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Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts

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Abstract

Insulin has been approved for inhaled application, but safety concerns remain, because of un-physiologically high insulin concentrations in the lung. Since insulin may act as growth factor, possible proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) on human lung fibroblasts were studied. As measure of proliferation [3H]-thymidine incorporation was studied in HEL-299, MRC-5, IMR-90 and primary human lung fibroblasts. In all cells, mRNA encoding IGF-1 receptors and two variants of insulin receptors was detected. Insulin and IGF-1 stimulated [3H]-thymidine incorporation in all cells. Comparison of the concentration-dependent effects in HEL-299 cells showed that IGF-1 and insulin glargine were more potent (EC50, 3 and 6 nM) and more effective (maximum increase, by 135–150%) than insulin and insulin detemir (EC50, 22 and 110 nM; maximum increase: by 80%). Proliferative effects of IGF-1 and insulin were inhibited to the same extent by an antibody (1H7) directed against the IGF-1 receptor α-subunit. Insulin-induced stimulation of [3H]-thymidine incorporation was reduced by 83% after siRNA-mediated down-regulation of IGF-1 receptor by about 75%, but not affected by a similar down-regulation of the insulin receptor. Insulin and IGF-1 caused rapid up-regulation of the early genes FOS, EGR-1 and EGR-2 as well as of the gene coding for IGF-1. In conclusion, in human lung fibroblasts insulin exerts marked proliferative effects and the pharmacological profile of this response as well as specific receptor knock-down experiments suggest mediation via IGF-1 receptors. The risk of unwanted structural lung alterations by long-term inhalative application of insulin should be considered.

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Acknowledgement

This work was supported by the Federal Institute for Drugs and Medical Devices (V-9908/68602/2007). The paper contains part of the Ph.D. thesis of UR. We thank Sabine Mering for excellent technical assistance.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Bonn, Reuterstraβe 2b, 53113, Bonn, Germany

    M. Warnken, U. Reitzenstein, A. Sommer, M. Fuhrmann & K. Racké

  2. Department of Pulmonary Diseases, University Hospital Bonn, Clinic and Policlinic II, Bonn, Germany

    U. R. Juergens

  3. Federal Institute for Drugs and Medical Devices, Bonn, Germany

    P. Mayer & H. Enzmann

Authors
  1. M. Warnken
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  2. U. Reitzenstein
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  3. A. Sommer
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  4. M. Fuhrmann
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  5. P. Mayer
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  6. H. Enzmann
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  7. U. R. Juergens
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  8. K. Racké
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Corresponding author

Correspondence to K. Racké.

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M. Warnken and U. Reitzenstein contributed equally

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Warnken, M., Reitzenstein, U., Sommer, A. et al. Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts. Naunyn-Schmied Arch Pharmacol 382, 511–524 (2010). https://doi.org/10.1007/s00210-010-0561-2

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  • DOI: https://doi.org/10.1007/s00210-010-0561-2

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