Abstract
IntroductionSeveral studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms.MethodA systematic literature search was performed on breast cell-line, animal and human studies using the key words ‘insulin analogue’ and ‘breast neoplasia’ in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies.ResultsIn total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations.ConclusionThere is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0611-2) contains supplementary material, which is available to authorized users.
Highlights
Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk
Studies were divided into three categories with the following selection criteria; 1) in vitro studies of mammary gland cell lines exposed to insulin analogues, in which direct proliferative effect was measured or pathway activation was monitored; 2) animal studies on models treated with insulin analogue, in which the mammary gland tumour progression/initiation was measured, or different insulin analogues were compared for their activation of mitogenic signalling pathways in mammary gland tissue, and 3) epidemiological and in vivo studies in humans, including patients with type 1 or type 2 Diabetes mellitus (DM) treated with insulin analogues before breast cancer diagnosis; cohort and case–control studies as well as randomized controlled trials were included
Evidence of mitogenic/carcinogenic potential Current evidence of the mitogenic/carcinogenic potential per insulin is described below, highlighting the most important findings displayed in the tables and figures
Summary
Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. Insulin analogues have been marketed since 1997 and are different from the human insulin molecule in that the amino acid sequence is modified to have an altered pharmacokinetic profile. These modifications afford greater flexibility in the treatment of diabetic patients. Structural transformation of human insulin might result in different binding affinity towards the insulin-like growth factor-1 (IGF-1) receptor (IGF1R). This may result in increased mitogenic action of insulin analogues. Glargine is theoretically most likely to have increased mitogenic action compared to human insulin, as the carboxy terminal of the B-chain of glargine has a positive charge, as is the case with IGF-1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
