Everolimus Directly Suppresses Insulin Secretion Independently of Cell Growth Inhibition

Everolimus, an orally administered mammalian target of rapamycin inhibitor, has been widely used as an immunosuppressant and an anticancer agent. Whereas everolimus can control recurrent hypoglycemia in patients with insulinoma, possibly through tumor regression and/or the direct inhibition of insulin secretion, time-dependent changes in serum insulin levels caused by everolimus still remain unclear. Here we report a clinical case of a patient with metastatic insulinoma, in which frequent monitoring of serum insulin levels demonstrated rapid and substantial changes in insulin secretion levels, a few days after the discontinuation as well as the readministration of everolimus. To further confirm the direct effect of everolimus on β-cell function, we performed in vitro experiments using mouse insulinoma cells (MIN6) and human induced pluripotent stem cell (hiPSC)–derived insulin-producing cells and found that everolimus significantly suppressed glucose-stimulated insulin secretion in both MIN6 cells and hiPSC–derived insulin-producing cells. Thus, both a patient with metastatic insulinoma and in vitro experiments demonstrated that everolimus directly suppresses insulin secretion, independently of its tumor regression effect.