Endocrine System 6: pancreas, stomach, small intestine and liver
James Taylor John Knight NT Contributor
This article, the sixth in an eight-part series, examines the anatomy and physiology of the endocrine glands and tissues associated with the gastrointestinal tract.
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Introduction

The endocrine system comprises glands and tissues that produce hormones for regulating and coordinating vital bodily functions. This sixth article of an eight-part series examines the anatomy and physiology of the endocrine glands and tissues that are associated with the gastrointestinal tract. We explore the endocrinology of the pancreas, liver and gut tissues, and the role their hormonal secretions play in regulating digestion and wider human physiology.

Pancreas

Situated in the abdomen, posterior to the stomach, the pancreas is a long, flat organ, which sits in the loop of the duodenum (Fig 1). It weighs approximately 100g and measures around 14-23cm in length (Longnecker, 2021).

Histologically, the pancreas consists of two regions:

Exocrine pancreas – this forms the greater portion of the organ and is dedicated to digestion. It produces a cocktail of enzymes, including lipases, proteases and amylases, that are suspended in a bicarbonate-rich fluid called pancreatic juice. The presence of alkaline bicarbonate neutralises the acidic chyme that arrives in the duodenum from the stomach, while the enzymes participate in the digestion of fat, protein and carbohydrates (Gorelick et al, 2018).

Endocrine pancreas – this is composed of tiny ‘islands’ of endocrine cells that are referred to as the islets of Langerhans. The cells of the pancreatic islets play key roles in regulating appetite and ensuring glucose homeostasis (Cook et al, 2021).

Histology of the endocrine pancreas

The average adult pancreas is estimated to possess around 3.2 million pancreatic islets (Ionescu-Tirgoviste et al, 2015). Each islet is composed of five main cell types, each responsible for the production of one or more peptide hormones:

Beta cells (insulin and amylin);

Alpha cells (glucagon);

Delta cells (somatostatin);

Gamma cells (pancreatic polypeptide);

Epsilon cells (ghrelin).

The insulin response

Insulin and glucagon are the primary hormones involved in glucose homeostasis. After the consumption of a meal that is high in carbohydrates, the beta cells detect an increase in blood–glucose concentration and secrete insulin directly into the blood. Insulin binds to insulin receptors, which are present on most cell types throughout the body. The binding of insulin to its receptor triggers the movement of glucose transporter type 4 (GLUT4) from inside the cytoplasm of the target cell to the plasma membrane where it is inserted.

GLUT4 acts as a channel protein that facilitates the rapid movement of glucose into the cell where it can be either used for metabolism or converted into glycogen or fat for storage. This process is referred to as the insulin response and is essential for decreasing and normalising blood–glucose concentrations.

Although most cell types possess insulin receptors, the major target tissues for insulin are the hepatocytes of the liver and adipocytes that form adipose tissue.

Amylin

Amylin is cosecreted with insulin from beta cells in response to high blood sugar. Although we are yet to understand the full extent of the effects of amylin on the human body, it is known to:

Inhibit glucagon secretion;

Supress emptying of the stomach contents;

Help regulate blood pressure through effects on the renin-angiotensin-aldosterone system (Zhang et al, 2016).

In addition, it has been noted that amylin plays a role in the maintenance of bone density through the inhibition of osteoclasts and bone resorption (Girgis et al, 2013).

Glucagon

Glucagon is produced by the alpha cells of the pancreatic islets from a larger precursor molecule called proglucagon. Glucagon primarily functions as the natural antagonistic hormone to insulin in maintaining glucose homeostasis (Park, 2016).

When blood-glucose levels fall – for example, when food has not been eaten for several hours – alpha cells release glucagon into the bloodstream. Glucagon exerts its effects by binding to glucagon receptors; these are present primarily in the liver but are also found in a range of tissue, including that of the kidneys, stomach, small intestine and thyroid (Rix et al, 2019).

Formation of these glucagon-receptor complexes serves to increase the blood-sugar level by promoting the breakdown of liver glycogen stores into glucose (a process called glycogenolysis). Once broken down, this glucose is then released into the blood, raising the blood-sugar level.

Alpha and beta cells are located in close contact with an extensive network of capillaries, allowing for the rapid release of hormones into the bloodstream to bring about a quick response to maintain the blood-sugar level in the normal, adult fasting range of 3.5–5.5 mmol/L (Güemes et al, 2016). When the blood-sugar level cannot be maintained in this range, the consequence is one of two conditions:

Hyperglycaemia – high blood-glucose concentration;

Hypoglycaemia – low blood-glucose concentration.

