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The pancreas is a slender, soft organ located primarily behind the stomach (Figure 29). This versatile gland serves a dual function, acting as both an exocrine and an endocrine organ vital to numerous bodily processes. About 98 percent of the pancreas consists of pancreatic acini, which are organized into a single layer of cells. The acinar cells carry out the exocrine function by coordinating the release of pancreatic juice, rich in various digestive enzymes, into the small intestine via the pancreatic duct. In contrast, the remaining two percent of pancreatic tissue is made up of the pancreatic islets, or islets of Langerhans. These small clusters of cells are responsible for secreting several hormones, including glucagon, insulin, somatostatin, and pancreatic polypeptide, which collectively play crucial roles in regulating various physiological functions.
Cells and Secretions of the Pancreatic Islets
The pancreatic islets house four distinct cell types (Table 8). Alpha cells, constituting roughly 20 percent of each islet, produce the hormone glucagon. It plays a vital role in regulating blood glucose levels, with its release triggered by low blood glucose levels and inhibited by normal glucose concentrations. Beta cells, comprising about 75 percent of each islet, produce the hormone insulin. Elevated blood glucose levels stimulate insulin release, while decreased glucose levels reduce its secretion. Delta cells, accounting for approximately four percent of islet cells, secrete the peptide hormone somatostatin. Pancreatic somatostatin inhibits the release of both glucagon and insulin. PP cells, representing around one percent of islet cells, release the pancreatic polypeptide hormone. This hormone is believed to influence appetite and regulate both pancreatic exocrine and endocrine secretions. Pancreatic polypeptide may reduce post-meal food consumption and is also released during fasting.
| Associated Hormones | Chemical Class | Effects |
|---|---|---|
| Insulin (Beta Cells) | Protein | Reduces blood glucose levels |
| Glucagon (Alpha Cells) | Protein | Increases blood glucose levels |
| Somatostatın (Delta Cells) | Protein | Inhibits insulin and glucagon release |
| Pancreatıc Polypeptide (PP Cells) | Protein | Role in appetite |
Glucose Transporters
Glucose, a vital energy source for all body cells, is pivotal in maintaining energy balance. Excess glucose not immediately utilized by cells for energy can be either stored in the liver and muscles as glycogen or converted into triglycerides and stored in adipose tissue.
Glucose transporters represent a family of membrane proteins responsible for facilitating the movement of glucose across a cell's plasma membrane. Several established isoforms of glucose transporters are recognized within this group, namely GLUT-1 through GLUT-4, each with distinct tissue distributions (Table 9). GLUT-1 is predominantly found in fetal tissues, erythrocytes, and the endothelial cells forming the blood-brain barrier. GLUT-2 exhibits primary expression in the liver, beta cells of the pancreas, basolateral membrane of the small intestinal epithelium, and renal tubular cells. GLUT-3 is prevalent in neurons and the placenta. GLUT-4, which relies on insulin for activation, is primarily expressed in adipose tissue and striated muscle cells.
|
Glucose Transporter |
Effects |
|---|---|
|
GLUT-1 |
Fetal tissues, blood-brain barrier |
|
GLUT-2 |
Liver, Beta cells, renal tubular cells |
|
GLUT-3 |
Neurons and placenta |
|
GLUT-4 (Insulin-dependent) |
Adipose tissue, skeletal and cardiac muscle |
Glucagon
Glucagon, a peptide hormone, secreted when glucose levels are low, triggers several essential processes to restore glucose levels to their normal range. It stimulates the liver to initiate glycogenolysis, the conversion of stored glycogen back into glucose, which is then released into the bloodstream for utilization by body cells. Additionally, glucagon prompts the liver to extract amino acids from the blood, subsequently converting them into glucose through gluconeogenesis. Furthermore, glucagon promotes lipolysis, the breakdown of stored triglycerides into free fatty acids and glycerol. Glycerol, once released into the bloodstream, makes its way to the liver, where it undergoes conversion into glucose, contributing to the process of gluconeogenesis. Collectively, these actions exert a significant influence on elevating blood glucose levels. Crucially, the activity of glucagon is subject to regulation through a negative feedback mechanism. As blood glucose levels rise, this mechanism inhibits the further production and secretion of glucagon, ensuring a balanced response to changing glucose concentrations.
