Chemical structure and synthesis of insulin
When insulin is secreted into the bloodstream, it circulates mostly in its free form. Because it has an average half-life of only about 6 minutes, most of it is eliminated from circulation.
Insulin is a small protein. Human insulin is a 5808 kDa molecule, consisting of two amino acid chains (see figure) linked together by disulfide bonds. When these two amino acid chains are separated, the insulin molecule loses its function.
Figure. Schematic diagram of the human proinsulin molecule, which is cleaved in the Golgi apparatus of pancreatic beta cells to form connecting peptides (C peptides) and insulin, consisting of A and B chains connected by disulfide bonds. Peptide C and insulin are packaged as granules and secreted in equal amounts, along with a small amount of proinsulin.
Insulin is synthesized in beta cells by the cell's normal protein synthesis system, which, as discussed in Chapter 3, begins with the translation of the insulin RNA by ribosomes attached to the granulomatous endoplasmic reticulum to form PR proinsulin. The PR proinsulin molecule is initially 11500 kDa but is then cleaved at the endoplasmic reticulum to form proinsulin, which has a mass of 9000 kDa and consists of three polypeptide chains A, B, and C. Most of the proinsulin is cleaved further at the Golgi apparatus for insulin formation, consisting of two chains A and B linked together by disulfide bridges, and peptide C chain, called connecting peptide (peptide C). Insulin and C peptide are packaged together in secretory granules and are excreted in equal amounts. About 5-10% of the final secreted product remains in the form of proinsulin.
Proinsulin and C peptide have almost no effect of insulin. However, the C peptide binds to a cell membrane structure, most likely a G protein-coupled membrane receptor (GPCR), and induces the activation of at least two enzyme systems, Na- K adenosine triphosphatase and endothelial NO synthase. Although both of these enzyme systems have many physiological functions, the importance of C peptides in the regulation of these enzymes remains unclear.
C-peptide levels can be measured by radioimmunoassay (Radioimmunoassay: RIA) in insulin-treated diabetic patients to detect how much natural insulin is still being synthesized. Patients with type 1 diabetes who cannot produce insulin will often have significantly reduced levels of C peptides.
When insulin is secreted into the bloodstream, it circulates mostly in an unbound form. Because it has an average half-life of only about 6 minutes, most of it is eliminated from circulation in 10-15 minutes.
With the exception of the part of insulin that binds to receptors at the target cell, insulin breakdown by the enzyme insulins occurs mainly in the liver, to a lesser extent in the kidneys and muscles, and to a very small extent in other tissues. The rapid clearance of insulin from the plasma is important because it rapidly "turns off" the control functions that have been "turned on" by insulin.