Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10

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. W...

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Bibliographic Details
Published in:	PloS one Vol. 7; no. 5; p. e34274
Main Authors:	Hansen, Bo F, Glendorf, Tine, Hegelund, Anne C, Lundby, Anders, Lützen, Anne, Slaaby, Rita, Stidsen, Carsten Enggaard
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 08-05-2012 Public Library of Science (PLoS)
Subjects:	Affinity Analysis Binding Biology Cancer Cells, Cultured Diabetes Female Fibroblasts Humans Hypoglycemic Agents - pharmacokinetics Hypoglycemic Agents - pharmacology Infrared radiation Insulin Insulin Detemir Insulin Glargine Insulin, Long-Acting - pharmacokinetics Insulin, Long-Acting - pharmacology Insulin, Regular, Human - pharmacokinetics Insulin, Regular, Human - pharmacology Insulin-like growth factor I Insulin-Like Growth Factor I - analogs & derivatives Insulin-Like Growth Factor I - pharmacokinetics Insulin-Like Growth Factor I - pharmacology Insulin-like growth factors Isoforms Life sciences Ligands Measurement methods Medicine Mitogenicity Mitosis - drug effects Phosphorylation Phosphorylation - drug effects Physiology Protein Binding Receptor mechanisms Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Receptors Rodents Smooth muscle Stimulation Studies Denmark
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Summary:	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. We measured binding of ligands to membrane-bound and solubilised receptors, receptor activation and mitogenicity in a number of cell types. 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. Detailed analysis of receptor binding, activation and in vitro mitogenicity indicated no molecular safety concern with detemir.
Bibliography:	Conceived and designed the experiments: BFH TG. Performed the experiments: BFH TG ACH A. Lundby A. Lützen RS CES. Analyzed the data: BFH TG ACH A. Lundby A. Lützen RS CES. Contributed reagents/materials/analysis tools: BFH TG ACH A. Lundby A. Lützen RS CES. Wrote the paper: BFH TG ACH A. Lundby A. Lützen RS CES.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0034274