[12‐ASPARAGINE‐B] HUMAN INSULIN: An Analogue with Modification in the Hydrophobic Core of Insulin*

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Abstract
The human [12-asparagine-B] insulin ([Asn12-B] insulin), which differs from the parent molecule in that the valine residue at position B12 is substituted by an asparagine residue, was synthesized. In stimulating glucose oxidation and lipogenesis the analog exhibited potencies of 0.19% and 0.14%, respectively, as compared to insulin. In insulin receptor binding [rat liver plasma membranes] [Asn12-B] insulin possessed a potency of around 0.29% compared to the natural hormone. At high concentrations this analog has the same maximal activity in the in vitro assays as the natural hormone. Despite the low affinity of the analog for the insulin receptor, the analog-receptor complex is fully capable of initiating the series of chemical events that leads to the biological response. The B12 valine contributes greatly in the maintenance of a structure possessing the proper receptor-binding characteristics, but does not have any role in modulating the activity of the hormone-receptor complex. The potency of this analog by radioimmunoassay is at least 100-fold higher than the in vitro biological assays; the immunological determinants of insulin can be essentially unrelated to the biological activity of the molecule.