Anticancer Agent Also Suppresses Insulin Secretion in Metastatic Insulinoma

The immunosuppressant and anticancer agent everolimus has been shown to directly suppress insulin secretion in metastatic insulinoma, independently of the drug’s effect on tumor growth, according to a study recently published in the Journal of the Endocrine Society.

Researchers led by Takeshi Miyatsuka, MD, PhD, of the Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine in Tokyo, Japan, write that everolimus has been used to treat neuroendocrine tumors and has been found to increase survival rates in progression-free patients with advanced pancreatic neuroendocrine tumors. The drug also can be used to control hypoglycemia in patients with malignant insulinoma. “Thus, whereas everolimus has been proved to be effective in the management of insulinoma, it remains unclear as to whether everolimus directly suppresses insulin secretion in pancreatic beta-cells, independently of tumor regression,” the authors write.

“Alternatively, everolimus might improve hyperinsulinemia independently of blood glucose levels in vivo, in contrast with the in vitro findings in this study.”

The authors report on a case of a 53-year-old woman with insulinoma treated with everolimus, whose lab data was frequently measured, so the authors were able to see the rapid changes in insulin levels when they discontinued and then restarted the everolimus, showing that everolimus directly suppresses insulin secretion, independently of its effect on tumor regression. To confirm this finding, the researchers performed in vitro experiments using mouse insulinoma cells (MIN6) and human induced pluripotent stem cell (hiPSC)–derived insulin-producing cells demonstrated that everolimus inhibited glucose-stimulated insulin secretion (GSIS), even after accounting for cell growth rates.

The authors write that their in vitro experiments showed that everolimus suppresses GSIS, but insulin secretion is not significantly changed under low glucose conditions. However, their clinical case showed immediate and significant suppression of hyperinsulinemia under low glucose conditions during fasting. “Although there is no direct explanation for this difference, it is possible that everolimus suppressed the dysregulated hyperinsulinemia during the postprandial period, which has been reported in patients with insulinoma, and subsequently improved sustained hypoglycemia during fasting,” the authors write. “Alternatively, everolimus might improve hyperinsulinemia independently of blood glucose levels in vivo, in contrast with the in vitro findings in this study.”

Based on these findings, the authors conclude that both a patient with metastatic insulinoma and in vitro experiments demonstrated that everolimus directly suppresses insulin secretion, independently of its tumor regression effect.

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