Educational guide
Gastrointestinal Polypeptide - an overview
Chapters and Articles You might find these chapters and articles relevant to this topic. Gastrointestinal peptides The GI tract produces a variety of chemical transmitters (GI peptides) that are involved in controlling GI motility, secretion, absorption, growt
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Chapters and Articles
You might find these chapters and articles relevant to this topic.
Gastrointestinal peptides
The GI tract produces a variety of chemical transmitters (GI peptides) that are involved in controlling GI motility, secretion, absorption, growth, and development.11 While the cells that produce GI peptides are dispersed throughout the GI tract, regulatory peptides are found in the esophagus, stomach, small and large intestines, and the pancreas. Although GI peptides are typically considered hormones, most of them act on the same cells from which they are released, on neighboring cells via classic endocrine mechanisms, and on cells following their release from nerves.11,16 Many of the peptides in the GI tract are also found in the enteric nervous system and the central nervous system. The secretory site, target, and function of the nutritionally important GI peptides are listed in Table 2.1.
Table 2.1. GI peptides (hormones) and their function.
| Names | Secretory sites | Main target sites | Functions |
|---|---|---|---|
| Gastrin | G cell (pyloric antrum, duodenum and pancreas) | Parietal cell | Acid secretion, gastric contraction |
| Secretin | S cell (duodenum) | Pancreas | Water and bicarbonate secretion |
| Cholecystokinin | I cell (duodenum and jejunum) | Pancreas Gall bladder | Pancreatic enzyme secretion, gall bladder contraction |
| Gastric inhibitory peptide (GIP) | K cell (duodenum and jejunum) | Pancreas | Insulin secretion |
| Glucagon like peptide-1 | L cell (small intestine) | Pancreas | Insulin secretion |
| Glucagon like peptide-2 | L cell (small intestine) | Small intestine | Intestinal growth (crypt cell) |
| Peptide YY | L cell (small intestine) | Brain stem | Slows gastric emptying, reduces appetite |
| Somatostatin | Delta cell (pyloric antrum) Hypothalamus | GI tract Pituitary gland | Suppresses the release of gastrointestinal hormones |
Dietary proteins and AAs enter the GI tract via both endogenous and exogenous routes. Endogenous sources include desquamated mucosal cells, digestive enzymes, and other glycoproteins such as mucus. Such endogenous protein entering the digestive tract and serving to also dilute dietary protein has been estimated as equal to or greater than the amount of dietary protein consumed.17 Exogenous or dietary protein sources in the form of meat, poultry, fish, milk products, grains, legumes, and vegetables provide both energy and AAs essential to the body.9
In the GI tract, the exogenous proteins are digested into peptides and free AAs through a series of hydrolytic reactions and feedback mechanisms (Fig. 2.2). Minimal protein digestion occurs within the mouth or esophagus. Once proteins reach the stomach, however, hydrochloric acid (HCl) is released by the parietal cells of the stomach. HCl release may be stimulated by the hormone gastrin, the neurotransmitter acetylcholine from vagal nerve stimulation, the neuropeptide gastrin-releasing peptide, or the amine, histamine.11 HCl denatures protein structures to make them more susceptible to enzymatic action and converts pepsinogen, an inactive proenzyme or zymogen released by the stomach's chief cells, to its active form, pepsin.18 Pepsin in turn may activate other pepsinogen molecules or hydrolyze specific peptide bonds into large polypeptides, oligopeptides, and free AAs as reaction end products.11
Figure 2.2. Protein digestion and absorption.
