The insulin receptor is a protein structures exposed on the extracellular side of the plasma membrane of many cells of the human body and other mammals. The natural ligand for this receptor is insulin.
Insulin is a hormone synthesized by the ß cells of the islets of Langerhans of the endocrine portion of the pancreas, an organ located in the abdominal cavity that synthesizes digestive enzymes and hormones.
The insulin synthesized and released by the pancreas binds to its receptor on the plasma membrane of the target cells and as a consequence of this ligand-receptor binding, a series of intracellular processes are triggered that finally promote the entry of glucose into said cells.
Insulin is responsible for the activation of many anabolic or synthetic reactions related to the metabolism of carbohydrates, fats and proteins.
Insulin receptors are glycoproteins formed by four subunits with their amino and carboxyl terminal portions in the cytoplasmic region. When these receptors bind to insulin they clump together and endocyte.
In obesity and type II diabetes, the number of insulin receptors is decreased and this partly explains the insulin resistance that accompanies these pathological conditions.
Insulin receptors are part of a family of membrane receptors that have binding sites for hormones of a protein nature. These types of hormones cannot cross cell membranes so their metabolic effects are carried out through their receptors.
Insulin is a peptide hormone related to promoting synthetic reactions collectively called anabolic reactions, which are related to the metabolism of carbohydrates, fats, and proteins.
Many cells have insulin receptors, mainly muscle cells, liver cells, and adipose tissue cells. However, other cells that are apparently not insulin target cells also possess insulin receptors.
The entry of glucose into cells, in some tissues, is dependent on insulin since, in them, the proteins responsible for the facilitated diffusion of glucose are found in small pieces of membrane forming intracellular vesicles.
When insulin binds to its receptor in this type of insulin-dependent cells, the glucose transporters located in the intracellular vesicles move and appear on the surface of the cell membrane when these vesicles fuse with this membrane.
The skeletal muscle and adipose tissue cells are, among others, an example of this mechanism.
Insulin receptors have a relatively short half-life of about 7 to 12 hours, so they are constantly being synthesized and degraded. In mammals, the receptor concentration is approximately 20,000 receptors per cell.
When insulin binds to the receptor, a receptor conformational change occurs, neighboring receptors move, micro-aggregates are produced, and then the receptor is internalized. At the same time, signals are generated that will then amplify the responses.
The gene that codes for the insulin receptor is located on chromosome 19 and has 22 exons. This receptor is made up of four disulfide-linked glycoprotein subunits.
It is synthesized in the endoplasmic reticulum initially as a single polypeptide chain of about 1,382 amino acids that is then phosphorylated and cleaved to form the α and β subunits.
The four subunits of the insulin receptor are two alphas (α) with a molecular weight of 140,000 Da and two smaller betas (β) with an approximate molecular weight of 95,000 Da.
The α subunits are extracellular and are exposed on the outer surface of the cell membrane. The β subunits, on the other hand, traverse the membrane and are exposed or protrude on the inner surface of the membrane (facing the cytoplasm).
The α subunits contain the binding site for insulin. In the β units, there is a binding site for ATP that activates the kinase function of this subunit and induces receptor autophosphorylation at the tyrosine residues of the β subunit.
These receptors are part of a family of receptors associated with cytoplasmic enzymes such as tyrosine kinase, an enzyme that is activated when insulin binds to the receptor and initiates a process of phosphorylation and dephosphorylation of a series of enzymes that will be responsible for the effects. metabolic rates of insulin.
The α subunit of insulin receptors has the binding site for insulin. When this unit binds to its ligand, conformational changes occur in the receptor structure that activate the β subunits that are responsible for the mechanisms of signal transduction and, therefore, for the effects of insulin.
A tyrosine kinase is activated in the cytoplasmic domains of the receptor, which initiates the transmission of signals through a cascade of kinases. The first thing that happens is the phosphorylation or autophosphorylation of the insulin receptor and then the so-called insulin receptor substrates or IRS are phosphorylated.
Four insulin receptor substrates designated IRS-1, IRS-2, IRS-3, and IRS-4 have been described. The phosphorylation of these occurs in tyrosine, serine and threonine residues. Each of these substrates is related to different kinase cascades involved in the metabolic effects of insulin.
- IRS-1s appear to be related to the effect of insulin on cell growth.
- IRS-2 are related to the metabolic effects of the hormone, such as the increase in the synthesis of glycogen, lipids and proteins, and with the translocation of proteins such as receptor and glucose transport proteins.
Diabetes is a disease that affects a very high percentage of the world’s population and is related to defects in the production of insulin, but also to a poor function of insulin receptors.
There are two types of diabetes: type I diabetes or juvenile diabetes, which is insulin-dependent, and type II diabetes or adult diabetes, which is not insulin-dependent.
Type I diabetes is due to insufficient insulin production and is associated with hyperglycemia and ketoacidosis. Type II diabetes is associated with genetic factors that affect both insulin production and receptor function and is associated with hyperglycemia without ketoacidosis.
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