Diabetes

Diabetes is a chronic condition that is characterised by hyperglycaemia resulting from the absence of, or an impaired, insulin response, affecting utilisation of glucose. The two main types of diabetes are type 1 and type 2.

Type 1 diabetes

Type 1 diabetes, an autoimmune disorder, is the rarer of the two forms and accounts for approximately 8% of all cases of diabetes; however, it is the most common form of diabetes seen in children. In type 1 diabetes, the body’s ability to produce insulin is diminished through the autoimmune attack of the pancreatic beta cells. The disease is primarily managed with insulin therapy.

Type 2 diabetes

Type 2 diabetes is the most common form of diabetes, accounting for around 90% of cases, and the predominant form diagnosed in adults. Pancreatic beta cells produce insulin but the usual physiological effects are not achieved due to insulin resistance. Insulin resistance is hypothesised to occur as a result of changes to the structure of the insulin receptor, affecting binding (Yaribeygi et al, 2019). This leads to increased insulin production by the beta cells in compensation (Freeman and Pennings, 2021).

Ghrelin and pancreatic polypeptide

Ghrelin and pancreatic polypeptide are antagonistic hormones that help to regulate appetite. Levels of ghrelin, commonly referred to as the hunger hormone, fluctuate throughout the day. Ghrelin levels are typically at their highest before the three main meals of the day (Cook et al, 2021), resulting in increased appetite. Ghrelin also inhibits the secretion of insulin from beta cells, allowing the blood-sugar level to rise in the period after a meal (Tong et al, 2010).

Ghrelin is released from the epsilon cells of the pancreatic islets and transported via the bloodstream, where it binds to specific receptors in the hypothalamus called growth hormone secretagogue-receptors (GHS-Rs), more commonly referred to as ghrelin receptors (Alamri et al, 2016). This induces the feeling of hunger we experience. Ghrelin is also secreted by the gastric mucosa of the stomach, where it is produced by P/D1 cells found predominantly in the upper region of the stomach, known as the fundus (Alamri et al, 2016).

Conversely, following a meal, pancreatic polypeptide is secreted from the gamma cells (also known as pancreatic polypeptide, or PP, cells) of the pancreatic islets and binds preferentially to Y4 receptors in the hypothalamus, inducing feelings of satiety. When compared with the other pancreatic hormones, relatively little is understood of the actions of pancreatic polypeptide, although roles have been noted in satiety signalling, anxiety-induced behavioural changes and the processing of fear (Verma et al, 2016).

Somatostatin

Produced by pancreatic delta cells (D cells), as well as several other tissues throughout the body, including the D cells of the gastric mucosa (Cook et al, 2021), somatostatin – also known as growth hormone-inhibiting hormone – has a broad range of activity, depending on the tissue of origin (Ampofo et al, 2020). In the pancreas, it modulates pancreatic function by inhibiting the secretion of insulin, glucagon, pancreatic polypeptide and ghrelin. Additionally, it reduces production of gastric secretions, including hormones of the gastrointestinal tract (Ampofo et al, 2020), and helps to modulate the release of growth hormone.

The stomach

The stomach is a muscular sac with an average capacity of approximately 1.5L in adults. It is located in the upper-left quadrant of the abdominal cavity and consists of three main regions (Fig 2):

Fundus;

Body;

Antrum.

The primary function of the stomach is to act as a vessel for ingested food; it undergoes regular rhythmic contractions to ensure the efficient mixing of food with gastric juice to produce a partially digested fluid called chyme. Food enters the stomach from the oesophagus via the lower oesophageal sphincter, with chyme leaving the stomach and entering the duodenum via the pyloric sphincter (Fig 2).

Gastric histology

The lining of the gastrointestinal tract comprises four distinct layers. From the innermost to the outermost layer, these are the mucosa, submucosa, muscularis propria and serosa. The mucosa is generally considered the most important and complex of the layers in terms of overall functionality.

The layered mucosa of the stomach is folded into tight structures, termed ‘rugae’, which allow the stomach to expand. In the rugae are minute depressions termed gastric pits (Fig 3), which contain four main secretory cells:

Parietal cells – these produce hydrochloric acid (HCl), which aids digestion, neutralises harmful bacteria and activates the proteolytic enzyme, pepsin (Engevik et al, 2020);

Mucous cells – also present on the surface of the stomach lining, these secrete alkaline mucus, which protects the stomach lining from gastric secretions. In the gastric pits they are referred to as mucous neck cells;

Chief cells – these secrete pepsinogen, a precursor molecule converted to pepsin through exposure to HCl. Pepsin is a protease that initiates the chemical digestion of proteins. Chief cells also secrete the lipolytic enzyme referred to as human gastric lipase, responsible for the breaking down

of fat;

Endocrine cells – these are responsible for the secretion of several hormones, as outlined below.

