Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10.
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-mitogeni...
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doaj-d1519954efca4a8d8c21f7a6d0537d0e2020-11-25T02:26:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0175e3427410.1371/journal.pone.0034274Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10.Bo F HansenTine GlendorfAnne C HegelundAnders LundbyAnne LützenRita SlaabyCarsten Enggaard StidsenAIMS/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.http://europepmc.org/articles/PMC3348127?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bo F Hansen Tine Glendorf Anne C Hegelund Anders Lundby Anne Lützen Rita Slaaby Carsten Enggaard Stidsen |
spellingShingle |
Bo F Hansen Tine Glendorf Anne C Hegelund Anders Lundby Anne Lützen Rita Slaaby Carsten Enggaard Stidsen Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. PLoS ONE |
author_facet |
Bo F Hansen Tine Glendorf Anne C Hegelund Anders Lundby Anne Lützen Rita Slaaby Carsten Enggaard Stidsen |
author_sort |
Bo F Hansen |
title |
Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. |
title_short |
Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. |
title_full |
Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. |
title_fullStr |
Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. |
title_full_unstemmed |
Molecular characterisation of long-acting insulin analogues in comparison with human insulin, IGF-1 and insulin X10. |
title_sort |
molecular characterisation of long-acting insulin analogues in comparison with human insulin, igf-1 and insulin x10. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3348127?pdf=render |
work_keys_str_mv |
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