Proinsulin is the prohormone precursor to insulin made in the beta cells of the Pancreatic Islets, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. The pancreatic islets only secrete between 1% and 3% of proinsulin intact. However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967.
Structure
Proinsulin is made up of 86 residues in humans (81 in cows), and formed by three distinct chains. The A chain, B chain, and the area connecting the two named the C peptide. There are three disulfide bonds that are necessary for mature insulin to be the correct structure. Two of these disulfide bonds are between the A and B chains, and one is an intra-A chain bond.
The C peptide is between the A and B chains of proinsulin. The C peptide-A chain junction occurs between residues 64 and 65 of proinsulin. These are lysine and arginine molecules, respectively. That said, the residues of the C peptide that are conserved across species interact with similarly conserved residues on the A and B chains. When proinsulin is transported through the Golgi apparatus the C-peptide is cleaved. Type I endoproteases, PC1 and PC3, disrupt the C peptide-B chain connection. 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. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species.<!-- The differences are in the amino acid composition of the respective insulins. While some skin injuries were due to the non-highly purified insulins causing immunogenic reactions, these issues are still present due to various poor injection techniques, and can occur with any that is poorly used. http://www.endocrine-abstracts.org/ea/0012/ea0012p40.htm These same amino acid differences in insulin species can cause longer duration which can be a "positive" aspect in some cases. Bovine Ultralente is peakless and lasts longer than Lantus because of this But I question whether this belongs on a page about proinsulin.--> Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue. With respect to their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may 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 help to prolong its pharmacological and biological half lives.
Medical Relevance
Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin or proinsulin:insulin ratio in relation to these diseases has become increasingly clear.
Diabetes Mellitus
Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes. Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding. Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus.