Insulin Synthesis

Insulin is synthesized in significant quantities only in beta cells in the pancreas. Since it is a protein or a polypeptide structure it is synthesized like most other proteins via transcription and translation of DNA into mRNA and amino acid chains or polypeptide chains. Thereafter the protein undergoes structural changes to achieve its final form.

Steps in insulin synthesis

The insulin mRNA is translated as a single chain precursor called preproinsulin. Thereafter the removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin.

Proinsulin consists of three domains:

• an amino-terminal B chain
• a carboxy-terminal A chain
• a connecting peptide in the middle known as the C peptide

In the endoplasmic reticulum the proinsulin is exposed to several specific endopeptidases which excise the C peptide. This forms the mature form of insulin. Insulin and free C peptide are packed in the Golgi bodies into secretory granules which accumulate in the cytoplasm.

Secretion of insulin

When the beta cell is appropriately stimulated, insulin is secreted from the cell by exocytosis. The insulin then diffuses into small blood vessels of the pancreas. C peptide is also secreted into blood, but has no known biological activity.

Regulation of insulin synthesis

Insulin synthesis is regulated by several mechanisms. These include:

• Regulation at the transcription from the insulin gene to mRNA formation
• Stability of the formed mRNA
• Regulation at the translation of the mRNA to polypeptide chains
• Regulation at the posttranslational modifications and quaternary structure formation

Regulation of insulin secretion

Insulin is secreted in primarily in response to elevated blood concentrations of glucose. Thus insulin is secreted as the body detects high blood glucose and helps regulate the levels of glucose. There are some other stimuli like sight and taste of food, increased blood levels of amino acids and fatty acids that may also promote the release of insulin.

The steps in regulation of insulin release include:

• Glucose from blood transported into the beta cell by facilitated diffusion through a glucose transporter GLUT2
• This leads to elevated concentrations of glucose within the beta cell. The glucose undergoes glycolysis and releases multiple high-energy ATP molecules
• The high levels of ATP lead to closing of the potassium channels (K+). This leads to membrane depolarization that causes a burst of incoming calcium within the beta cell. The calcium comes in via the voltage controlled calcium channels (Ca2+)
• Increased calcium within the cell leads to exocytosis of insulin-containing secretory granules. This is by activation of enzymes phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4 into inositol 1 and diacylglycerol.
• There are other pathways that regulate insulin release as well. Some of these include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings (parasympathetic nervous system), released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP).
• Three amino acids (alanine, glycine and arginine) act similar to glucose and cause release of insulin by changing the membrane potential of beta cells. Acetylcholine triggers insulin release through phospholipase C and GIP acts via adenyl cyclase.

Fluctuations in insulin release

During digestion (around one or two hours following a meal), insulin release is not continuous, but occurs in bursts. The oscillations occur within a period of 3–6 minutes and result in changes of blood insulin levels from more than ~800 pmol/l to less than 100 pmol/l.

Degradation and termination of action

After the insulin acts on its receptor site it may be released back into the extracellular environment, or it may be degraded by the cell. Degradation involves intake or engulfing (endocytosis) of the insulin-receptor complex followed by the action of insulin degrading enzyme.

The degradation mainly takes place in the liver. An insulin molecule produced by the beta cells of the pancreas is degraded within approximately one hour after its initial release into circulation.