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• W2000903025 startingPage "e34274" @default.
• W2000903025 abstract "Aims/Hypothesis There is controversy with respect to molecular characteristics of insulin analogues. We report a series of experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparison with human insulin, IGF-1, and the super-mitogenic insulin, X10. Methods We measured binding of ligands to membrane-bound and solubilised receptors, receptor activation and mitogenicity in a number of cell types. Results Detemir and glargine each displayed a balanced affinity for insulin receptor (IR) isoforms A and B. This was also true for X10, whereas IGF-1 had a higher affinity for IR-A than IR-B. X10 and glargine both exhibited a higher relative IGF-1R than IR binding affinity, whereas detemir displayed an IGF-1R:IR binding ratio of ≤1. Ligands with high relative IGF-1R affinity also had high affinity for IR/IGF-1R hybrid receptors. In general, the relative binding affinities of the analogues were reflected in their ability to phosphorylate the IR and IGF-1R. Detailed analysis revealed that X10, in contrast to the other ligands, seemed to evoke a preferential phosphorylation of juxtamembrane and kinase domain phosphorylation sites of the IR. Sustained phosphorylation was only observed from the IR after stimulation with X10, and after stimulation with IGF-1 from the IGF-1R. Both X10 and glargine showed an increased mitogenic potency compared to human insulin in cells expressing many IGF-1Rs, whereas only X10 showed increased mitogenicity in cells expressing many IRs. Conclusions Detailed analysis of receptor binding, activation and in vitro mitogenicity indicated no molecular safety concern with detemir." @default.
• W2000903025 created "2016-06-24" @default.
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• W2000903025 date "2012-05-08" @default.
• W2000903025 modified "2023-10-03" @default.
• W2000903025 title "Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10" @default.
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• W2000903025 doi "https://doi.org/10.1371/journal.pone.0034274" @default.
• W2000903025 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3348127" @default.
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