The clinical course and potential underlying mechanisms of everolimus-induced hyperglycemia.

Abstract

The mechanistic target of rapamycin (mTOR) inhibitor everolimus is an antitumor agent known to cause hyperglycemia. However, the clinical course of everolimus-induced hyperglycemia, its pathophysiological basis, and the treatment strategy are not clear. In this case series report, we present the clinical course of everolimus-induced hyperglycemia in four patients. Hyperglycemia occurred 3-8 weeks after the administration of everolimus irrespective of the body mass index (range, 21.3-29.1 kg/m2) or pre-existing diabetes. Insulin or insulin secretagogues were required for glycemic control in most of the patients. Of note, the hyperglycemia was reversible in all patients, and none of the patients required anti-diabetic agents to achieve adequate glycemic control after cessation of everolimus therapy. To investigate the underlying mechanism of everolimus-induced hyperglycemia, we assessed insulin secretion and sensitivity by 75 g oral glucose tolerance test, arginine challenge test, and/or hyperinsulinemic-euglycemic clamp study using stable isotope-labeled glucose tracer in two patients. Everolimus did not affect insulin sensitivity in the liver, skeletal muscle, or the adipose tissue. In contrast, everolimus impaired insulin secretion and thereby increased basal hepatic glucose production. These findings further our understanding of the role of mTOR in glucose homeostasis in humans and provide insights for treatment strategies against everolimus-induced hyperglycemia.

• Authors: Jun Tanimura, Hiromi Nakagawa, Takeo Tanaka, Akihiro Kikuchi, Sachie Osada, Yoshiaki Tanaka, Kumpei Tokuyama, Toshinari Takamura
• Journal: Endocrine journal (Endocr J) Vol. 66 Issue 7 Pg. 615-620 (Jul 28 2019) ISSN: 1348-4540 [Electronic] Japan
• PMID: 30982794 (Publication Type: Case Reports, Journal Article)

Chemical References

• Insulin
• Everolimus
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Aged
• Disease Progression
• Everolimus (adverse effects)
• Female
• Glucose Clamp Technique (methods)
• Glucose Tolerance Test
• Humans
• Hyperglycemia (chemically induced, metabolism, pathology)
• Hyperinsulinism (metabolism)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Insulin Secretion (drug effects)
• Male
• Middle Aged
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)