Insulin analogs and cancer: a note of caution.

Joseph A M J L Janssen,Aimee J Varewijck

doi:10.3389/fendo.2014.00079

Joseph A M J L Janssen, Aimee J Varewijck

Open Access

https://doi.org/10.3389/fendo.2014.00079

Copy DOI

Abstract

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.

Highlights

Insulin analogs have been developed in an attempt to achieve a more physiological replacement therapy of insulin, thereby achieving a better glycemic control
In view of the lifelong exposure and large patient populations involved, insulin analogs with increased mitogenic effects in comparison to human insulin may constitute a major health problem, since these analogs could induce the growth of pre-existing neoplasms
In 2009, several large observational studies suggested that use of insulin analogs and especially the use of insulin glargine was associated with an increased risk of cancer [1,2,3,4]

Summary

Introduction

Insulin analogs have been developed in an attempt to achieve a more physiological replacement therapy of insulin, thereby achieving a better glycemic control. Some long-acting analogs activate the mitogenic signaling pathway more effectively than insulin and cause increased cell proliferation [16]. By using the IGF-I KIRA assay, we compared IGF-IR activation in vitro induced by human insulin, two short-acting insulin analogs (insulin aspart and insulin lispro) and two long-acting insulin analogs (insulin glargine and insulin detemir).

Results

Conclusion