Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling

L. Sciacca, M. F. Cassarino, M. Genua, G. Pandini, R. Le Moli, S. Squatrito, R. Vigneri

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis: Five insulin analogues, with modified insulin-like molecular structures, are currently approved for treating diabetic patients. They activate cell signalling and biological responses via insulin receptor isoforms (IR-A and IR-B), each having specific characteristics for eliciting cell responses. The molecular and biological effects of these analogues on receptor isoforms in comparison to native insulin are not well defined, and their effects on the IGF1 receptor (IGF1R) are controversial. The characterisation of these effects was the aim of the present study. Methods: Short-acting (insulin lispro [B28Lys,B29Pro human insulin], insulin aspart [B28Asp human insulin], insulin glulisine [B3Lys,B29Glu human insulin]) and long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human insulin], insulin detemir [B29Lys(ε-tetradecanoyl),desB30 human insulin]) insulin analogues were studied in three engineered cell models (R-, IGF1R-deprived mouse fibroblasts transfected with either only human IR-A or IR-B or IGF1R). Receptor binding and phosphorylation, AKT and extracellular signal-regulated kinase (ERK) activation, cell proliferation and colony formation were evaluated after exposing the cells to each analogue and were compared with insulin, IGF1 and the carcinogenic analogue B10Asp. Results: All short-acting insulin analogues produced molecular and biological effects similar but not identical to those of insulin. Relative to insulin, long-acting analogues more strongly activated the ERK pathway via both IR-A and IGF1R as well as increased cell proliferation. At the concentration tested, no analogue (except B10Asp via IR-A) had increased transforming activity. Conclusions/interpretation: Cell models that permit comparisons of the activity of insulin to that of insulin analogues via each receptor individually indicate that only minor differences exist between insulin and short-acting analogues. By contrast, long-acting analogues activate the mitogenic signalling pathway more effectively than insulin and cause increased cell proliferation.

Original languageEnglish
Pages (from-to)1743-1753
Number of pages11
JournalDiabetologia
Volume53
Issue number8
DOIs
Publication statusPublished - Aug 2010

Fingerprint

Insulin Receptor
Protein Isoforms
Insulin
Short-Acting Insulin
Insulin Aspart
Long-Acting Insulin
Extracellular Signal-Regulated MAP Kinases
Cell Proliferation
Insulin Lispro
Molecular Structure

Keywords

  • IGF1R
  • Insulin analogues
  • Insulin receptor
  • Insulin receptor isoforms
  • Intracellular signalling
  • Mitogenic effects

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Sciacca, L., Cassarino, M. F., Genua, M., Pandini, G., Le Moli, R., Squatrito, S., & Vigneri, R. (2010). Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia, 53(8), 1743-1753. https://doi.org/10.1007/s00125-010-1760-6

Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. / Sciacca, L.; Cassarino, M. F.; Genua, M.; Pandini, G.; Le Moli, R.; Squatrito, S.; Vigneri, R.

In: Diabetologia, Vol. 53, No. 8, 08.2010, p. 1743-1753.

Research output: Contribution to journalArticle

Sciacca, L, Cassarino, MF, Genua, M, Pandini, G, Le Moli, R, Squatrito, S & Vigneri, R 2010, 'Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling', Diabetologia, vol. 53, no. 8, pp. 1743-1753. https://doi.org/10.1007/s00125-010-1760-6
Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S et al. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia. 2010 Aug;53(8):1743-1753. https://doi.org/10.1007/s00125-010-1760-6
Sciacca, L. ; Cassarino, M. F. ; Genua, M. ; Pandini, G. ; Le Moli, R. ; Squatrito, S. ; Vigneri, R. / Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. In: Diabetologia. 2010 ; Vol. 53, No. 8. pp. 1743-1753.
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