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

Angela Lombardi, Jessica Gambardella, Xue-Liang Du, Daniela Sorriento, Maurizio Mauro, Guido Iaccarino, Bruno Trimarco, Gaetano Santulli

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 ß cells in a dose- and timedependent 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.

Original languageEnglish (US)
Article number15823
JournalScientific Reports
Volume7
DOIs
StatePublished - Jan 1 2017

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Insulin-Secreting Cells
Sirolimus
Calcium
Diabetes Mellitus
Insulin
Glucose
Immunosuppressive Agents
Islets of Langerhans
Endoplasmic Reticulum
Pharmaceutical Preparations
Respiration
Transplantation
Incidence

ASJC Scopus subject areas

  • General

Cite this

Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells. / Lombardi, Angela; Gambardella, Jessica; Du, Xue-Liang; Sorriento, Daniela; Mauro, Maurizio; Iaccarino, Guido; Trimarco, Bruno; Santulli, Gaetano.

In: Scientific Reports, Vol. 7, 15823, 01.01.2017.

Research output: Contribution to journalArticle

Lombardi, Angela ; Gambardella, Jessica ; Du, Xue-Liang ; Sorriento, Daniela ; Mauro, Maurizio ; Iaccarino, Guido ; Trimarco, Bruno ; Santulli, Gaetano. / Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells. In: Scientific Reports. 2017 ; Vol. 7.
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