Insulin
The discovery of insulin in 1921 by Canadian surgeon Frederick G. Banting and his assistant Charles Best marked a pivotal moment in medical history. Their groundbreaking research on insulin's role in regulating glucose revolutionized the treatment of diabetes and has since saved countless lives.
Insulin consists of two polypeptide chains, α, and β, connected by two disulfide bonds. The synthesis of insulin commences with preproinsulin, progressing to proinsulin. In storage granules, proteases remove a connecting peptide called the C peptide, leaving behind the mature insulin molecule (Figure 30). Notably, the C peptide is co-secreted alongside insulin, and monitoring its concentration is essential for assessing beta cell function in diabetic patients receiving exogenous insulin therapy.
Insulin plays a pivotal role in facilitating glucose uptake by body cells. Its primary actions target the liver, adipose tissue, and skeletal muscle. However, certain tissues, such as the brain, red blood cells, and specific cells in the liver, kidneys, and small intestine, operate independently of insulin. These tissues lack insulin receptors on their cell membranes and can uptake glucose without the need for insulin mediation.
Mechanism of Insulin Secretion
The insulin release process begins with glucose uptake through the GLUT-2 transporter within the beta cells of the pancreatic islets. Once inside the cell, glucose undergoes phosphorylation, leading to an increase in ATP levels. Elevated ATP concentrations subsequently trigger the closure of ATP-sensitive potassium ion channels. As a result, the outflow of potassium ions from the cell diminishes, reducing membrane potential. This depolarization event within the beta cell initiates the opening of voltage-sensitive calcium channels. The entry of calcium ions into the cell, in turn, facilitates the exocytotic release of insulin from its storage vesicles (Figure 31).
During periods of postabsorption or fasting, the concentration of blood glucose is rigorously maintained within the range of 70 to 110 mg/dL. If blood glucose levels exceed this range, the beta cells respond by releasing insulin, which facilitates the uptake of glucose from the bloodstream into various body cells. Conversely, glucagon is secreted if blood glucose concentrations dip below this range. Glucagon prompts the liver to release glucose into the blood (Figure 32).
Figure 32 | Overview of the Mechanisms involved in the Homeostatic Regulation of Blood Glucose Levels | 32. This figure illustrates the dynamic balance between insulin and glucagon, the primary hormones responsible for maintaining glucose homeostasis. When blood glucose levels rise after a meal, pancreatic beta cells secrete insulin. Insulin promotes the uptake of glucose by muscle and fat cells, stimulates glycogenesis in the liver, and inhibits gluconeogenesis. As blood glucose levels decrease, pancreatic alpha cells secrete glucagon. Glucagon stimulates glycogenolysis and gluconeogenesis in the liver, increasing glucose release into the bloodstream.
The insulin receptor is a glycoprotein composed of two alpha and two beta subunits interconnected by disulfide bonds. The alpha subunit is located externally and encompasses the insulin-binding region. Conversely, the beta subunit comprises an extracellular domain, a transmembrane domain, and an intracellular domain endowed with insulin-stimulated kinase activity toward its tyrosine residues. The pivotal initiation of insulin's influence on glucose metabolism hinges upon insulin receptor phosphorylation of the beta subunit, activating the insulin receptor tyrosine kinase (Figure 33).
Upon activation, insulin receptor tyrosine kinase phosphorylates specific intracellular proteins, culminating in the translocation of intracellular vesicles harboring glucose transporters (GLUT-4) to the cell membrane (Figure 32). Consequently, insulin orchestrates the rapid mobilization of a reservoir of glucose transporter vesicles to the cell membrane, where they merge and expose glucose transporters to the extracellular milieu. Subsequently, these transporters facilitate the diffusion of glucose into the cell. This insulin-driven uptake of glucose primarily occurs in muscle tissue. Once inside the cell, the liberated glucose undergoes metabolic processes regulated by insulin. During anabolic conditions, insulin spurs glycogen synthesis.
