Pancreatic hormones

Insulin, glucagon, and somatostatin are products of the endocrine pancreas.

Insulin

Insulin is a dipeptide made of A and B chains linked by disulphide bridges. It contains 51 amino acids.

Synthesis: Insulin is coded on the short arm of chromosome 11 and is synthesised in the β cells of the pancreatic islets of Langerhans as its precursor, proinsulin. Proinsulin is synthesised on ribosomes of the rough endoplasmic reticulum (RER) from mRNA as pre-proinsulin. Removal of the signal peptide forms proinsulin, which then acquires its characteristic three-dimensional structure in the endoplasmic reticulum. Secretory vesicles transfer proinsulin from the RER to the Golgi body, where proinsulin is cleaved to release C-peptide and form mature insulin. Insulin and C-peptide are released into the bloodstream by exocytosis.

Regulation of insulin release: Glucose entry into the β cell is sensed by glucokinase, which phosphorylates glucose to glucose-6-phosphate and generates ATP. ATP closes K±ATP-dependent channels, causing membrane depolarization. Depolarization opens voltage-dependent calcium channels, increasing intracellular calcium concentration; this triggers pulsatile insulin secretion.

In response to a stimulus such as glucose, insulin secretion is characteristically biphasic:

• an initial rapid phase of insulin secretion
• a less intense but more sustained second phase

Some mediators of insulin release, such as acetylcholine (ACh), activate phospholipases and protein kinase C. Vagus nerve stimulation results in pancreatic insulin secretion. This is thought to mediate the “cephalic phase” of insulin secretion, which occurs when food is seen, smelled, or acutely ingested. Islet cell cholinergic muscarinic receptors activate phospholipase C; subsequent intracellular events activate protein kinase C, phospholipase A2, and mobilize intracellular calcium.

Catecholamines, through α2-adrenoceptors, typically inhibit insulin release during stress and exercise. The pancreas also has β-adrenoceptors, which enhance insulin secretion via cAMP.

Hormones such as vasoactive intestinal peptide (VIP), GLP-1, and GIP stimulate adenylyl cyclase activity and activate β cell protein kinase A, which potentiates insulin secretion. These factors appear to play a significant role in the second phase of glucose-mediated insulin secretion.

Longer-term regulation of insulin secretion may be mediated via effects on β cell mass. Growth hormone, prolactin, placental lactogen, and GLP-1 not only increase glucose-stimulated insulin release and insulin gene expression, but also increase β cell proliferation.

Insulin receptor: The insulin receptor is located on the cell membrane and is composed of 2 α and 2 β glycoprotein subunits linked by disulphide bonds. It has tyrosine kinase activity. The gene coding for the insulin receptor is located on the short arm of chromosome 19.

Insulin binds to the extracellular α subunit, causing a conformational change that enables ATP to bind to the intracellular component of the β subunit. ATP binding triggers phosphorylation of the β subunit, conferring tyrosine kinase activity. This enables tyrosine phosphorylation of insulin responsive substrates (IRS). IRS can then bind other signalling molecules that mediate further cellular actions of insulin.

• PI 3-kinase mediates insulin’s metabolic effects (e.g. cellular glucose uptake).
• RAS significantly mediates insulin’s mitogenic effects.
• PI 3-kinase appears to be essential for translocation of GLUT 4 to the cell membrane in muscle cells and adipocytes.

There are about 14 types of GLUTs (glucose transporters). GLUTs are proteins comprising 12 membrane-spanning regions with intracellularly located amino and carboxyl terminals. They transport glucose across the plasma membrane by facilitated diffusion.

Important GLUT types

Insulin actions: Insulin is an anabolic hormone with vital roles in metabolism.

Under the action of insulin:

• Glycogen synthesis increases and glycogen breakdown decreases, by dephosphorylation of glycogen synthase and glycogen phosphorylase kinase respectively.
• Glycolysis is stimulated and gluconeogenesis is inhibited by dephosphorylation of pyruvate kinase and 2,6 biphosphate kinase.
• Insulin enhances the irreversible conversion of pyruvate to Acetyl Co-A by activation of the intra-mitochondrial enzyme complex pyruvate dehydrogenase.

Acetyl-CoA may then be directly oxidised via the Krebs’ cycle, or used for fatty acid synthesis.

Insulin stimulates fatty acid synthesis in adipose tissue, liver, and lactating mammary glands, along with formation and storage of triglycerides in adipose tissue and liver.

• Fatty acid synthesis increases by activation and increased phosphorylation of acetyl-CoA carboxylase.
• Fat oxidation is suppressed by inhibition of carnitine acyltransferase.
• Triglyceride synthesis is stimulated by esterification of glycerol phosphate.
• Triglyceride breakdown is suppressed by dephosphorylation of hormone sensitive lipase.
• Cholesterol synthesis increases by activation and dephosphorylation of HMG Co-A reductase.
• Cholesterol ester breakdown appears to be inhibited by dephosphorylation of cholesterol esterase.