This mixture, known as acid chyme, next passes into the duodenum and small intestine where most of protein digestion takes place. The end products within the acid chyme stimulate the secretion of the hormones secretin and cholecystokinin (CCK), which in turn travel through the bloodstream to pancreatic acinar cells to stimulate the release of alkaline pancreatic juice. Secretin and CCK also stimulate the release of digestive proenzymes trypsinogen, procarboxypeptidases, chymotrypsinogen, and proelastase (Table 2.2). The higher pH of the duodenum deactivates the pepsin and provides an optimal pH for the activity of the pancreatic enzymes. By releasing proteolytic enzymes initially in their inactive form, the enzyme-forming cells are protected from self-digestion.19,11
Table 2.2. Some proteolytic enzymes responsible for digesting protein.
| Zymogen | Enzyme or activator | Enzyme | Site of activity |
|---|---|---|---|
| Pepsinogen | HCl or pepsin | Pepsin | Stomach |
| Trypsinogen | Enteropeptidase; trypsin | Trypsin | Intestine |
| Chymotrypsinogen | Trypsin | Chymotrypsin | Intestine |
| Procarboxypeptidases | Trypsin | Carboxypeptidases A, B Aminopeptidases | Intestine |
URL: https://www.sciencedirect.com/science/article/pii/B9780323661621000020
Motilin
Based on structural and effect-related similarities, motilin, a 22-amino-acid GI peptide, and ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), are considered to represent a novel GI hormone family. Motilin is secreted from the endocrine cells of the mucosa of the upper part of the small intestine. This peptide stimulates GI motor activity especially in the antrum and upper duodenum, and it is widely acknowledged that motilin is involved in the regulation of interdigestive motility.
The production of motilin in the brain has been debated. Early studies suggest that motilin immunoreactivity is present in the Purkinje cells of the cerebellum in mice, rats, pigs, monkeys, and humans, as well as in the cerebrum, pituitary body, hypothalamus, and epiphysis in mice, rats, dogs, pigs, cows, monkeys, and humans. Motilin is also reported to excite neurons in the cerebral cortex and spinal cord of rats. Using longitudinal muscle/myenteric plexus (LMMP) preparations and cultures of myenteric neurons of the guinea pig ileum, it was observed that most of the motilin-immunoreactive and motilin receptor-immunoreactive neurons were also positive for neuronal nitric oxide synthase, with only a few being positive for choline acetyltransferase. In contrast, ghrelin was mainly co-localized with choline acetyltransferase. Motilin, ghrelin, and ghrelin receptor mRNA transcripts were found in LMMP preparations and in cultured myenteric neurons, suggesting that both peptides may play a role in the activation of the enteric nervous system and in the regulation of GI motility.
Motilin has been reported to possess orexigenic actions. A significant increase in food intake was observed after acute icv administration of motilin in both mice and rats. This effect was attenuated markedly by the motilin receptor antagonist GM-109. These results are consistent with the possibility that motilin receptors are present in the brain and may have a role in the regulation of food intake. Furthermore, peripheral administration of motilin has also been found to stimulate feeding in rats. In agreement with the effect of motilin on food intake it was reported that circulating motilin levels rise progressively during fasting and fall to a nadir within an hour of refeeding.
In addition to its actions on food intake, motilin is also considered to be an important factor in the control of the interdigestive migrating motor complex in the upper GI tract. In the fasting state, exogenous administration of motilin has been reported to induce a contraction pattern in the gastric antrum of both dogs and humans, and motilin also contracts the porcine gastric fundus in vitro. Moreover, administration of motilin causes a contraction of the proximal stomach in humans and increases meal-induced satiety in clinical studies.
URL: https://www.sciencedirect.com/science/article/pii/B9780080450469004435
1.4.1.3 Whole-animal Models
Whole-animal studies have been useful in assessing the contribution of transcriptional control to the regulation of several gastrointestinal peptides, including gastrin, cholecystokinin (CCK), and somatostatin.453–455 Brand and Stone456 showed that gastrin mRNA levels in the antrum increase under conditions of chemical or surgical achlorhydria and coincide with a reciprocal decrease in somatostatin mRNA. These observations are correlated with prior observations that gastrin plasma levels rise under conditions of achlorhydria.453,457 Furthermore, infusion of the somatostatin analog octreotide blocks the rise in gastrin mRNA.456 Walsh and co-workers458,459 found that gastrin mRNA levels are predictably regulated by cycles of fasting and refeeding. Infusion of the pro-inflammatory cytokine interferon γ into mice was used to recapitulate the effect of Helicobacter pylori infection on gastrin and somatostatin.460 Similarly, studies on the dietary control of CCK gene expression have been reported.454 Although such studies permit the linkage of transcriptional regulation to physiological events, they do not allow dissection of the responsible regulatory elements.
URL: https://www.sciencedirect.com/science/article/pii/B9780123820266000014
II.A Classical and More Recently Discovered Neuropeptides
The classical brain peptides can be grouped into broad families such as the hypothalamic-releasing hormones, the neurohypophyseal hormones, the pituitary peptides, the gastrointestinal peptides, the opioids, and the tachykinins (Table I). The classical brain peptides are located differentially throughout the CNS (Fig. 3). For example, forebrain structures (cerebral cortex, striatum, and amygdala) tend to have greater diversity in neuropeptides than hindbrain structures (cerebellum and spinal cord). Remarkably, regions that have the same embryonic derivation within the diencephalon (thalamus versus hypothalamus) can have vastly different neuropeptide profiles (Fig. 3).
Figure 3. General locations of some classical neuropeptides in the human CNS. The top image is a view of the brain and upper spinal cord from a midsagittal perspective, and the two lower panels are transverse views through the forebrain and anterior or mid-diencephalon. Some of the major neuropeptides found in these regions are indicated.
Major advances have been made in understanding brain peptide regulation of feeding and body weight. In the 1950s a recessive obesity mutation was identified that results in profound obesity and adult-onset (type II) diabetes. It was thus postulated that an obese gene product may be a component in a signaling pathway regulating body fat deposition. Mice with mutations in the obese gene are obese and diabetic and are found to have reduced activity, metabolism, and body temperature. It was discovered that leptin, a 16-kDa secreted protein hormone, is the product of the obese gene and is believed to be synthesized only in adipose tissue. Leptin is an integral component in a homeostatic loop that regulates body weight. Leptin acts to control food intake and energy expenditure by both classical and newly discovered neuropeptides in the hypothalamus. One classical neuropeptide that functions in weight control is neuropeptide Y (Table I).
The brain neuropeptides that function in this loop are the orexins (or hypocretins because they are hypothalamic neuropeptides similar to the gut hormone secretin). Orexin-A and orexin-B are peptides of 33 and 28 amino acid residues, respectively, that are derived from the proteolytic processing of a single prepro-orexin precursor protein. These peptides are produced exclusively by a specific group of neurons in the lateral hypothalamus (Fig. 3) called the perifornical nucleus. These orexin-utilizing neurons have widespread projections to the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brain stem. These brain peptides are endogenous ligands for two G-protein-coupled receptors found in the brain that function at synapses to increase the presynaptic release of GABA and glutamate.
In addition to these peptides functioning in energy homeostasis, it has been discovered that the orexin neuropeptide–receptor system functions in sleep regulation. Two animal models dramatically highlight this point. Mice deficient in the orexin gene display abnormal sleep–wakeful states, and autosomal recessive mutations of the hypocretin (orexin) receptor-2 gene cause a sleep disorder in Doberman Pinschers. Both of these abnormalities are believed to cause sleep disorders similar to narcolepsy in humans. Support for this conclusion is derived from studies showing that orexin is undetectable in many people with narcolepsy.
