Insulin

Insulin (from Latin insula, "island", as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary effector in carbohydrate homeostasis, it has effects on fat metabolism. It can change the liver's ability to release fat stores. Insulin's concentration (more or less, presence or absence) has extremely widespread effects throughout the body.

Insulin is used medically in some forms of diabetes mellitus. Patients with type 1 diabetes mellitus depend on exogenous insulin (injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with type 2 diabetes mellitus have either relatively low insulin production or insulin resistance or both, and a non-trivial fraction of type 2 diabetics eventually require insulin administration when other medications become inadequate in controlling blood glucose levels.

Insulin has a molecular weight of 5.8 kDa.

Insulin structure varies slightly between species of animal. Its carbohydrate metabolism regulatory function strength in humans also varies. Porcine (pig) insulin is particularly close to humans'.

Structure and production


Insulin undergoes extensive posttranslational modification along the secretory pathway. Cell components and proteins in this image are not to scale.

Insulin is synthesized in humans and other mammals within the beta cells (β-cells) of the islets of Langerhans in the pancreas. One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine part accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60-80% of all the cells.

In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications liberate the center portion of the molecule, or C-peptide, from the C- and N- terminal ends of the proinsulin. The two remaining polypeptides, the B- and A- chains, are held together by disulfide bonds and together constitute 51 amino acids. Confusingly, the primary sequence of insulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.

Amongst vertebrates, insulin is highly conserved. Bovine insulin differs from human insulin in three amino acid residues, and porcine insulin in one residue. Even insulin from some species of fish is also close enough to human insulin to be effective in humans.

Actions on cellular and metabolic level

The actions of insulin on the global human metabolism level include:

- Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about 2/3 of body cells).
- Increase of DNA replication and protein synthesis via control of amino acid uptake.
- Modification of the activity of numerous enzymes (allosteric effect).

The actions of insulin on cells include:

- Increased glycogen synthesis - insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is useful in reducing high blood glucose levels as in diabetes.
- Increased fatty acid synthesis - insulin forces fat cells to take in glucose which is converted to triglycerides; lack of insulin causes the reverse.
- Increased esterification of fatty acids - forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse.
- Decreased proteinolysis - forces reduction of protein degradation; lack of insulin increases protein degradation.
- Decreased lipolysis - forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
- Decreased gluconeogenesis - decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
- Increased amino acid uptake - forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
- Increased potassium uptake - forces cells to absorb serum potassium; lack of insulin inhibits absorption.
- Arterial muscle tone - forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.

Signal transduction

There are special transport channels in cell membranes through which glucose from the blood can enter a cell. These channels are, indirectly, under insulin control in certain body cell types. A lack of circulating insulin will prevent glucose from entering those cells (eg, in untreated Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e.g. the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is the same: elevated blood glucose levels.

Activation of insulin receptors leads to internal cellular mechanisms which directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane which transport glucose into the cell.

Two types of tissues are most strongly influenced by insulin as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess food energy against future needs. Together, they account for about 2/3 of all cells in a typical human body.

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