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

Authors:
Angela Lombardi
Angela Lombardi
Second University of Naples
Italy
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Maurizio Mauro
Maurizio Mauro
University of Rhode Island
United States
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy
Bruno Trimarco
Bruno Trimarco
Federico II University
Napoli | Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy

Sci Rep 2017 Nov 20;7(1):15823. Epub 2017 Nov 20.

Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA.

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 (Ca) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca uptake. Crucially, the reduced mitochondrial Ca uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca 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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-15283-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696524PMC

Still can't find the full text of the article?

We can help you send a request to the authors directly.
November 2017
10 Reads
4 Citations
5.080 Impact Factor

Article Mentions


Provided by Crossref Event Data
twitter
Twitter: Yon_wahyu
November 30, 2017, 1:54 am EST
twitter
Twitter: Brunorm84
November 27, 2017, 12:22 pm EST
twitter
Twitter: Seccionhbpaec
November 27, 2017, 2:10 am EST
twitter
Twitter: Sstrumello
November 26, 2017, 8:09 pm EST
twitter
Twitter: PancreaticCell
November 26, 2017, 5:35 pm EST

Publication Analysis

Top Keywords

depletion intracellular
8
mitochondrial uptake
8
diabetes mellitus
8
sirolimus
5
mitochondrial
5
content endoplasmic
4
depletes calcium
4
endoplasmic reticulum
4
calcium content
4
decreases glucose-stimulated
4
crucially reduced
4
reduced mitochondrial
4
uptake crucially
4
glucose-stimulated mitochondrial
4
markedly depletes
4
reticulum decreases
4
importantly demonstrate
4
murine pancreatic
4
pancreatic islets
4
human murine
4

References

(Supplied by CrossRef)
Article in N Engl J Med
AM Shapiro et al.
N Engl J Med 2006
Article in Lancet
AJ Krentz et al.
Lancet 2005
Article in Endocr Rev
V Shivaswamy et al.
Endocr Rev 2016
Article in J Mol Endocrinol
E D’Amico et al.
J Mol Endocrinol 2005
Article in BMC Gastroenterol
LC Li et al.
BMC Gastroenterol 2017
Article in N Engl J Med
AM Shapiro et al.
N Engl J Med 2000
Article in Diabetes
EA Ryan et al.
Diabetes 2005
Article in N Engl J Med
H Ekberg et al.
N Engl J Med 2007
Article in Science
DW Lamming et al.
Science 2012
Article in Diabetes Care
J Hjelmesaeth et al.
Diabetes Care 2001

Similar Publications