Insulin is produced from proinsulin in the pancreas and released upon physiological stimulation by protein and glucose in the blood (Rhodes and Halban, J. Cell Bio).  In target cells, insulin binds to the insulin receptor (Menting et al. Nature) and initiates a signal transduction cascade (Avruch, Insulin Action), which has the effect of increasing the number of GLUT4 glucose transporters (Huang and Czech, Cell Metabolism) on the cell surface resulting in increased glucose uptake and storage. Finally, insulin is endocytosed by the cell and degraded by the insulin degrading enzyme (Shen et al. Nature) which terminates the response.

Insulin consists of two polypeptide chains, the A and B chains, linked together by 3 disulfide bonds (Blundell et al. Diabetes) Insulin is first synthesized as a single polypeptide called preproinsulin (Bell et al. Nature) which contains a 24-residue signal peptide.  The signal peptide is cleaved when to form proinsulin which folds into the native conformation whereupon the 3 disulfide bonds are formed.

Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases and the exoprotease carboxypeptidase E (Steiner and Oyer, PNAS). The endopeptidases cleave at 2 positions, releasing a fragment called the C-peptide (Steiner et al, Science), and leaving 2 peptide chains, the B and – chains, linked by 2 disulfide bonds and one intramolecular disulfide bond within the A chain. The C-peptide is the central portion of proinsulin, and the primary sequence of proinsulin goes in the order “B-C-A”. Proinsulin is a major autoantigen giving rise to Type 1 diabetes (Narendran et al. Autoimmunity Reviews) and is commonly used in assays to detect prediabetic islet autoimmunity (Yu et al. Diabtes Care).

Proinsulin (Human)