Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

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Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues. / Lundby, Anders; Bolvig, Pernille; Hegelund, Anne Charlotte; Hansen, Bo F; Worm, Jesper; Lützen, Anne; Billestrup, Nils; Bonnesen, Christine; Oleksiewicz, Martin B.

In: Journal of Applied Toxicology, Vol. 35, No. 7, 07.2015, p. 842-850.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Lundby, A, Bolvig, P, Hegelund, AC, Hansen, BF, Worm, J, Lützen, A, Billestrup, N, Bonnesen, C & Oleksiewicz, MB 2015, 'Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues', Journal of Applied Toxicology, vol. 35, no. 7, pp. 842-850. https://doi.org/10.1002/jat.3082

APA

Lundby, A., Bolvig, P., Hegelund, A. C., Hansen, B. F., Worm, J., Lützen, A., Billestrup, N., Bonnesen, C., & Oleksiewicz, M. B. (2015). Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues. Journal of Applied Toxicology, 35(7), 842-850. https://doi.org/10.1002/jat.3082

Vancouver

Lundby A, Bolvig P, Hegelund AC, Hansen BF, Worm J, Lützen A et al. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues. Journal of Applied Toxicology. 2015 Jul;35(7):842-850. https://doi.org/10.1002/jat.3082

Author

Lundby, Anders ; Bolvig, Pernille ; Hegelund, Anne Charlotte ; Hansen, Bo F ; Worm, Jesper ; Lützen, Anne ; Billestrup, Nils ; Bonnesen, Christine ; Oleksiewicz, Martin B. / Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues. In: Journal of Applied Toxicology. 2015 ; Vol. 35, No. 7. pp. 842-850.

Bibtex

@article{8350b28609734b79b8dd2ac615e6ab08,
title = "Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues",
abstract = "There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC50 values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. Copyright {\textcopyright} 2014 John Wiley & Sons, Ltd.",
author = "Anders Lundby and Pernille Bolvig and Hegelund, {Anne Charlotte} and Hansen, {Bo F} and Jesper Worm and Anne L{\"u}tzen and Nils Billestrup and Christine Bonnesen and Oleksiewicz, {Martin B}",
note = "Copyright {\textcopyright} 2014 John Wiley & Sons, Ltd.",
year = "2015",
month = jul,
doi = "10.1002/jat.3082",
language = "English",
volume = "35",
pages = "842--850",
journal = "Journal of Applied Toxicology",
issn = "0260-437X",
publisher = "JohnWiley & Sons Ltd",
number = "7",

}

RIS

TY - JOUR

T1 - Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

AU - Lundby, Anders

AU - Bolvig, Pernille

AU - Hegelund, Anne Charlotte

AU - Hansen, Bo F

AU - Worm, Jesper

AU - Lützen, Anne

AU - Billestrup, Nils

AU - Bonnesen, Christine

AU - Oleksiewicz, Martin B

N1 - Copyright © 2014 John Wiley & Sons, Ltd.

PY - 2015/7

Y1 - 2015/7

N2 - There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC50 values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. Copyright © 2014 John Wiley & Sons, Ltd.

AB - There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC50 values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. Copyright © 2014 John Wiley & Sons, Ltd.

U2 - 10.1002/jat.3082

DO - 10.1002/jat.3082

M3 - Journal article

C2 - 25413577

VL - 35

SP - 842

EP - 850

JO - Journal of Applied Toxicology

JF - Journal of Applied Toxicology

SN - 0260-437X

IS - 7

ER -

ID: 162900116