pro-Insulin

pro-Insulin is synthesized as a single chain, 110 amino acid (aa) preproprecursor that contains a 24 aa signal sequence and an 86 aa proinsulin propeptide. Following removal of the signal peptide, the pro-insulin peptide undergoes further proteolysis to generate mature insulin, a 51 aa disulfide linked dimer that consists of a 30 aa B chain (aa 25 54) bound to a 21 aa A chain (aa 90 110). The 34 aa intervening peptide (aa 55 89) that connects the B and A chains is termed the C-peptide. Human proIinsulin shares 84% and 80% aa sequence identity with the rat and bovine protein, respectively. Most of the sequence variation between species occurs in the region of the C-peptide (1).

This peptide generates a structural conformation that allows for the correct formation of the intrachain disulphide bonds (1). Insulin is a molecule that facilitates the cellular uptake of glucose. This is accomplished by regulating the appearance of membrane glucose transporters. Low insulin levels or lack of insulin are associated with type 2 and type 1 diabetes mellitus, respectively. These conditions are associated with an increased risk for microvascular complications such as retinopathy, nephropathy, and peripheral neuropathy (3). pro-Insulin also circulates, but its physiologic role is less well understood. It does possess about 25% of the activity of mature insulin, but it would seem unlikely to be a natural substitute for insulin (4). In type 2 diabetes, an elevated pro-insulin to insulin ratio in the circulation is a wellknown abnormality (5 9). Perhaps this abnormality represents either compromised proteolytic processing or a general inability to process increased levels of insulin precursor (5). In any event, pro-insulin will stimulate amylin secretion by β-cells, and amyloid formation in pancreatic islets that promotes decreased β cell function (10). Studies also suggest that fasting serum proinsulin may be a better predictor of future type 2 diabetes than fasting insulin levels in obese children (11).