URL: https://www.sciencedirect.com/science/article/pii/B0122272102002739
Discovery of CCK
As the first GI hormone implicated in the control of food intake, CCK’s effects on feeding have been studied longer and more intensively than other GI peptides. In fact, subsequent to the first reports that exogenous CCK reduced food intake in rats and monkeys, CCK has repeatedly been found to reduce intake in rats, monkeys, the human, and other animals. The discovery of CCK activity was published, in 1928, by Ivy and Oldberg. They reported that extracts from small intestinal mucosa of the swine evoked contraction of canine gall bladder. Accordingly, they named the putative active agent CCK. In 1943, Harper and Raper reported that intestinal mucosal extracts evoked protein secretion by the exocrine pancreas, and named the active agent pancreozymin. However, by the 1960s purification and characterization of mucosal extracts in the laboratory of Viktor Mutt revealed that pancreazymin and CCK were the same substance, and cholecystokinin became its official name.
In the GI tract, CCK is synthesized and secreted by the enteroendocrine I cells located primarily in the duodenal and jejunal portions of the small intestine. Plasma CCK concentrations rise following food intake, especially when foods are high in fat or protein content. In rats plasma CCK concentration is also elevated by direct intestinal infusion of long-chain fatty acids, protein, or peptones, but not by infusion of carbohydrate.
URL: https://www.sciencedirect.com/science/article/pii/B9780080453965001913
Carcinoid
Carcinoid tumors are well-differentiated neoplasms of the diffuse endocrine system and arise from cells of endodermal origin in the GI epithelium. These cells synthesize a variety of GI peptides and hormones, and consequently the tumors that result from them may secrete a variety of physiologically active substances, resulting in the carcinoid syndrome. More commonly, however, these tumors are hormonally inactive.
Carcinoid tumors are uncommon. In a large autopsy series, they were found in 1 to 2% of people and account for a similar percentage of clinically evident GI neoplasms in adults.44 As in adults, childhood carcinoid tumors are most commonly found in the appendix (40% in adults), but have been found in all parts of the GI tract including the small intestine, pancreas, and biliary system and in Meckel’s diverticulum and GI duplications.45-47
Although most carcinoids are found incidentally in adults, children usually present with acute appendicitis48,49 where the tumor may or may not have played an obstructive role in its development. Ileal and colonic lesions are more likely to present as a palpable mass because of their increased size (90% over 2 cm) and to be metastatic at diagnosis.50 Presentation of the tumor with symptoms attributable to the carcinoid syndrome is rare in children, with only a few reports in the literature.47,51 As in adults, this syndrome is most common with metastatic tumors in the liver from a small bowel primary. Hormonal activity in carcinoid tumors results in the secretion of GI peptides and hormones including serotonin, 5-hydroxytryptophan, histamine, prostaglandins, catecholamines, and bradykinins. Resultant symptoms may include diarrhea, bronchoconstriction, edema, and flushing. Bradykinin may additionally induce fibrogenesis both locally and in the heart, resulting in the reports of valvular stenosis.52
Most carcinoid tumors are solitary and sporadic without predisposing factors. Loss of heterozygosity at the MEN-1 gene locus is significantly associated with gastrin-producing tumors arising in the duodenum and upper jejunum within the setting of multiple endocrine neoplasia.53 Periampullary somatostatin-producing tumors occur in neurofibromatosis type 1.54
The majority of appendiceal endocrine tumors are found incidentally as firm whitish masses in the distal end; more proximal tumors may produce obstruction that results in appendicitis. The usual appearance of a carcinoid tumor in the appendix and elsewhere is that of multiple well-demarcated rounded or insular islands of closely packed cells with peripheral palisading that are separated by fibrotic stroma. The tumor cells are uniformly bland and have round nuclei with finely stippled (“salt and pepper”) chromatin that are surrounded by a moderate amount of lightly eosinophilic granular cytoplasm (Figure 49-7). Their neuroendocrine features can be confirmed by silver impregnation techniques or immunohistochemical staining for generic endocrine cell markers such as chromogranin A and PGP 9.5. The tumors arise in the mucosa, but the bulk of the mass often occupies the muscular walls and can extend into the mesoappendix.
