| First Author | Shirakawa J | Year | 2014 |
| Journal | Endocrinology | Volume | 155 |
| Issue | 6 | Pages | 2102-11 |
| PubMed ID | 24712877 | Mgi Jnum | J:213137 |
| Mgi Id | MGI:5582964 | Doi | 10.1210/en.2013-2032 |
| Citation | Shirakawa J, et al. (2014) Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, beta-cell functions, and beta-cell proliferation in male mice. Endocrinology 155(6):2102-11 |
| abstractText | The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic beta-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, beta-cell mass, and beta-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the beta-cell mass and beta-cell proliferation rate were significantly increased. The insulin signals in the beta-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the beta-cell mass may expand in response to chemotherapy with this drug. |
