ArticleDiabetologia2012
Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).
Article in Diabetologia, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 74 citations in OpenAlex.
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- Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics.Biomedicines · 2026Review
- Tunable Chemical and Optical Control of ER-Plasma Membrane Contact Site Geometry and Dynamics with High-Fidelity Visualization.bioRxiv : the preprint server for biology · 2026Article
- Molecular diagnostics in pancreas transplantation: past, present, and future.Frontiers in molecular biosciences · 2026Review
- Diabetic Kidney Disease in Post-Kidney Transplant Patients.Journal of clinical medicine · 2024Review
- Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation.Frontiers in immunology · 2024Review
- Protein Kinases in Obesity, and the Kinase-Targeted Therapy.Advances in experimental medicine and biology · 2024Review
- Advanced Delivery Strategies for Immunotherapy in Type I Diabetes Mellitus.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2023Review
- mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation.Frontiers in medicine · 2023Review
- Kaempferol sensitizes cell proliferation inhibition in oxaliplatin-resistant colon cancer cells.Archives of pharmacal research · 2021Article
- Dissecting the biology of mTORC1 beyond rapamycin.Science signaling · 2021Article
- Regulation and metabolic functions of mTORC1 and mTORC2.Physiological reviews · 2021Review
- Review
- mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?Frontiers of medicine · 2021Review
- Roles of mTOR in Diabetic Kidney Disease.Antioxidants (Basel, Switzerland) · 2021Article
- A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis.Function (Oxford, England) · 2021Article
- In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors.Molecules (Basel, Switzerland) · 2020Article
- Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells.Investigational new drugs · 2019Article
- The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts.Biology open · 2018Article
- Everolimus Directly Suppresses Insulin Secretion Independently of Cell Growth Inhibition.Journal of the Endocrine Society · 2018Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
aims/hypothesisRapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells.
methodsExperiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB.
resultsRapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. CONCLUSIONS/
interpretationThis report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.
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