Dissertation

Carcinogenicity of insulin analogues

Promotor: Prof.dr. B. van de Water, Co-promotores: J.W. van der Laan, C.L.E. Siezen

Author: S.J. ter Braak
Date: 18 June 2015
Links: Thesis in Leiden Repository

There is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin glargine (LANTUS) was the only commercial insulin analogue with an increased mitogenic potential. In the human body the injected insulin glargine is rapidly degraded into two main metabolites with a metabolic activity. These two compounds have a mitogenic potential that was not increased compared to regular insulin. Gene expression analysis on a stimulated MCF7-based cell line panel showed that the insulin-like growth factor 1 (IGF1) receptor was the main receptor involved in the insulin analogue induced mitogenic signaling. A chronic exposure experiment with the humanized p53R270H+/-WAPCre mouse model revealed that none of the commercially available insulin analogues induced mammary gland tumor multiplicity or decreased the tumor latency time. However, a follow-up whole transcriptome analysis indicated that some tumors in the insulin glargine treatment group had a higher Warburg potential. Altogether, these results suggest that insulin glargine exposure was not involved in tumor initiation but it might have affected tumor progression.