved, while in children the tumor may present as a ganglioneuroma or ganglioblastoma in the sympathetic chain or adrenal medulla. A VIPoma is rarely pancreatic in children but is more likely to be mediastinal or retroperitoneal. Treatment includes surgical resection whenever possible, potassium repletion, rehydration, and the use of octreotide, interferon-α, streptozotocin, or doxorubicin.¹⁶

Pancreatic Polypeptide

Physiology

Pancreatic polypeptide (PP) is secreted in response to vagal-mediated signals with eating, suppresses appetite centrally, possibly via the NPY type 4 receptor in the hypothalamus and brainstem, and decreases CCK release in the small intestine. It is a product of a gene located at 17q21.31 and is secreted from PP cells in the islets. PP is thought to have a role in long-term appetite control, regulating the appetite level over weeks and months. Obese individuals typically have low levels of PP, in response to recognition of an energy-sufficient (or overly sufficient) state.¹⁹

Pathophysiology

Elevated PP levels can be a useful marker for islet cell tumors in patients with MEN1, as well as islet cell hyperplasia. One sign of PP excess is secretory diarrhea. Interestingly, elevated levels of PP are also seen in anorexia nervosa and may contribute to lack of interest in eating. Deficiency of PP may be manifest by impaired hepatic response to insulin, and it has been described in patients with chronic pancreatitis who develop diabetes mellitus (DM). Deficiency of PP has also been described in children with cystic fibrosis and in those with PWS.¹²

Incretins

Physiology

Incretins are hormones that stimulate insulin release in response to oral intake of calories (Table 10-7). Incretins slow nutrient absorption and postprandial serum glucose spikes by increasing insulin secretion, delaying gastric emptying, inhibiting glucagon release, and decreasing subsequent food intake. Native incretins include GLP-1 and GIP. Both GIP and GLP-1 are rapidly degraded by dipeptidyl peptidases (specifically DPP-4) and have extremely short half-lives. Thus, the native forms of the hormones do not have clinical utility in management of DM. However, synthetic forms of incretins with prolonged half-lives created by structural modification, as well as drugs that inhibit their degradation (DPP-4 inhibitors), have garnered significant interest in the management of T2DM.²⁰

Both GLP-1 and GIP arise from preproglucagon, encoded by a gene on chromosome 2 and differ from each other and from glucagon as a result of posttranslational modifications. These modifications are accomplished by prohormone converstase-1 in ileal and colonic L cells and in the CNS. GLP-2 is also produced from the same pathway.

Glucagon-Like Peptide

Physiology

Native glucagon-like peptide-1 (GLP-1) has a half-life of less than 2 minutes and exists in multiple forms. One truncated form, GLP 7-36, with N-terminal modifications, demonstrates conservation and physiologic significance across mammalian species. GLP-1 secretion from the distal ileum cells and neurons is increased by glucose and gastrin. GLP-1 binds to a G_sα receptor, increasing cAMP and protein kinase A activity. Receptor binding stimulates insulin secretion, suppresses glucagon secretion, inhibits β-cell apoptosis, stimulates β-cell differentiation and proliferation, and inhibits gastric motility and secretion. It also prevents hepatic glucose production (Figure 10-5). GLP-1 and GLP-2 have a role in regulation of appetite and satiety, suppressing hunger, with neurotransmitter function in the CNS. Both are produced in the thalamus, pituitary, and dorsovagal complex, and their receptors have been identified in the arcuate, periventricular, and supraoptic nuclei of the hypothalamus.²¹

Both GLP-1 and GLP-2 are secreted in proportion to the amount of calories ingested. The secretion occurs biphasically, with the initial phase occurring in response to proximal gut calories and abolished by vagotomy. The second phase occurs as L cells of the jejunum encounter calories.

Pathophysiology

GLP-1 excess has been described in isolated case reports of patients with ovarian and pancreatic neuroendocrine tumors. Hypoglycemia is a prominent feature of tumors that hypersecrete GLP-1.^22,23 Patients who have undergone Roux-en-Y surgery for weight loss have also been reported to have hypersecretion of GLP-1 with resultant hyperinsulinemic hypoglycemia.²⁴

Gastric Inhibitory Polypeptide

Physiology

Gastric inhibitory polypeptide (GIP) is the product of a gene on chromosome 17q21.3 and is also known as glucose-dependent insulinotropic polypeptide. It is secreted by the K cells concentrated in the jejunum and duodenum as a 153-amino acid proprotein, and its circulating form is a 42-amino acid peptide. It binds a G_sα protein receptor that increases cAMP and calcium, and it is found in the brain, β cell, and adipose tissue. Its actions include increasing β-cell responsiveness to glucose, and GIP is secreted in amounts proportional to meal size. Significantly increased GIP levels may inhibit gastric acid motility and GI motility.