Figure 33 | Insulin-mediated glucose uptake | 33 Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
Insulin plays several vital roles, such as promoting the conversion of excess glucose into glycogen for storage in the liver, inhibiting enzymes involved in glycogenolysis and gluconeogenesis, and facilitating triglyceride and protein synthesis while impeding the breakdown of proteins and lipids. The secretion of insulin is subject to regulation via a negative feedback mechanism, whereby a decrease in blood glucose levels leads to the inhibition of further insulin release.
Without insulin, GLUT-4 typically undergoes sluggish recycling between the cell membrane and the cell interior. In addition to its role in glucose regulation, insulin exerts several other crucial effects. It contributes to the reduction of blood amino acid levels and stimulates the synthesis of proteins. Likewise, insulin facilitates the storage of triglycerides while concurrently inhibiting enzymes involved in processes like lipolysis, glycogenolysis, and gluconeogenesis.
Experiments involving mutagenesis have demonstrated that insulin receptors devoid of tyrosine kinase activity exhibit ineffectiveness in mediating insulin's capacity to stimulate cellular metabolism. Likewise, mutagenesis affecting any of the three major phosphorylation sites results in impaired insulin receptor kinase activity, reducing insulin's immediate metabolic and growth-promoting impacts.
In the resting state, about 50% of the body's glucose is used by the brain, which does not depend on insulin. Another 25% is taken up by the liver and gastrointestinal tissues (splanchnic), also independently of insulin. The remaining 25% of glucose metabolism happens in insulin-dependent tissues, mainly muscles. The amount of glucose used by the body matches what the body produces. About 85% of glucose production occurs in the liver, with the kidneys producing the rest (about 5-20%). Half of the liver's glucose comes from breaking down glycogen (glycogenolysis), and the other half from making new glucose (gluconeogenesis).
After eating, when blood sugar rises, insulin is released from beta cells. This increase in insulin stimulates glucose uptake by the liver, gut, and muscle tissues while reducing the body’s natural glucose production. Most of the glucose (about 80-85%) absorbed by peripheral tissues goes to muscles, with only a small portion (around 4-5%) going to fat cells. While fat cells play a small role in glucose use, they are important for glucose balance. Insulin suppresses fat breakdown (lipolysis), and even small increases in insulin significantly reduce the levels of free fatty acids in the blood. Lower free fatty acid levels help muscles take up more glucose, and these changes in response to insulin and glucose are essential for maintaining normal glucose levels in the body. 34
The Incretin Effect
Glucagon-like peptide-1 (GLP-1) is a hormone released from the intestinal mucosa, linked to the release of insulin in response to an oral glucose load rather than direct injection into the vein. This phenomenon is known as "the incretin effect." GLP-1 lowers plasma glucose levels by affecting insulin and glucagon secretion and slowing gastric emptying. One mechanism by which GLP-1 stimulates insulin release is by inhibiting the ATP-dependent opening of potassium channels. GLP-1 is currently utilized to enhance insulin release, proving to be effective for patients with diabetes. It also offers additional benefits such as appetite suppression and weight loss.35-36
Food in the small intestine triggers the release of gastrointestinal tract hormones, including glucose-dependent insulinotropic peptide (formerly known as gastric inhibitory peptide or GIP). This initial release of GIP catalyzes insulin production and subsequent secretion by the pancreatic beta cells. Following nutrient absorption, the resultant surge in blood glucose levels further stimulates the secretion of insulin. Insulin secretion is increased by other factors like amino acids, fatty acids, and the activation of the parasympathetic nervous system whereas glucagon secretion is increased by amino acids, exercise, incretins, and the activation of the sympathetic nervous system.
This page titled 7.16: The Endocrine Pancreas was last modified on Wed, 19 Mar 2025 23:12:38 GMT and is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Chaya Gopalan (Consortium of Academic and Research Libraries in Illinois (CARLI)) .
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