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.
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.
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama 236-0004, Japan.
Jun
J
Shirakawa
Tomoko
T
Okuyama
Eiko
E
Yoshida
Mari
M
Shimizu
Yuka
Y
Horigome
Takayuki
T
Tuno
Moe
M
Hayasaka
Shiori
S
Abe
Masahiro
M
Fuse
Yu
Y
Togashi
Yasuo
Y
Terauchi
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005951:Glucose Tolerance Test; D007093:Imidazoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011719:Pyrazines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*
C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D001786:Blood Glucose; D007093:Imidazoles; D011719:Pyrazines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin