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Monomeric insulins obtained by protein engineering and their medical implications

Monomeric insulins obtained by protein engineering and their medical implications,10.1038/333679a0,Nature,J. Brange,U. Ribel,J. F. Hansen,G. Dodson,M.

Monomeric insulins obtained by protein engineering and their medical implications   (Citations: 145)
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The use of insulin as an injected therapeutic agent for the treatment of diabetes has been one of the outstanding successes of modern medicine. The therapy has, however, had its associated problems, not least because injection of insulin does not lead to normal diurnal concentrations of insulin in the blood. This is especially true at meal times when absorption from subcutaneous tissue is too slow to mimic the normal rapid increments of insulin in the blood. In the neutral solutions used for therapy, insulin is mostly assembled as zinc-containing hexamers1 and this self-association, which under normal physiological circumstances functions to facilitate proinsulin transport, conversion and intracellular storage2, may limit the rate of absorption. We now report that it is possible, by single amino-acid substitutions, to make insulins which are essentially monomeric at pharmaceutical concentrations (0.6 mM) and which have largely preserved their biological activity. These monomeric insulins are absorbed two to three times faster after subcutaneous injection than the present rapid-acting insulins. They are therefore capable of giving diabetic patients a more physiological plasma insulin profile at the time of meal consumption.
Journal: Nature , vol. 333, no. 6174, pp. 679-682, 1988
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    • ...An early study using the insulin analogue B10ASP showed greater carcinogenic action of this engineered insulin than human insulin [30, 31]...

    S. Suissaet al. Long-term effects of insulin glargine on the risk of breast cancer

    • ...Insulin X10 is a human insulin analogue in which the histidine-B10 residue has been replaced with an aspartic acid residue, resulting in a rapid-acting insulin analogue [10, 11]...
    • ...With the advent of recombinant DNA technology, single amino acid substitutions could be targeted to regions involved in hexamer formation that also lie on the periphery of the insulin receptor (IR) binding regions [10]...
    • ...One of the analogues described by Brange and colleagues [10] replaced this histidine residue with the negatively charged aspartic acid, creating the insulin analogue known as insulin X10...

    B. F. Hansenet al. Insulin X10 revisited: a super-mitogenic insulin analogue

    • ...The concentrations of the samples were determined from the absorbance at 276 nm, using an extinction coefficient of 6200 M −1 cm −1 (23)...
    • ...Subsequently, the supernatant was removed and the protein concentration determined by UV spectroscopy using ε276= 6200 M −1 cm −1 (1,23), and the adsorbed amount was then...

    Charlotte Pinholtet al. Influence of Acylation on the Adsorption of Insulin to Hydrophobic Sur...

    • ...In the case of insulin, much effort has been put into the modification of the dimerization interactions [38,39] and hexamer formations [40,41], but less focus has been on the inter-hexamer interactions in solution or within crystals...

    Mathias Norrmanet al. Crystallographic characterization of two novel crystal forms of human ...

    • ...That is why all the modifications of the insulin molecule are in the COOH-terminus of the B chain (B26, 27, 28, 29, 30), the region of the molecule important for dimer formation, but not involved in insulin receptor binding [7,8,11]...

    Ivana Zibet al. Novel insulin analogues and its mitogenic potential

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