Insulin Signalling: Essential Role of a 222 Da Molecular Mediator, Co-Insulin (Co-Ins)

An attempt has been made to probe into the molecular basis of insulin resistance. The target was to look into the existence of a molecule that could interfere with insulin receptor-mediated molecular signaling. Human plasma was chromatographed on an affinity column of insulin receptor (IR) Sepharose, and the IR bound fraction was collected and subjected to analysis. In the process, what was revealed was a small molecule that bound to insulin and not to insulin receptor. This 222 Da molecule has been designated as Co-Insulin (Co-Ins). Its structural identity is 3-(2-amino-5-(aminomethyl)-2-hydroxy-1,3-dioxolan-4-yl)-2,3-dihydroxypropanal. Molecular modeling studies show that Co-Ins binds to a specified site on the A-chain of insulin. An interaction between the A and B chains of insulin ensues, leading to the binding of insulin B-chain with the α-subunit of IR. The ensuing interaction between IRα and IRβ leads to auto-tyrosine phosphorylation of IRβ and tyrosine phosphorylation of the IRS family consisting of at least four proteins. From this point onwards, insulin action proceeds in two directions; ‘Immediate’ and ‘Delayed.’ ‘Immediate’ is represented by the hypoglycemic response, already known to be mediated by Glut-4, apparently influenced by the binding of one of the 4 tyrosine-phosphorylated IRS molecules. ‘Delayed’ is represented by the hitherto unknown nuclear entry of the tyrosine-phosphorylated 43 kDa and 49 kDa fragments of IRβ, mediated by yet another tyrosine-phosphorylated IRS. Indirect evidence indicates that this IRS recognizes nuclear localization signals on the IRβ fragments. The striking observation made in these studies is that Co-Ins has no independent role to perform other than binding to its specified site on insulin and initiating the signaling events. The study opens up a hitherto unrecognized question: are there similar small molecules that mediate the actions of other peptide hormones in the mammalian system?