Effects of the Antitumor Drug OSI-906, a Dual Inhibitor of IGF-1 Receptor and Insulin Receptor, on the Glycemic Control, β-Cell Functions, and β-Cell Proliferation in Male Mice

• Published in: Endocrinology (Philadelphia) 2014-06, Vol.155 (6), p.2102-2111
• Main Authors: Shirakawa, Jun, Okuyama, Tomoko, Yoshida, Eiko, Shimizu, Mari, Horigome, Yuka, Tuno, Takayuki, Hayasaka, Moe, Abe, Shiori, Fuse, Masahiro, Togashi, Yu, Terauchi, Yasuo
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antitumor activity; Beta cells; Blood Glucose - drug effects; Blood levels; Cancer; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Diabetes mellitus; Drug dosages; Glucokinase; Glucose; Glucose tolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinemia; Imidazoles - pharmacology; Inhibitors; Insulin; Insulin receptors; Insulin resistance; Insulin secretion; Insulin-like growth factor I; Insulin-like growth factors; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Intolerance; Male; Males; Mice; Mice, Inbred C57BL; Nutrient deficiency; Oral administration; Pyrazines - pharmacology; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, Insulin - antagonists & inhibitors; Receptors; Therapeutic targets
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-2032

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 β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-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 β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-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 β-cell mass may expand in response to chemotherapy with this drug.