GIP also has significant effects on energy storage in adipose tissue and in bone. In bone, osteoblast proliferation and inhibition of apoptosis are both mediated by GIP.²⁵

Pathophysiology

A rare syndrome of ectopic GIP action has been described—food-sensitive Cushing syndrome—in which adrenocortical tumor cells express GIP receptors, causing excess cortisol to be secreted in response to a meal. In these patients, administration of oral, but not intravenous, glucose produces a rise in cortisol levels.²⁶ A positive test is regarded as one in which an oral glucose tolerance test or standard mixed meal produces more than a 50% rise in cortisol from baseline; firm diagnosis requires two positive tests.²⁷ Initial treatment may include SRIH analog therapy, but definitive treatment is surgical. GIP deficiency has been described in the context of a patient with intestinal malabsorption caused by CCK deficiency.¹⁴

Incretin Therapeutics

Significant scientific and popular literature has been devoted to possible roles of incretins in treatment of type 2 or even type 1 diabetes. Because native incretins have such short half-lives, synthetic forms have been sought for glucose stabilization. Synthetic forms of GLP-1 include the agonist exenatide (from the saliva of the Gila monster) and the analog liraglutide, both of which must be given by injection. These synthetic incretins stimulate insulin secretion, slow gastric emptying, inhibit glucagon secretion, and decrease appetite.²⁸ Weight loss can be a positive side effect of their use as visceral adiposity in the abdomen decreases. Their utility in treating DM can be limited by a risk of pancreatitis, and they are contraindicated in patients with a personal or family history of medullary thyroid cancer (MTC), as there is uncertainty regarding a possible relationship between synthetic GLP-1 and development of MTC.²⁰

As GLP-1 and GIP are rapidly degraded by DPP-4, the development of oral DPP-4 inhibitors has introduced another mechanism for control of blood glucose in patients with DM. The prototype DPP-4 inhibitor is sitagliptin, given alone or in combination with metformin. DPP-4 inhibitors raise levels of GLP-1 and GIP in the serum, thus decreasing glucagon, stimulating insulin release, decreasing gastric emptying, and decreasing blood glucose spikes. Patients receiving DPP-4 inhibitors have an increased risk of pancreatitis and blistering rash, and in vitro stimulation of colon cancer cells has been noted, though human studies have not yet clearly documented an increase in malignancies.

Amylin

Amylin is a 37-amino acid peptide hormone that is cosecreted from pancreatic β-cells with insulin, as well as from the stomach and duodenum, in response to the nutrient stimulus after food intake. A calcitonin-type receptor bound to one of three receptor activity-modifying proteins (RAMP1, 2, or 3) binds amylin to mediate its effects. The primary effects of amylin are short- and long-term decreases in food intake and body weight. The heterodimeric amylin receptor is distributed not only in the GI system, but is also found in the brainstem, the area of postrema, nucleus tractus solitarii, and hypothalamus. Within the CNS, the anorexic effects of amylin are mediated by an increase in sympathetic nervous system activity.²⁹ Amylin slows gastric emptying and inhibits gastric acid and pancreatic enzyme secretion, thus preventing a rapid rise in blood glucose postprandially. It increases satiety and suppresses glucagon release. Though not an incretin because it does not stimulate insulin release, amylin, also known as islet amyloid polypeptide, is another hormone under scrutiny for the management of type 2 DM (T2DM) and even T1DM. An injectable analog of amylin, pramlintide, is available for use in patients with T2DM before meals to decrease hyperglycemia, and it can result in significant hypoglycemia.³⁰ Another intriguing possibility would be the use of an amylin analog with a leptin analog to address hypothalamic obesity.³¹

Endocrinology of enteric hormones may still be in its infancy, but it is rapidly toddling into childhood. What seemed to be a simple relationship of GI organ stimulation → hormone secretion → end-organ effect has been demonstrated to be a much more complex delicate interplay of the central and peripheral nervous systems and GI organs, with enteric hormones arising from, stimulating, and inhibiting multiple sites throughout the nervous system and the GI system. Enteric hormones participate in growth, homeostasis, reproduction, memory, feeding behaviors, digestion, appetite control, and energy regulation. The future holds promise for new therapeutics as our understanding of enteric hormones advances. Cancer diagnosis and therapeutics, DM, psychiatric disease, and growth are but a few of the medical fields advancing as our knowledge of enteric hormone and receptor biology grows. The endocrinologist should understand the capabilities of the enteric hormones and their analogs, particularly in maintenance of appetite, satiety, and digestion, recognizing the serious deviations from normalcy that can rarely occur to trigger appropriate use of diagnostic testing that separates the disease caused by an enteric hormone abnormality from common variations of appetite, metabolism, digestion, and weight control.