mTOR and Cardiovascular Diseases: Diabetes Mellitus
The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection after transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and frequently induce diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors but high when used in combination with calcineurin inhibitors (from 11.0% to 38.1%). mTOR inhibitors used as anticancer agents (everolimus, temsirolimus) increase significantly the risk for new-onset diabetes and induce a 5-fold increase in the risk for severe hyperglycemia. The deleterious effect of mTOR inhibitors on glucose metabolism is due to an increased insulin resistance secondary to a reduction of the insulin signaling pathway within the cell and a reduction of insulin secretion via a direct effect on the pancreatic beta cells. Because of the risk for diabetes, it is recommended, when starting a treatment with an mTOR inhibitor, to check fasting blood glucose every 2 weeks during the first month of treatment then every month and HbA1c every 3 months and to intensify self-monitoring of blood glucose in patients with known diabetes. When fasting blood glucose is more than 126 mg/dL (7.0 mmol/L), when plasma glucose is more than 200 mg/dL at any time, or when HbA1c is more than 6.5%, it is recommended to start antidiabetic treatment.