Diagnosis is usually made on finding the tumor mass at surgery. In the unusual circumstances of carcinoid syndrome, the urine level of 5-HIAA (5-hydroxyindoleacetic acid), a major metabolite of serotonin, may be diagnostically elevated, especially on a 24-hour urine specimen (greater than 30 mg is indicative of carcinoid syndrome).55 Foods rich in serotonin and certain drugs may artificially alter the results. Computed tomography of the abdomen is useful in localizing mass lesions and can identify any hepatic metastases, but GI contrast radiographic studies miss most GI carcinoids.
Surgical resection is the mainstay of therapy for carcinoid tumors. When the tumor mass is less than 2 cm in diameter, an appendectomy is sufficient,48,49,56 but for larger tumors a right hemicolectomy is recommended. Any tumor without distant metastases should be completely resected.57 Patients with symptoms attributable to the carcinoid syndrome may get symptomatic relief with long-acting somatostatin analogues, such as octreotide,58,59 and proton-pump inhibitors are useful in treating the gastric acid hypersecretion resultant from gastrin-producing duodenal carcinoids (gastrinomas).59 Octreotide alone or in combination with interferon alpha may also provide antiproliferative affects to control tumor growth, in 50% of patients, but tumor regression is less common.59 Chemotherapeutic agents have not been found useful in the treatment of slowly growing carcinoids. For nonresectable liver tumors, cryotherapy has been used to provide transient symptomatic relief in carcinoid syndrome but does little to improve long-term survival.60 Transcatheter arterial chemoembolization of liver metastases, however, has resulted in long-term palliation and may prove to be the treatment of choice in this situation.61
The prognosis of individuals with carcinoid tumors is good. Appendiceal tumors have a low chance of nodal or liver metastasis (4%) and a 5-year survival of 89% with surgical resection only. Colonic and ileojejunal tumors have much higher chances of local or distant metastasis (55% and 70%, respectively) but still have 5-year survivals of 75% and 68%, respectively.62 The presence of distant metastases significantly worsens the prognosis compared with localized tumors only, but even in this situation there are long-term survivors, some for decades after the diagnosis, because of the slow rate of tumor growth.
URL: https://www.sciencedirect.com/science/article/pii/B9781437707748100491
Publisher Summary
The first neuropeptide is identified and named vasopressin, a nine-amino-acid peptide secreted by the nerve endings in the neural lobe of the pituitary. Similar to vasopressin, a number of gastrointestinal peptides, such as cholecystokinin (CCK), are also found at high concentrations in the nervous system. Neuropeptides are present in tissues at much lower concentrations than classical neurotransmitters. The source of the vasopressin is the magnocellular neurons of the hypothalamus that send axons to the neurohypophysis, the peptides are then released into the blood in classic neurosecretory fashion. The supply of conventional neurotransmitters in small synaptic vesicles is replenished in nerve terminals by local synthesis, and many conventional neurotransmitters are recaptured after secretion. In addition, peptides can exert their actions after traveling through some or all of the vasculature to reach their target (endocrine effects), as in the case of hypothalamic releasing factors and neurohypophyseal hormones. Neuropeptide expression is extremely plastic, even in the adult. For example, the hypothalamic neurons that express vasopressin and those that synthesize corticotropin-releasing hormone (CRH) are situated close to each other but constitute separate and virtually non-overlapping populations of neurons in the normal animal.
URL: https://www.sciencedirect.com/science/article/pii/B9780123749475000201
Since the first investigations of satiety, it has been believed that the effects of food composition are mediated by post-prandial physiological responses. These involve changes in gastric distention, laxation, and emptying together with the release of gastro-intestinal peptides including cholecystokinin (CCK), glucagon-like peptide (GLP-1), peptide YY (PYY), insulin, and others. For many years, CCK was regarded as the unique single satiety signal. It should be noted that all these peptides have other important roles in the management of food within the body through the processes of digestion and absorption, such as the slowing of gastric emptying and the release of bile for the emulsification of fat. Therefore, an effect on satiety may be secondary to these other functions. It remains a point of debate whether gut peptides are biomarkers or the true causes of satiety. Since different foods may have similar effects on satiety but generate quite distinct physiological profiles, it appears that there is no unique pattern underlying satiety. The same degree of satiety may be associated with different post-prandial physiological changes. There is considerable interest in the post-prandial physiological effects of highly- and ultra-processed foods.
