Proinsulin is a protein molecule that serves as a precursor hormone, or prohormone, to insulin. Insulin is produced by the beta cells, which are pancreatic cells located in the islets of Langerhans, specifically through the cleavage of proinsulin by enzymes called protease. This cleavage process is important because measurement of the cleavage products can help doctors predict the actual amount of insulin production by the pancreas.
The insulin (INS) gene, located in chromosome 11, is first translated into a primary protein called preproinsulin, which is made up of 110 amino acids. After synthesis in the ribosomes, preproinsulin is transported to the endoplasmic reticulum. At one end of preproinsulin, there is a short chain of amino acids called signal peptide, which binds to a signal recognition particle (SRP). Binding of the signal peptide to the SRP allows intracellular transport of preproinsulin from the cytoplasm to the endoplasmic reticulum. When preproinsulin reaches the endoplasmic reticulum, an enzyme called signal peptide peptidase cleaves off the signal peptide, thereby turning preproinsulin to proinsulin.
Proinsulin is composed of 86 amino acids. It has three domains, or distinct peptide chains: alpha chain, beta chain, and C-peptide. Within the endoplasmic reticulum, enzymes called endopeptidases act on the whole prohormone to generate biologically active insulin. In particular, the endopeptidase called proprotein convertase 1 plays a significant role in the removal of the C-peptide in order to generate mature insulin. Another endopeptidase, called proprotein convertase 2, plays a minor role in the cleavage process, but has a greater role in the enzymatic production of glucagon, another hormone that regulates blood sugar.
Through the action of the proprotein convertase, mature insulin, which contains the alpha and beta chains, is generated. Mature insulin is made up of 51 amino acids. C-peptide, on the other hand, is composed of 31 amino acids. The remaining four amino acids are removed altogether and have no clinical significance.
The measurement of proinsulin in blood serum can be used to assess the status of the pancreatic beta cells. When its blood levels deviate from normal, dysfunction of either proinsulin secretion and/or processing is suspected. A deficiency or excess of this prohormone could give a clue as to why a person has diabetes, and how that person should be treated. For instance, people who have non-insulin-dependent diabetes mellitus (NIDDM) could have elevated proinsulin levels. The measurement of the proinsulin cleavage product called C-peptide is also useful in determining whether a person has type 1 or type 2 diabetes.