Introduction

The pancreas is a composite organ that has exocrine and endocrine functions. The endocrine portion is arranged as discrete islets of Langerhans, composed of 5 endocrine cell types (alpha, beta, delta, epsilon, and upsilon) that secrete at least 5 hormones, including glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide, respectively.

Function

The endocrine pancreas produces several hormones that work together to regulate glucose homeostasis, energy storage, and metabolism. Insulin, glucagon, amylin, somatostatin, ghrelin, and pancreatic polypeptide are secreted by specialized islet cells and exert coordinated effects on target tissues, including the liver, muscle, adipose tissue, and the central nervous system. Through tightly regulated endocrine and paracrine signaling, these hormones maintain metabolic balance by controlling blood glucose levels, nutrient utilization, appetite, and digestive processes.

Insulin

• Source: Beta cells of the islets of the pancreas.
• Synthesis: Insulin is a peptide hormone. The insulin mRNA is translated as a single-chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases, which excise the C peptide (one of three domains of proinsulin), thereby generating the mature form of insulin. Insulin is secreted from the cell by exocytosis and diffuses into the islet capillary blood. C-peptide is also secreted into the blood in a 1:1 molar ratio with insulin. Although C-peptide has no established biological activity, it is used as a marker of insulin secretion.
• Transport: Insulin circulates entirely in unbound form (T1/2 = 6 min).
• Main Target cells: Hepatic, muscle, and adipocyte cells (ie, cells specialized for energy storage).
• Mechanism of action: Insulin binds to a specific receptor tyrosine kinase on the plasma membrane and increases its activity to phosphorylate numerous regulatory enzymes and other protein substrates (see Image. Insulin Receptor and Paracrine Interaction in Pancreatic Islet Cells).
• Regulation of its secretion: Plasma glucose levels are the primary regulator of insulin secretion. The change in plasma glucose concentration that occurs in response to feeding or fasting is the main determinant of insulin secretion. Modest increases in plasma glucose level provoke a marked increase in plasma insulin concentration. Glucose is taken up by beta cells via glucose transporters. The subsequent metabolism of glucose increases cellular adenosine triphosphate (ATP) concentrations and closes ATP-dependent potassium channels in the beta cell membrane, causing membrane depolarization and an influx of calcium. Increased intracellular calcium concentration increases insulin secretion. Increased plasma amino acid and free fatty acid concentrations induce insulin secretion as well. Glucagon is also known to be a strong insulin secretagogue.
• Physiological functions: Insulin plays an important role in keeping plasma glucose value within a relatively narrow range throughout the day (glucose homeostasis). Insulin’s main actions are (1) in the liver, insulin promotes glycolysis and storage of glucose as glycogen (glycogenesis), as well as conversion of glucose to triglycerides, (2) in muscle, insulin promotes the uptake of glucose and its storage as glycogen, and (3) in adipose tissue, insulin promotes the uptake of glucose and its conversion to triglycerides for storage.

Amylin (diabetes-associated peptide)

• Source: Beta cells of the islets of the pancreas; this is co-secreted with insulin in response to caloric intake (feeding state). 
• Target cells: Alpha cells of the islets of the pancreas and the hypothalamus.
• Physiological functions: This suppresses glucagon secretion from pancreatic islet alpha cells via paracrine signaling between beta and alpha cells. Amylin also slows gastric emptying, which delays absorption of glucose from the small intestine into the circulation. Also, it stimulates the brain's satiety center to limit food intake.

Glucagon

• Source: Alpha cells of the islets of the pancreas
• Synthesis: The initial gene product is the mRNA encoding preproglucagon. A peptidase removes the signal sequence of preproglucagon during translation of the mRNA in the rough endoplasmic reticulum to yield proglucagon. Proteases in the alpha cells subsequently cleave proglucagon to produce the mature glucagon molecule.
• Target cells: Hepatic cells
• Mechanism of action: glucagon binds to a receptor that activates the heterotrimeric G protein Gas, which stimulates membrane-bound adenylyl cyclase. The cyclic adenosine monophosphate (cAMP) formed by adenylyl cyclase, in turn, activates protein kinase A, which phosphorylates numerous regulatory enzymes and other protein substrates.
• Regulation of its secretion: The amino acids released by the digestion of a protein meal appear to be the main determinant of glucagon secretion. 
• Physiological functions: Glucagon acts exclusively on the liver to antagonize insulin effects on hepatocytes. It enhances glycogenolysis and gluconeogenesis; it also promotes fat oxidation, which can lead to the formation of ketone bodies.

