In view of the lifelong exposure and large patient populations involved, insulin analogs with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogs may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogs are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogs, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR). However, the classical model of the IGF-IR signaling may be insufficient to explain (all) mitogenic effects of insulin analogs since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase) pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some) insulin analogs than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs) also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A) in (pre) cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogs). Further studies are required to unravel whether the IR-A is involved in the development of cancers and whether, in this respect (some) insulin analogs differ from human insulin.
Keywords: insulin, insulin analogs, IGF-I receptor, insulin receptor-A, insulin receptor-B, cancer, hyperglycemia
Citation: Janssen JAMJL and Varewijck AJ (2014) Insulin analogs and cancer: a note of caution. Front. Endocrinol. 5:79. doi: 10.3389/fendo.2014.00079
Received: 24 March 2014; Paper pending published: 15 April 2014;
Accepted: 10 May 2014; Published online: 26 May 2014.
Edited by:Antongiulio Faggiano, Federico II University of Naples, Italy
Reviewed by:Piero Ferolla, University of Perugia, Italy
Copyright: © 2014 Janssen and Varewijck. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Joseph A. M. J. L. Janssen, Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Room D-443, ‘s-Gravendijkwal 230, Rotterdam 3015 CE, Netherlands e-mail: firstname.lastname@example.org