PMID- 23881200
OWN - NLM
STAT- MEDLINE
DCOM- 20131001
LR  - 20211203
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 62
IP  - 8
DP  - 2013 Aug
TI  - Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the 
      underlying molecular mechanisms.
PG  - 2674-82
LID - 10.2337/db13-0106 [doi]
AB  - Rapamycin is used frequently in both transplantation and oncology. Although 
      historically thought to have little diabetogenic effect, there is growing 
      evidence of beta-cell toxicity. This Review draws evidence for rapamycin toxicity 
      from clinical studies of islet and renal transplantation, and of rapamycin as an 
      anticancer agent, as well as from experimental studies. Together, these studies 
      provide evidence that rapamycin has significant detrimental effects on beta-cell 
      function and survival and peripheral insulin resistance. The mechanism of action 
      of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This 
      Review describes the complex mTOR signaling pathways, which control vital 
      cellular functions including mRNA translation, cell proliferation, cell growth, 
      differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms 
      for rapamycin toxicity in beta-cells. These mechanisms include reductions in beta-cell 
      size, mass, proliferation and insulin secretion alongside increases in apoptosis, 
      autophagy, and peripheral insulin resistance. These data bring into question the 
      use of rapamycin as an immunosuppressant in islet transplantation and as a 
      second-line agent in other transplant recipients developing new-onset diabetes 
      after transplantation with calcineurin inhibitors. It also highlights the 
      importance of close monitoring of blood glucose levels in patients taking 
      rapamycin as an anticancer treatment, particularly those with preexisting glucose 
      intolerance.
FAU - Barlow, Adam D
AU  - Barlow AD
AD  - Department of Transplant Surgery, University Hospitals of Leicester, Leicester, 
      UK. adambarlow@doctors.net.uk
FAU - Nicholson, Michael L
AU  - Nicholson ML
FAU - Herbert, Terry P
AU  - Herbert TP
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antibiotics, Antineoplastic)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology/therapeutic use/*toxicity
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Insulin-Secreting Cells/*drug effects
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/pharmacology/therapeutic use/*toxicity
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3717855
EDAT- 2013/07/25 06:00
MHDA- 2013/10/18 06:00
PMCR- 2014/08/01
CRDT- 2013/07/25 06:00
PHST- 2013/07/25 06:00 [entrez]
PHST- 2013/07/25 06:00 [pubmed]
PHST- 2013/10/18 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 62/8/2674 [pii]
AID - 0106 [pii]
AID - 10.2337/db13-0106 [doi]
PST - ppublish
SO  - Diabetes. 2013 Aug;62(8):2674-82. doi: 10.2337/db13-0106.