Glucagon

Glucagon is a hormone that’s involved in raising the blood glucose levels or glycemia while fasting. Glucagon is produced by some small islands of cells in the pancreas called the Langerhans islets.

The pancreas lies in the upper left part of the abdomen, right behind the stomach. The vast majority of the pancreas is made up by exocrine glands in charge of secreting digestive enzymes into the small intestine to help digestion.

But about 1 to 2% of the mass of the pancreas is made up by the islets of Langerhans, which are endocrine glands made up by five different cell types, and each cell type secretes a specific hormone.

The most abundant are the beta cells, which produce insulin. But you can also find alpha cells that secrete glucagon, delta cells that secrete somatostatin, gamma cells that secrete pancreatic polypeptide, and finally epsilon cells that secrete ghrelin.

Let’s focus on alpha cells. Alpha cells are in charge of producing glucagon, which is a peptide hormone encoded by the GCG gene on chromosome 2.

Glucagon is first synthesized as a single polypeptide called preproglucagon. Preproglucagon has a short tail called a leader or signal peptide which is cleaved off to form proglucagon, and proglucagon is then further cleaved to form glucagon.

This mature glucagon is stored inside granules within the alpha cells where it waits until it’s released into the blood.

The most important glucagon regulator is glucose. Alpha cells are sensitive to glucose concentrations in blood, and when blood glucose levels are low - for instance during fasting or after intense physical activity - alpha cells secrete glucagon into the blood to help increase those levels.

Glucagon secretion is also stimulated by adrenaline from the sympathetic nervous system, which is activated during stressful situations with high energy consumption.

Glucagon secretion is also stimulated by cholecystokinin which is secreted by intestinal cells to stimulate digestion and absorption.

But when blood glucose is high, alpha cells stop secreting glucagon, and beta cells start secreting insulin, which both lowers glucose levels and inhibits glucagon secretion in the process.

Another molecule that inhibits glucagon production is somatostatin, which is classified as an inhibitory hormone that avoids the excessive release of pancreatic hormones and other hormones like growth hormone.

Now, when glucagon is released, it binds to the glucagon receptor located in the membrane of its target cells - mainly in the liver, but also in fat or adipose tissue.

The glucagon receptor is a seven pass transmembrane receptor, meaning they are really long proteins that have one end that sits outside the cell and binds glucagon, then the snake-like protein dips in and out of the cell membrane seven times, and finally ends on the inside of the cell.

The end of the protein within the cell activates intracellular proteins. Glucagon is a catabolic hormone, which means that when it binds to the glucagon receptor, it promotes the breakdown of large storage molecules like glycogen inside the cells of the liver and separately, fat in adipose tissue, into small energy molecules in the blood - like glucose and fatty acids.

The major target of glucagon is the liver, where it promotes the breakdown of glycogen stores into glucose through glycogenolysis.

Additionally in the liver, glucagon promotes glucose production from lactic acid and from noncarbohydrate molecules through gluconeo - genesis.

All of this glucose is released to the blood by liver cells, ultimately causing blood glucose levels to rise. Glucagon also promotes breakdown of fat through lipolysis in the liver and adipose tissue, which causes them to release fatty acids into the bloodstream as an additional source of energy.

Now, glucose levels are tightly regulated through the interplay of glucagon and insulin. Insulin has the opposite function, which is to decrease glucose levels in blood.

Secretion of glucagon by alpha cells is sustained over time during fasting, but after a meal, when glycemia rises, beta cells in the pancreas secrete insulin, which inhibits glucagon secretion.

When glycemia drops, insulin production drops and glucagon is once again secreted. Alright, as a quick recap, glucagon is a hormone produced by the alpha cells of the Langerhans islets in the pancreas.

During fasting, glucagon is secreted into the bloodstream to increase blood glucose levels by triggering the breakdown of glycogen or fats stored in the liver and adipose tissue.