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

Abstract

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.

Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906

“…We previously reported that the once daily administration of 40 mg/kg of OSI-906 for 7 days significantly increased β cell proliferation and β cell mass 25 . Similarly, OSI-906 had significantly increased the β cell mass and β cell proliferation by day 7 in the present study (Fig.…”

“…We previously showed that the administration of OSI-906 at 50 or 75 mg/kg not only induced hyperglycemia and hyperinsulinemia but also reduced the survival rate of mice 25 . In contrast, OSI-906 at 40 mg/kg once daily for 7 days elicited sustained hyperglycemia, but not a low survival rate 25 . In this study, we used 45 mg/kg of OSI-906 for 7 days, and no adverse effects on the survival rate were seen.…”

“…OSI-906 has also shown preliminary evidence of anti-tumor activity in several solid tumors in phase I clinical trials 24 . We previously showed that the oral administration of OSI-906 not only exacerbated severe glucose intolerance and insulin resistance in a rapid manner, but also increased the β cell mass and β cell proliferation in mice 25 .…”

Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats

“…5b). A number of studies using pharmacological [23, 24] or genetic [25–27] tools have demonstrated that insulin resistance leads to beta cell hyperplasia in rodents, and the protease inhibitor serpin B1 was recently identified as a liver-derived circulating factor mediating this response in insulin-resistant mice [5]. In the context of nutrient-induced insulin resistance, however, the respective contributions of nutrients themselves vs their indirect effect through insulin resistance on beta cell proliferation remain unclear, and in this regard our study provides important insights.…”

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

“…However, besides to the involvement of GSK3 in tumor development, it is also a key enzyme in glycogen synthesis and the overall IGF-1 R/IR signaling is crucial for regulating glucose metabolism23. Due to the findings that OSI-906 decreased acute glucose consumption dose-dependently in starved NCI-H292 cells42 and that C57BL/6 J mice showed a deteriorated glucose tolerance64 we examined markers of energy metabolism in the BALB-CTA, too. Although we were able to detect a slightly elevated phosphorylation of the energy sensor AMPK after OSI-906 treatment, we found no difference in ATP content or oxygen consumption on day 22 of the BALB-CTA.…”