Gastric hormones

Several types of endocrine cells are present in the gastric mucosa; these secrete hormones that regulate gastric physiology and digestion.

G cells and gastrin

G cells are principally found in the antrum of the stomach and secrete preprogastrin, a 101 amino acid precursor molecule that is converted into the active hormone gastrin (Engevik et al, 2020). Gastrin production is triggered by the stretching of the stomach wall and the ingestion of protein. Its primary function is to regulate stomach acidity by modulating the secretion of HCl by the parietal cells.

Gastrin stimulates enterochromaffin-like (ECL) cells (present in the gastric mucosa) to release the inflammatory mediator histamine; this binds to receptors on the parietal cells, which then secrete HCl (Engevik et al, 2020). Many of the early drugs used to treat gastric ulceration and gastric reflux, such as cimetidine, block the binding of histamine to its receptors, reducing the secretion of HCl. Additionally, HCl secretion is regulated via several other mechanisms, including the pancreatic hormones ghrelin and somatostatin (Engevik et al, 2020).

Gastrin also maintains tissue integrity through epithelial cell proliferation in the gastrointestinal tract, maintenance of the gastric mucosa and stimulation of parietal and ECL cell proliferation (Schubert and Rehfeld, 2019).

D cells and somatostatin

Also found in the antrum are D cells, which are responsible for the secretion of the peptide hormone somatostatin. As previously discussed, this hormone is also produced by the D cells of the pancreas.

Somatostatin helps to regulate the pH of the stomach contents by inhibiting G-cell production of preprogastrin and, therefore, gastrin itself. In the absence of gastrin, parietal cells are not stimulated to produce gastric acid, resulting in increased pH of the stomach contents.

Somatostatin also has direct inhibitory effects on the parietal and ECL cells, further supressing the production of gastric acid. The G and D cells, therefore, work closely together to maintain an optimal pH for effective digestion (Schubert and Rehfeld, 2019).

P/D1 cells and ghrelin

P/D1 cells are found predominantly in the fundus and secrete the peptide hormone ghrelin, which, as previously noted, is also produced by the epsilon cells of the pancreas (Alamri et al, 2016). Before a meal and when the stomach is empty, the relaxed state of the stomach lining stimulates the P/D1 cells to secrete ghrelin, triggering feelings of hunger. Conversely, after a meal and when the lining of the stomach is stretched, the secretion of ghrelin from the P/D1 cells is supressed (Cook et al, 2021).

The small intestine

Measuring approximately 6-7m in length, the small intestine marks the part of the gastrointestinal tract in which the majority of digestion occurs. It comprises three main regions:

Duodenum (start);

Jejunum (middle);

Ileum (end).

Despite being the shortest section, the duodenum is the principal region of digestion. Digestion here is regulated by several hormones secreted by endocrine cells that are present in the small intestine. The duodenum comprises four key regions, namely the superior, descending, transverse and ascending regions (Fig 1).

Histology of the small intestine

The mucosal layers, which are in contact with the food being digested, contain cells that secrete hormones, mucus and digestive enzymes. Here, mucus again provides protection (particularly for the duodenum) from acidic chyme arriving from the stomach. To increase the surface area and give the small intestine elasticity, the mucosa is highly folded into structures known as plicae circulares, or circular folds. The mucosal layer also comprises additional folds forming the finger-like projections of the villi, which greatly increase surface area for more effective nutrient absorption.

In the columnar epithelial layer of the mucosa, between the villi, are pits that are referred to as the crypts of Lieberkühn. They give rise to the majority of the defensive and hormonal activity in the small intestine, via the paneth and enteroendocrine cells respectively.

Intestinal hormones

Found primarily in the crypts, the entero-endocrine cells of the mucosa secrete several hormones including secretin, cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP).

Secretin

Secretin is released in response to the presence of acidic chyme and fatty acids. Binding to secretin receptors, it has several roles primarily relating to acid neutralisation and digestion; however, secretin also stimulates insulin release from the pancreas in response to glucose ingestion (Afroze et al, 2013).

In its primary role, secretin signals the pancreas to release bicarbonate ions into the pancreatic juice, increasing the pH to between 8 and 8.3 (Melamed and Melamed, 2014; Parikh and Thevenin, 2021) to neutralise the acidic chyme. This protects the lining of the duodenum and provides optimal conditions for the actions of the digestive enzymes in the pancreatic juice.

Secretin also regulates gastrin release, HCl production and contraction of the pyloric sphincter, as well as enhancing small intestine motility (Afroze et al, 2013).

