Abstract
Obesity and type 2 diabetes are associated with an increased risk for development of certain forms of cancer, including colon cancer. The publication of highly controversial epidemiological studies in 2009 raised the possibility that use of the insulin analog glargine increases this risk further. However, it is not clear how mitogenic effects of insulin and insulin analogs measured in vitro correlate with tumor growth-promoting effects in vivo. The aim of this study was to examine possible growth-promoting effects of native human insulin, insulin X10 and IGF-1, which are considered positive controls in vitro, in a short-term animal model of an obesity- and diabetes-relevant cancer. We characterized insulin and IGF-1 receptor expression and the response to treatment with insulin, X10 and IGF-1 in the murine colon cancer cell line (MC38 cells) in vitro and in vivo. Furthermore, we examined pharmacokinetics and pharmacodynamics and monitored growth of MC38 cell allografts in mice with diet-induced obesity treated with human insulin, X10 and IGF-1. Treatment with X10 and IGF-1 significantly increased growth of MC38 cell allografts in mice with diet-induced obesity and we can therefore conclude that supra-pharmacological doses of the insulin analog X10, which is super-mitogenic in vitro and increased the incidence of mammary tumors in female rats in a 12-month toxicity study, also increase growth of tumor allografts in a short-term animal model.
Highlights
Obesity and type 2 diabetes are associated with an increased risk for certain forms of cancer, such as breast, pancreatic and colon cancer [1,2,3,4,5]
In agreement with previous proliferations studies in MCF-7 cells, and < 9-fold higher expression of IGF-1 receptor (IGF-1R) than insulin receptor (IR) in MCF-7 cells [42], the mitogenic effect was largest for IGF-1.X10.human insulin (HI), whereas in M38 cells the ranking for mitogenic effect was X10$IGF-1.HI
We show that the MC38 cell line, derived from a murine colon cancer, expresses IRs and IGF-1Rs and is insulin sensitive, as treatment with HI, X10 and IGF-1 results in activation of the
Summary
Obesity and type 2 diabetes are associated with an increased risk for certain forms of cancer, such as breast, pancreatic and colon cancer [1,2,3,4,5]. The reassuring results concerning glargine do not diminish the prior evidence for an association between type 2 diabetes and increased risk or worse prognosis of certain cancers, including colon cancer, and the mechanisms behind this association remains an important topic. In this context, the insulin analog X10 is an interesting ligand. Further development of X10 for clinical use was discontinued, but the mechanisms behind the increased tumor incidence have never been fully clarified (see [16] for a detailed review)
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