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

PLoS One. 2012;7(5):e34274. doi: 10.1371/journal.pone.0034274. Epub 2012 May 8.

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.

Publication types

  • Comparative Study

MeSH terms

  • Cells, Cultured
  • Female
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • 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 / analogs & derivatives*
  • Insulin-Like Growth Factor I / pharmacokinetics
  • Insulin-Like Growth Factor I / pharmacology
  • Mitosis / drug effects
  • Phosphorylation / drug effects
  • Protein Binding
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*

Substances

  • Hypoglycemic Agents
  • Insulin, Long-Acting
  • Insulin, Regular, Human
  • LR(3)IGF-I
  • Insulin Glargine
  • Insulin Detemir
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1