Insulin, chemical structure and metabolism
Insulin is a polypeptide hormone formed, after elimination of C peptide by hydrolysis, of two chains of 21 and 30 amino acids, connected by two disulfide bridges. It is secreted by the ß cells of the islets of Langerhans of the pancreas and exerts an hypoglycemic action. It belongs to the group of peptides called IGF (insulin like growth factors) or somatomedins.
Proinsulin, Insulin, chains A and B linked by two disulfide bonds, and C peptide
Insulin is produced in beta cells which constitute 75% of the islets of Langerhans of the pancreas. Alpha cells secrete glucagon, delta cells somatostatin.
Insulin is synthesized in the form of a single polypeptide chain, preproinsulin which is transformed into proinsulin which, itself, catalyzed by proteases called furines, gives insulin and C peptide (C for connecting, because connecting the two chains A and B). Bound to two zinc atoms, insulin is stored in granules as a polymer, probably a hexamer.
Insulin, as well as C peptide, are released by exocytosis into the portal venous system which leads it directly to the liver, which takes up nearly 50%. The remainder of insulin is distributed throughout the body.
With a basal secretion of approximately 40 microgram/h under fasting conditions, there are increases of secretion linked to meals. To these slow variations are superimposed peaks of pulsatile secretion. The aim of the treatments by exogenous insulin is to approach the physiological curve of secretion.
The principal stimulant of insulin secretion is glucose; it elicits a biphasic release: an immediate effect of short duration and a sustained effect. The cells of the islets are connected by tight junctions, which allow the transfer of ions, of metabolites, secondary messengers from one cell to another, and thus play an important part in synchronizing the secretions.
The stimulation of insulin secretion by glucose requires several steps:
- penetration of glucose into beta cells, by Glut2 carriers, independently of the presence of insulin.
- phosphorylation of glucose by glucokinase, then its metabolisation with synthesis of ATP whose intracellular concentration increases. This increase in ATP induces the closing of ATP-dependant potassium channels and the cessation of potassium exit, with as a consequence depolarization and opening of the voltage-dependant calcium channels. The entry of calcium elicits the activation of A2 and C phospholipases and the secretion of insulin.
The other stimulants of insulin secretion are amino acids (arginine, lysine), fatty acids and ketonic bodies.
Hormones, others that insulin, and transmitters modulate insulin secretion.
Some increase it:
- catecholamines by ß2-mimetic effect. The ß-blockers could theoretically worsen hyperglycemia by decreasing insulin secretion but, in fact, they inhibit especially the hyperglycemic effect of catecholamines and worsen hypoglycemia.
- acetylcholine and various hormones of intestinal origin: gastrin, secretin, cholecystokinin, glucagon.
Others decrease it:
- alpha-2 sympathomimetics, of which antihypertensive drugs with central effect which can thus worsen hyperglycemia.
- somatostatin which inhibits glucagon and insulin secretion and could take part in the regulation of their secretion. Somatostatin is present in delta cells of the pancreas. In large doses, somatostatin inhibits also the release of other hormones such as growth hormone and TSH. It also inhibits intestinal absorption and motility. Somatostatin secretion is stimulated by glucose, various amino acids and various intestinal hormones.
- leptin, by activating leptin receptors of the pancreas.
After intravenous injection, the half-life of insulin in the plasma is approximately six minutes in healthy subjects and in diabetics. Its volume of distribution is equal to the volume of the extracellular fluid, that is to say approximately 20% of the body weight. Insulin, present in plasma as a free monomer, diffuses into tissues and can cross the blood-brain barrier thanks to carriers.
Insulin is inactivated by enzymatic biotransformations: hydrolyze by metalloproteinases and reduction, i.e. cleavage of disulfide bonds. The renal insulin elimination is low because, after filtration, it is reabsorbed by the tubule.