Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells

Sci Rep. 2017 Nov 20;7(1):15823. doi: 10.1038/s41598-017-15283-y.


Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal β cells in a dose- and time-dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca2+) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca2+ uptake. Crucially, the reduced mitochondrial Ca2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics
  • Glucose / metabolism*
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Secretion / genetics
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Sirolimus / adverse effects
  • Sirolimus / pharmacology*


  • Insulin
  • Glucose
  • Calcium
  • Sirolimus