Somatostatin

• Source: Delta cells of the islets of the pancreas, hypothalamus, and D cells of gastric glands.
• Target cells: Beta cells of islets of the pancreas, somatotroph cells in the anterior pituitary gland, and the G cells of the gastric glands.
• Mechanism of action: Somatostatin binds to a receptor that activates the heterotrimeric inhibitory G protein, which inhibits membrane-bound adenylyl cyclase and cAMP formation.
• Regulation of its secretion: Glucagon stimulates somatostatin secretion via paracrine interaction between alpha cells and delta cells of the islets of the pancreas.
• Physiological functions: Somatostatin inhibits the secretion of multiple hormones, including growth hormone, insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP), and thyroid-stimulating hormone.

Ghrelin

• Source: Epsilon cells of the islets of the pancreas, endocrine cells in the stomach, and the hypothalamus.
• Target cells: Beta cells of the islets of the pancreas and somatotroph cells in the anterior pituitary gland.
• Physiological functions: Ghrelin inhibits insulin secretion from pancreatic beta cells via paracrine interactions between delta and beta cells in the pancreatic islets; it also stimulates appetite and growth hormone secretion.

Pancreatic Polypeptide 

Pancreatic polypeptide is secreted from upsilon (F) cells of the islets of the pancreas. Dietary nutrient intake alters pancreatic polypeptide secretion; its function is not yet well understood. 

Paracrine interaction between pancreatic endocrine cells

Insulin secreted by beta cells is a key hormone in glucose homeostasis. Insulin and amylin inhibit glucagon secretion by alpha cells. Whereas glucagon activates insulin and somatostatin secretion, somatostatin secreted by delta cells and ghrelin by epsilon cells inhibit insulin secretion.[1][2][3]

Clinical Significance

Diabetes mellitus is a chronic disease that occurs when the pancreas cannot produce enough insulin or the body cannot effectively use insulin, resulting in high plasma glucose levels (hyperglycemia) and tissue damage over time. There are 2 common types of diabetes mellitus that account for most cases: type 1 and type 2.[4][5][6]

Type 1 Diabetes 

This is a chronic autoimmune disease in which the beta cells of the pancreatic islets are destroyed, resulting in insulin deficiency.

• Pathophysiology: This is not yet fully understood, but it is caused by a combination of events in genetically susceptible individuals. Three mechanisms lead to islet cell destruction: genetic susceptibility, autoimmunity, and environmental insult(s). A virus or allergen (environmental insults) in genetically susceptible individuals induces the production of autoantibodies against beta cells in the pancreatic islets. This autoimmune reaction generates autoreactive T cells that destroy beta-islet cells and lead to loss of insulin secretion.
• Diagnosis: The serum autoantibodies serve as a marker. The autoantibodies are typically present years before the diagnosis of type 1 diabetes is made because clinical manifestations appear after 80% of beta-islet cells have been destroyed.[7]

Type 2 Diabetes

This is a progressive disease that develops from a continued decline in beta-cell function and/or a defect in insulin sensitivity, leading to hyperglycemia. The development and rate of progression of type 2 diabetes are influenced by both genetic and environmental factors, such as obesity and physical inactivity.

Pathophysiology: Beta-cell dysfunction manifests in different ways: (1) reductions in insulin release, (2) changes in pulsatile insulin secretion, (3) an abnormality in the efficiency of proinsulin to insulin conversion, and (4) reduced release of amylin. Insulin resistance is present in most patients with type 2 diabetes. Insulin resistance is characterized by a higher-than-expected plasma glucose level with a corresponding increase in plasma insulin secretion. In patients with type 2 diabetes, insulin stimulation fails to induce normal GLUT4 protein translocation to the sarcolemma in skeletal muscle membranes. Also, excessive production of free fatty acids and overexpression of TNF-alpha by adipocytes have been proposed as mechanisms for the development of insulin resistance.[8]

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Disclosure: Suzan Kamel-ElSayed declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Mukherjee declares no relevant financial relationships with ineligible companies.