CKK

CCK is a peptide hormone released from mucosal cells in the duodenum and jejunum. It is crucial to the functioning of the small intestine and mediates its primary effects on digestion by binding to specific receptors in the gut, pancreas and gall bladder. Some of the primary effects include:

Signalling secretion of digestive enzymes by the exocrine pancreas;

Stimulating bile production and release by initiating contraction of the gall bladder and relaxation of the sphincter of Oddi (Fig 1).

Additionally, CCK induces satiety and inhibits further gastric emptying, allowing bile and pancreatic juice to begin working in the small intestine (Rehfeld, 2017).

GIP

GIP, produced in the duodenum and jejunum, is secreted in response to nutrient ingestion. It binds to specific receptors in the pancreas and stimulates the release of insulin from the pancreatic beta cells, thereby lowering the blood–glucose concentration (Pederson and McIntosh, 2016).

The release of GIP is also triggered by low pH, resulting from the presence of chyme, leading to inhibition of HCl production and preventing acid-induced degradation of the duodenal mucosa. This is helped further through the secretion of mucus by the small intestine (physical protection) and the net effects of secretin and CCK (chemical protection) through the production and release of pancreatic juice and bile, which neutralise the chyme. GIP also limits gastric emptying by suppressing stomach motility, an effect triggered when the duodenum is full (Parikh and Thevenin, 2021).

The liver

The bulk of the liver is situated in the upper-right quadrant of the abdominal cavity. The liver is the largest of the visceral organs and, in adults, weighs an average of 1.4-1.6kg (Cook et al, 2021). It has over 500 documented functions including:

Storing and releasing energy;

Supporting the immune system;

Regulating lipid and cholesterol levels;

Detoxification;

Processing various xenobiotics, including many medicines;

Supporting digestion through the production of bile (Trefts et al, 2017).

Hepatic endocrine function

The liver plays an integral role in hormone synthesis and regulation. Cholesterol produced by the liver is used as the substrate to synthesise the steroid hormones produced by the adrenal cortex (Knight et al, 2021) and the sex hormones produced by the ovaries and testes (which will be covered in part 7 of this series).

The liver also works in tandem with the skin and kidneys to synthesise vitamin D (Cook et al, 2021), and produces its own hormones and precursors that influence platelet formation, iron homeostasis, growth and blood pressure. Three of the key hormones produced are thrombopoietin, hepcidin and insulin-like growth factor-1 (IGF-1). Angiotensinogen produced in the liver is the sole precursor to angiotensin and plays a key role in the renin-angiotensin system that regulates blood pressure.

Thrombopoietin

Thrombopoietin is a glycoprotein hormone that is crucial in platelet formation; for this reason, it also plays a key role in the process of haemostasis and, in particular, in blood clotting (Patel et al, 2005).

Hepcidin

Hepcidin regulates the concentration, absorption, and distribution of iron and is closely related to erythrocyte production (Pagani et al, 2019). It is mainly produced by hepatocytes but is also generated by other tissues and cells throughout the body, including adipocytes, macrophages and brain tissue (Nemeth and Ganz, 2009).

Increased iron concentration, indicated by a saturation of hepatocyte iron stores, triggers the release of hepcidin, which blocks iron absorption in the small intestine. Anaemia, hypoxia and erythropoietic activity suppress hepcidin secretion, allowing for increased iron absorption and the release of iron from stores to support erythropoiesis. Specifically, hepcidin controls iron transport between cells, plasma and extracellular fluid through the hepcidin receptor and iron transport protein, ferroportin.

In addition to its regulatory function, hepcidin production is also elevated in response to infection and inflammation. It is hypothesised that hepcidin limits iron availability to micro-organisms during infection, thereby contributing an accessory role in non-specific immune response (Silvestri et al, 2019).

IGF-1

Formerly referred to as somatomedin, IGF-1 is primarily produced by liver hepatocytes and is structurally similar to insulin. Its production and secretion are stimulated by the release of growth hormone, also known as somatotropin, from the anterior pituitary gland in the brain. Once released from the hepatocytes, IGF-1 binds to the IGF-1 receptors (IGF-1R) which are present in most tissues throughout the body. This results in the activation of secondary signalling pathways that serve to upregulate anabolic processes throughout the body, stimulating growth and the maturation of tissue (Kineman et al, 2018).

It is generally considered that insulin plays a primary role in nutrient metabolism, while IGF-1 is more concerned with structural anabolic processes (Kineman et al, 2018).

Part 7 of this series will explore the endocrine function of the ovaries, testes and placenta.