Abstract
Abstract A number of insulin-like and proinsulin-like polypeptides were employed in the study of the structure-activity relationship of proinsulin. Glucose incorporation into CO2 and lipids, and the antilipolytic activity, were used as parameters to measure the biological activity of these polypeptides. The split proinsulin and the long A chain proinsulin, with 2 connecting amino acid residues, Arg-Arg, missing, have little more activity over that of native proinsulin. The long B chain proinsulin, with the absence of 2 connecting amino acid residues, Lys-Arg, has a 3- to 4-fold increase in activity compared to proinsulin. Further removal of amino acid residues from proinsulin molecule beyond Lys-Arg level can progressively increase proinsulin activity. These studies suggest that the decreased biological activity of proinsulin may be due essentially to the blocking of the A chain of insulin part in proinsulin molecule rather than the blocking of B chain. Insulin, with 1 or 2 arginine residues attached to COOH-terminal of B chain, loses 60% biological activity when compared to insulin molecule. The effect of positively charged groups may alter the insulin conformation or decrease the binding capacity between the insulin derivatives and the insulin receptor site, or both. C-peptide, a by-product in the proinsulin conversion to insulin, shows no insulin-like activity in homologous and heterologous fat tissues. No antagonistic or potentiating effect of C-peptide for insulin or proinsulin can be demonstrated in homologous and heterologous fat tissues. The feedback control of C-peptide on insulin or proinsulin action is not likely to exist in the adipose tissue.
Highlights
A number of insulin-like and proinsulin-like polypeptides were employedin the study of the structure-activity relationship of proinsulin
The long B chain proinsulin, with the absence of 2 connecting amino monehave beenelucidated from pancreatic tissuesof different species[3,4,5,6]
With 1 or 2 arginine residues attached to COOHterminal of B chain, loses 60% biological activity when compared to insulin molecule
Summary
A number of insulin-like and proinsulin-like polypeptides were employedin the study of the structure-activity relationship of proinsulin. Many studieson the biologicalpropertiesof proinsulin have been reported which suggestthat this prohormonehassignificantly less biological activity than insulin [9,10,11,12,13] Previous studiesfrom this laboratory with the isolatedfat cell indicated acid residues, Lys-Arg, has a 3- to 4-fold increase in activity that the biologicaleffect of proinsulinonthe conversionof glucose compared to proinsulin. Residuesfrom proinsulin molecule beyond Lys-Arg level can This effect was direct and not dependentupon the prior conprogressively increase proinsulin activity These studies version of proinsulin to insulin [10]. No antagonistic or potentiating effect of C-peptide for insulin or proinsulin can be demontionship between the structure and the biological activity of proinsulin, various polypeptide derivatives of proinsulin,’ from which certain amino acid residueshave been removed, were tested for biological activity in the fat cell system. The feedback control of C-peptide on insulin or proinsulin action is not likely to exist in the adiposetissue
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