Evidence for rapamycin toxicity in pancreatic b-Cells and a review of the underlying molecular mechanisms

Barlow, A. D. and Nicholson, M. L. and Herbert, T. P. (2013) Evidence for rapamycin toxicity in pancreatic b-Cells and a review of the underlying molecular mechanisms. Diabetes, 62 (8). pp. 2674-2682. ISSN 0012-1797

Full text not available from this repository.

Item Type:Article
Item Status:Live Archive

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 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 β-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 β-cells. These mechanisms include reductions in β-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.

The macrolide rapamycin is both an antiproliferative and potent immunosuppressant. It is produced commercially as sirolimus and its derivative, everolimus. Sirolimus is predominantly used as an immunosuppressant in transplantation, while everolimus is used mainly as an anticancer agent. Early data suggested little or no diabetogenic effects of rapamycin, particularly in comparison with other immunosuppressants, and it was this that prompted its use in islet cell transplantation. It was also for this reason that rapamycin has been promoted as a second-line therapy for recipients of solid organ transplants who have developed new-onset diabetes after transplantation (NODAT) while taking calcineurin inhibitors (CNIs). However, there is an increasing view that rapamycin has profound effects on pancreatic β-cells, as well as altering insulin sensitivity. Evidence for this arises from in vitro and in vivo experiments and clinical studies. This article will review this evidence and also explore the potential mechanisms of rapamycin toxicity, drawn from experiments of β-cell physiology.

Keywords:Diabetes
Subjects:B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
L Social studies > L510 Health & Welfare
B Subjects allied to Medicine > B990 Subjects Allied to Medicine not elsewhere classified
Divisions:College of Science > School of Pharmacy
Related URLs:
ID Code:28219
Deposited On:01 Nov 2017 08:58

Repository Staff Only: item control page