Insulin promotes protein synthesis, dependent on the availability of substrate amino acids. It affects transcription of specific mRNA, as well as translation of mRNA into proteins in ribosomes. Examples of enhanced mRNA transcription include the mRNA for glucokinase, fatty acid synthase, and albumin in the liver; pyruvate carboxylase in adipose tissue; casein in the mammary gland; and amylase in the pancreas.

Insulin promotes uptake of K+ into cells by increasing the activity of Na+K+ATPase.

Glucagon

Glucagon is a peptide hormone secreted from the alpha cells of the pancreatic islets of Langerhans.

Regulation: Glucagon release is regulated through endocrine and paracrine pathways, by nutritional substances, and by the autonomic nervous system. Glucagon secretion occurs by exocytosis of stored peptide vesicles initiated by secretory stimuli of the alpha cell.

Stimulatory regulators of glucagon release include hypoglycemia, fasting, exercise, amino acids, CCK, and the gut hormone glucose-dependent insulinotropic peptide (GIP). Hyperglycemia and GLP-1 inhibit glucagon release. In addition, glucagon release is inhibited in a paracrine fashion by factors such as somatostatin, insulin, zinc, and possibly amylin. Glucagon may regulate its own secretion indirectly via a stimulatory effect on beta cells to secrete insulin.

The most potent regulator of glucagon secretion is circulating glucose:

• Hypoglycemia stimulates the pancreatic alpha cell to release glucagon.
• Hyperglycemia inhibits glucagon secretion.

Mechanism in hypoglycemia: low intracellular ATP levels in the alpha cell close ATP-sensitive potassium channels, reducing potassium (K+) efflux. This depolarizes the cell membrane, which opens voltage-dependent Ca++ channels and allows Ca++ influx. The resulting rise in intracellular Ca++ is the primary trigger for exocytosis of glucagon granules from alpha cells.

Mechanism in hyperglycemia: increasing circulating glucose increases glucose influx to the alpha cell, generating an increase in intracellular ATP concentration. This opens K+ATP channels and leads to a membrane potential that closes voltage-dependent Ca2+ channels, preventing Ca2+ influx and glucagon secretion.

Glucagon receptor: The glucagon receptor is a seven transmembrane G protein-coupled receptor predominantly expressed in the liver. It is also found in varying amounts in the kidneys, adrenal glands, gastrointestinal tract, and pancreas, and has been suggested to be present in the heart and adipose tissue as well.

The main mode of intracellular signaling involves activation of Gs and Gq:

• Gs activation stimulates adenylyl cyclase, which produces cyclic adenosine monophosphate (cAMP) that activates protein kinase A (PKA). Activated PKA migrates to the nucleus and activates transcription factors such as cAMP response element-binding protein (CREB) through phosphorylation. This enables CREB to bind to response elements of target genes, recruiting coactivators and ultimately promoting gene expression.
• Activation of Gq by glucagon leads to activation of phospholipase C (PLC) and a subsequent increase in inositol 1,4,5-triphosphate (IP3), which signals enhanced release of calcium from the endoplasmic reticulum. This, in turn, activates downstream signaling cascades including CREB-regulated transcription co-activator (CRTC2).

Glucagon actions: Glucagon promotes hepatic conversion of glycogen to glucose (glycogenolysis), stimulates de novo glucose synthesis (gluconeogenesis), and inhibits glucose breakdown (glycolysis) and glycogen formation (glycogenesis). It is antagonistic to insulin regarding its effects on metabolism.

Hepatic glucose production is rapidly enhanced in response to a physiological rise in glucagon. This is achieved through stimulation of glycogenolysis, with minor acute changes in gluconeogenesis. This ability of glucagon is critical in the life-saving counterregulatory response to severe hypoglycemia. Additionally, it is a key factor in providing adequate circulating glucose for brain function and for working muscles during exercise.

Glucagon enhances breakdown of fatty acids to acetyl-coenzyme A molecules by beta-oxidation in the liver. These intermediates are either reduced to generate ATP in the tricarboxylic acid cycle or converted to ketone bodies (ketogenesis). Glucagon signaling inhibits de novo lipogenesis by inactivating the enzyme that catalyzes the first step in fatty acid synthesis from other substrates like carbohydrates.

Glucagon may lead to an increase in resting energy expenditure. Infusion of high doses of glucagon increases heart rate and cardiac contractility. In fact, infusion of glucagon is often used in the treatment of acute cardiac depression caused by calcium channel antagonist or beta-blocker overdoses.