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- Title
Evidence for Rapamycin Toxicity in Pancreatic β-Cell and a Review of the Underlying Molecular Mechanisms.
- Authors
Barlow, Adam D.; Nicholson, Michael L.; Herbert, Terry P.
- Abstract
Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal trans plantation, 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 β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamyci (mTOR). This Review describes the complex mTOR signaling path ways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cel 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.
- Subjects
RAPAMYCIN; DRUG toxicity; PANCREATIC beta cells; INSULIN resistance; BIOCHEMICAL mechanism of action; CELLULAR signal transduction; MESSENGER RNA; CELL proliferation
- Publication
Diabetes, 2013, Vol 62, Issue 8, p2674
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-0106