The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms
Open accessAbstract
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.
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Cites
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
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ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
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International trial of the Edmonton protocol for islet transplantation
Shapiro, A. M. J., Ricordi, C., Hering, B. J., Auchincloss, H., Lindblad, R., Robertson, R. P., Secchi, A., Brendel, M. D., Berney, T., Brennan, D. C., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061267 · Cited by 1,942
Five-Year Follow-Up After Clinical Islet Transplantation
Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R. T., & Shapiro, A. M. J. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2060 · Cited by 1,641
Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., Davis, J. G., Salmon, A. B., Richardson, A., Ahima, R. S., et al. (2012) · Science · doi:10.1126/science.1215135 · Cited by 1,199
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Improvement in outcomes of clinical islet transplantation: 1999–2010
Barton, F. B., Rickels, M. R., Alejandro, R., Hering, B. J., Wease, S., Naziruddin, B., Oberholzer, J., Odorico, J. S., Garfinkel, M. R., Levy, M., et al. (2012) · Diabetes Care · doi:10.2337/dc12-0063 · Cited by 725
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Cited by
Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., Javors, M. A., Li, X., Nadon, N. L., Nelson, J. F., et al. (2014) · Aging Cell · doi:10.1111/acel.12194 · Cited by 621
The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes
Belgardt, B.-F., Ahmed, K., Spranger, M., Latreille, M., Denzler, R., Kondratiuk, N., von Meyenn, F., Villena, F. N., Herrmanns, K., Bosco, D., et al. (2015) · Nature Medicine · doi:10.1038/nm.3862 · Cited by 278
Arriola Apelo, S. I., Neuman, J. C., Baar, E. L., Syed, F. A., Cummings, N. E., Brar, H. K., Pumper, C. P., Kimple, M. E., & Lamming, D. W. (2016) · Aging Cell · doi:10.1111/acel.12405 · Cited by 182
“With significant evidence that rapamycin impairs beta cell function (Barlow et al., 2013), we decided to investigate the impact of rapamycin dosing on islet function more closely.”
BackgroundCole, J. J., Robertson, N. A., Rather, M. I., Thomson, J. P., McBryan, T., Sproul, D., Wang, T., Brock, C., Clark, W., Ideker, T., et al. (2017) · Genome Biology · doi:10.1186/s13059-017-1185-3 · Cited by 182
A chemical approach for global protein knockdown from mice to non-human primates
Sun, X., Wang, J., Yao, X., Zheng, W., Mao, Y., Lan, T., Wang, L., Sun, Y., Zhang, X., Zhao, Q., et al. (2019) · Cell Discovery · doi:10.1038/s41421-018-0079-1 · Cited by 118
Metadata
- Authors
- Barlow, A. D., Nicholson, M. L., & Herbert, T. P.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-07-17
- Volume
- 62
- Issue
- 8
- Pages
- 2674-2682
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2143536481
- Cited by
- 191
- References
- 12
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
