It is not fully clarified whether insulin glargine, an analogue with a high affinity for insulin-like growth factor-1 receptor (IGF-1R), increases the risk for cancers that abundantly express IGF-1R such as breast cancer or some types of breast cancer. To gain insight into this issue, female Sprague–Dawley rats fed a high-fat diet were given the carcinogen N-methyl-N-nitrosourea and randomly assigned to vehicle (control), NPH (unmodified human insulin), glargine or detemir (n = 30 per treatment). Insulins were given subcutaneously (15 U/kg/day) 5 days a week. Mammary tumours were counted twice weekly, and after 6 weeks of treatment, extracted for analysis. None of the insulin-treated groups had increased mammary tumour incidence at any time compared with control. At 6 weeks, tumour multiplicity was increased with NPH or glargine (P < 0.05) and tended to be increased with detemir (P = 0.2); however, there was no difference among insulins (number of tumours per rat: control = 0.8 ± 0.1, NPH = 1.8 ± 0.3, glargine = 1.5 ± 0.4, detemir = 1.4 ± 0.4; number of tumours per tumour-bearing rat: control = 1.3 ± 0.1, NPH = 2.2 ± 0.4, glargine = 2.7 ± 0.5, detemir = 2.3 ± 0.5). IGF-1R expression in tumours was lower than that in Michigan Cancer Foundation-7 (MCF-7) cells, a cell line that shows greater proliferation with glargine than unmodified insulin. In rats, glargine was rapidly metabolised to M1 that does not have greater affinity for IGF-1R. In conclusion, in this model of oestrogen-dependent breast cancer in insulin-resistant rats, insulin and insulin analogues increased tumour multiplicity with no difference between insulin types.
Yusaku Mori, Eunhyoung Ko, Rudolf Furrer, Linda C Qu, Stuart C Wiber, I George Fantus, Mario Thevis, Alan Medline and Adria Giacca
Yusaku Mori, Hiroyuki Shimizu, Hideki Kushima, Tomomi Saito, Munenori Hiromura, Michishige Terasaki, Masakazu Koshibu, Hirokazu Ohtaki and Tsutomu Hirano
Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin-1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2-transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease.