Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

Abstract

Aims/hypothesis Insulin analogues were developed to improve the pharmacological properties of injected insulin and to better mimic endogenous insulin output. However, certain insulin analogues have been suggested to display IGF-I-like biological activities. Furthermore, several recent epidemiological studies have suggested a potential increase in cancer risk for treatment of diabetes patients with longacting analogue insulin glargine (A21Gly,B31Arg,B32Arg human insulin). Additional studies, however, reported no increased cancer risk. The purpose of the present study was to identify the receptor(s) and signal transduction pathways responsible for the biological actions of insulin glargine and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin). Methods The colon cancer-derived cell line HCT116 was treated with increasing doses of insulin glargine, insulin detemir, regular insulin or IGF-I, and receptor activation was evaluated by immunoprecipitation assays. IGF-I receptor (IGF-IR) internalisation following insulin glargine treatment was assessed by confocal microscopy. Activation of the Akt and extracellular signal-regulated kinase pathways was evaluated by western blots. The anti-apoptotic effect of the analogues was measured by poly-(ADP ribose) polymerase antibody and annexin assays. Results We found evidence for dual activation of the insulin receptor and IGF-IR by the analogues. Dosedependency experiments showed that insulin glargine was able to phosphorylate the IGF-IR at fivefold lower doses than those required to activate the insulin receptor. We also showed that insulin glargine can lead to prolonged activation of the receptors and therefore promote abnormal signalling. Confocal imaging experiments showed that insulin glargine, but not regular insulin induced IGF-IR internalisation similarly to IGF-I. Finally, both analogues displayed IGF-I-like anti-apoptotic activities and stimulated cell cycle progression. Conclusions/interpretation Our data indicate that insulin glargine and insulin detemir display atypical signalling activities that differ from those elicited by regular insulin and involve activation of the anti-apoptotic IGF-IR.

Proliferative and signaling activities of insulin analogues in endometrial cancer cells

“…The strong activation of IGF1R by glargine is consistent with published studies showing that glargine exhibited a 6-8-fold increased affinity for IGF1R compared with insulin in CHO cells overexpressing the receptor (Kurtzhals et al, 2000). These results are also in agreement with previous reports from our laboratory (Weinstein et al, 2009;Yehezkel et al, 2010). In these studies we showed that glargine and detemir elicited atypical signaling activities and displayed enhanced IGF1-like proliferative and anti-apoptotic activities in colon, breast, and prostate cancer cell lines.…”

Long-term effects of insulin glargine on the risk of breast cancer

“…Some experimental studies have suggested that insulin stimulation of growth of cancers is mediated by insulin stimulation of IGF-I receptors [22]. While this possibility is not excluded by recent data, the documentation of expression of insulin receptors by malignant cells indicates that even insulins that have no IGF-I receptor agonist activity could stimulate proliferation [23,24].…”

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

“…Indeed, some laboratory studies showed long-acting insulin analogs were associated with cancer cell proliferation and protected against apoptosis via their higher binding affinity to IGF-I receptors (3,4).…”