URL: https://www.sciencedirect.com/science/article/pii/B9780128218488001359
1 What is hypertrophic pyloric stenosis (HPS)?
HPS is the most common cause of gastric outlet obstruction in infants resulting in nonbilious vomiting. The pathogenesis of HPS is unknown; it is not thought to be a developmental defect. Hypotheses include nitric oxide deficiency, decreased neurotrophins, and alterations in growth factors and gastrointestinal peptides. It is more common in boys than girls (2:1). Offspring of an affected parent have an increased risk of HPS (10%); the highest rate (20%) occurs in boys born to affected mothers. The pylorus muscle grossly and histologically appears thickened and hypertrophied.
2 Describe the typical presentation of an infant with HPS
Typically, an otherwise healthy infant who was feeding without issue develops nonbilious emesis at 2–8 weeks of age. Initially, the emesis is not frequent or forceful. Over a period of days, the infant develops projectile vomiting with most feeds. The emesis may have a coffee-ground appearance as a result of gastritis or esophagitis. The infant remains hungry after emesis. In premature infants, the diagnosis often presents 2 weeks later. As HPS goes unrecognized, the infant becomes dehydrated.
3 What are the physical findings?
The infant may appear normal, especially if the diagnosis is made early. Some infants are dehydrated, malnourished, or lethargic. The abdomen is nondistended and soft. A palpable “olive” confirms the diagnosis. The pylorus can be palpated in a relaxed infant in the epigastrium. This is becoming a lost skill in the era of ultrasonography.
4 Why do some infants with HPS appear jaundiced?
Approximately 5% of infants have mild jaundice from indirect hyperbilirubinemia related to glucuronyl transferase deficiency.
5 How is the diagnosis confirmed?
Ultrasonography is the imaging test of choice. Ultrasonographic criteria include a pyloric muscle thickness of ≥3.5 mm, pyloric channel length of ≥15 mm, and pyloric diameter ≥14 mm. Muscle thickness of ≥3 mm is considered positive for infants younger than 30 days of age. If ultrasonography is not available or nondiagnostic, an upper gastrointestinal (UGI) contrast examination can assist with diagnosis or provides alternative causes of nonbilious vomiting (e.g., gastroesophageal reflux, malrotation, duodenal stenosis).
6 Describe the likely electrolyte abnormalities
Electrolytes are often normal because of earlier consideration of the diagnosis. In the case of long-standing vomiting, a hypokalemic, hypochloremic metabolic alkalosis results because of the loss of gastric acid (HCl). Dehydration is corrected with 0.9% sodium chloride (NaCl) with 20 mEq/L of potassium chloride (KCl). Withholding KCl while awaiting urine output delays appropriate replacement. The rare exception is acute renal compromise or preexisting renal impairment. Once the infant is resuscitated and electrolytes corrected, pyloromyotomy is performed. The serum bicarbonate level should be <30 mEq/L to avoid respiratory depression and prolonged postoperative intubation.
7 What procedure is performed to treat HPS?
The operative procedure of choice remains the Ramstedt pyloromyotomy. A superficial incision is made longitudinally over the pyloric muscle in an avascular area. The muscle’s fibers are fractured bluntly with either the back of a scalpel or a pyloric spreading clamp. A few pyloric muscle fibers are left intact on the duodenal end to reduce the risk of perforation. At conclusion of the pyloromyotomy, the gastric mucosa should bulge upward into the cleft. The pyloric muscle walls should move independently. Air is injected into the stomach via the nasogastric tube to identify mucosal perforation. Pyloromyotomy can be performed open (transverse right upper quadrant or supraumbilical incision) or laparoscopically (three small incisions).
