Proinsulin

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Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.

Proinsulin is the prohormone precursor to insulin made in the beta cell of the islets of Langerhans. It is synthesized in the endoplasmic reticulum, where it is folded and its disulfide bonds are oxidized. It is then transported to the Golgi apparatus where it is packaged into secretory vesicles, and where it is processed by a series of proteases to form mature insulin. Mature insulin has 39 fewer amino acids; 4 are removed altogether, and the remaining 35 form the C-peptide. The C-peptide is abstracted from the center of the proinsulin sequence; the two other ends (the B chain and A chain) remain connected by disulfide bonds.

When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed. When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. In most cases however, the iatrogenic immune response comes from slight differences between species of insulin rather than from proinsulin itself. Since the late 1970's, when highly-purified pork insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue. It should also be noted that in respect of their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may, in fact, be of positive advantage to all diabetics without endogenous insulin secretion (e.g. people with type 1 diabetes) because insulin binding antibodies effectively increase the insulin's clearance rate and distribution space and therefore helps to prolong its pharmacological and biological half lives.^[1]