Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes

Abstract

Aims/hypothesis Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth. Methods A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle. Results No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation. Conclusions/interpretation These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours.

Activation of insulin receptors and IGF-1 receptors in COLO-205 colon cancer xenografts by insulin and insulin analogue X10 does not enhance growth under normo- or hypoglycaemic conditions

“…7 Effect on blood glucose, body weight gain and epididymal fat mass after treatment with vehicle (large circles), human insulin 600 nmol/kg (small circles) or X10 600 nmol/kg (diamonds) for 18 days. (a) Treatment with human insulin and X10 decreased blood glucose compared with vehicle, X10 more potently than human insulin, in agreement with the data describing the area above the blood glucose curve ( Table 5) Our findings are in clear contrast to recent studies, which reported that none of human insulin, X10 or a nonmetabolisable analogue of insulin glargine in suprapharmacological doses up to 1200 nmol/kg was able to activate the IGF-1R in normal rats and mouse allograft models [12][13][14][15]. However, there are several differences in methods between our study and the previous ones.…”

“…A potential concern could be that growthstimulatory effects of insulin and X10 are masked by the hypoglycaemia. However, the original finding with X10 was in a 12 month chronic toxicity study performed in normal rats, which developed hypoglycaemia with each X10 treatment, and in several previous allograft experiments in normal mice, treatment with high doses of insulin and X10 increased tumour growth despite repeated reduction of blood glucose to a hypoglycaemic level, fully comparable with this study [12,13,18]. Furthermore, in the COLO-205 xenograft experiment performed in diabetic host animals, we explored the correlation between xenograft mass and the mean blood glucose during the experiment days and observed the largest tumours in the mice with the lowest blood glucose and a significant negative correlation between tumor mass and blood glucose, i.e.…”

“…First, the previous studies used either western blotting with an antibody that recognises phospho-epitopes on the IGF-1R as well as the insulin receptor (i.e. a non-specific antibody) or immunoprecipitation for detection of activated IGF-1R [12][13][14][15]. We used ELISAs, which are considered more suited for quantitative assessment than western blotting and immunoprecipitation.…”

“…We used ELISAs, which are considered more suited for quantitative assessment than western blotting and immunoprecipitation. Furthermore, Gallagher et al [12,13] do not state whether the IGF-1R activation observed in tumour allografts from IGF-1-treated mice represent the basal activation state after repeated treatment for 14 days, or activation seen shortly after an acute treatment. We demonstrate that activation of IGF-1R clearly depends on time.…”

“…X10 displays increased binding affinity to the insulin receptor and IGF-1 receptor (IGF-1R) and decreased dissociation rate from the insulin receptor [8][9][10]; each of these characteristics correlates with an increased mitogenic potency in vitro [9,11]. However, recent studies in rodent models reported that insulin and insulin analogues are not able to activate the IGF-1R in vivo [12][13][14][15]. This is in clear contrast to in vitro observations, and clarification of this is important for understanding possible growth-stimulatory effects of insulin and insulin analogues.…”