8 What are the complications of pyloromyotomy?
Incomplete pyloromyotomy, mucosal perforation, wound infection, and abdominal wall hernias are some of the potential complications. Most incomplete pyloromyotomies are a result of failure to extend it far enough on the proximal antrum. Laparoscopic pyloromyotomy benefits include faster recovery and advancement to full feeds, decreased pain, and improved cosmesis. Incomplete pyloromyotomy risk is slightly higher with the laparoscopic approach (1%) compared to the open approach (0.3%); mucosal perforation rates are equivalent.
9 What should be done if a mucosal perforation is identified?
Mucosal perforation is a rare event (0.5%). The submucosa should be approximated with interrupted fine absorbable suture and covered with an omental patch. An infrequently needed alternative is closure of the original myotomy and a second, parallel myotomy made 180 degrees on the opposite side of the pylorus.
10 When can postoperative feeding begin?
Small-volume feedings are started after the infant has recovered from anesthesia (2–3 hours). The feeds are advanced to goal. Small-volume emesis is common (20%), but most infants achieve full feeds 24 hours postoperatively. An incomplete pyloromyotomy is considered when symptoms of gastric outlet obstruction persist for 7 days postoperatively.
Key Points: Hypertrophic Pyloric Stenosis
1.Infants with HPS present with nonbilious, projectile vomiting. A hypokalemic, hypochloremic metabolic alkalosis can develop with long-standing emesis.
2.Ultrasonography is the diagnostic test of choice to confirm HPS; a positive study shows a muscle thickness of ≥3.5 mm and pyloric channel length of ≥15 mm.
3.After resuscitation and correction of electrolyte abnormalities, pyloromyotomy, laparoscopic or open, is performed. Complications of the pyloromyotomy include mucosal perforation and incomplete pyloromyotomy.
URL: https://www.sciencedirect.com/science/article/pii/B9780323478731000863
Hormones
Experimental data that clearly show the involvement of hormones and more specifically GI hormones during fetal pancreas development are rather scattered. Studies by Swenne indicate that growth hormone (GH) can stimulate the in vitro replication of fetal rat beta cells, an effect mimicked by prolactin and placental lactogen. However, because of the doses used, the physiological significance of the observed effects was called into question. Later, Swenne proposed that part of GH's mitogenecity in beta cells could be attributed to insulin-like growth factor-I (IGF-I). Rhodes described IGF-I and GH signal transduction pathways and suggested that each molecule operates via its own specific route to activate different mitogenic signals.
Although cholecystokinin (CCK), a gastrointestinal peptide hormone, can stimulate proliferation of the exocrine pancreas after birth, it remains unlikely that it would be involved during fetal development since its expression in fetal life is negligible. However, by immunochemistry and immunofluorescence methods, Sarvetnick detected CCK in pancreatic cells located in the acinar region of the pancreas on embryonic day 16. These data suggest that CCK signaling could be established early in development but its exact function remains unknown. However, treatments throughout pregnancy with caerulein, a CCK analogue, led Morisset to show that it induced pancreas aplasia in the mature fetus; unfortunately, the endocrine pancreas was not examined in this study. Another GI hormone that could influence the growth of the endocrine pancreas is gastrin, as it is transiently expressed in the islets, its major source in the fetus. Although the role of pancreatic gastrin in islet development remains undefined, it may influence islet growth since fetal pancreas has high levels of CCKB/gastrin receptor mRNA transcripts and high concentrations of gastrin. Although once again endocrine pancreas was not investigated, Morisset clearly demonstrated that pentagastrin treatment throughout pregnancy resulted in fetal pancreas hypertrophy, whereas treatment with L365,260, a specific CCKB receptor antagonist, caused pancreas atrophy. It may be hypothesized that the endocrine pancreas could also have been affected.
URL: https://www.sciencedirect.com/science/article/pii/B0124755704004273