Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo
Open accessAbstract
Insulin resistance is closely related to inflammatory stress and the mammalian target of rapamycin/S6 kinase (mTOR/S6K) pathway. The present study investigated whether rapamycin, a specific inhibitor of mTOR, ameliorates inflammatory stress-induced insulin resistance in vitro and in vivo. We used tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) stimulation in HepG2 hepatocytes, C2C12 myoblasts and 3T3-L1 adipocytes and casein injection in C57BL/6J mice to induce inflammatory stress. Our results showed that inflammatory stress impairs insulin signaling by reducing the expression of total IRS-1, p-IRS-1 (tyr632) and p-AKT (ser473); it also activates the mTOR/S6K signaling pathway both in vitro and in vivo. In vitro, rapamycin treatment reversed inflammatory cytokine-stimulated IRS-1 serine phosphorylation, increased insulin signaling to AKT and enhanced glucose utilization. In vivo, rapamycin treatment also ameliorated the impaired insulin signaling induced by inflammatory stress, but it induced pancreatic β-cell apoptosis, reduced pancreatic β-cell function and enhanced hepatic gluconeogenesis, thereby resulting in hyperglycemia and glucose intolerance in casein-injected mice. Our results indicate a paradoxical effect of rapamycin on insulin resistance between the in vitro and in vivo environments under inflammatory stress and provide additional insight into the clinical application of rapamycin.
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Rapamycin has both beneficial and detrimental effects on metabolism.
“Rapamycin has been shown to have both beneficial and detrimental effects on metabolism, a disparity that has been largely attributed to non-specific effects depending on the time-course of administration [64, 65].”
From AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma (2021) · cites this paper as [64]
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- Authors
- Yang, P., Zhao, Y., Zhao, L., Yuan, J., Chen, Y., Varghese, Z., Moorhead, J. F., Chen, Y., & Ruan, X. Z.
- Affiliations
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Chongqing University of Education (CN)
- The Royal Free Hospital (GB)
- Corresponding author
- Chen, Yaxi
- ORCID
- Venue
- Scientific Reports
- Published
- 2015-10-09
- Volume
- 5
- Issue
- 1
- Pages
- 14959-14959
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4598825
- OpenAlex
- W2399255106
- Cited by
- 21
- References
- 44
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 2 · 2016: 1
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Natural Science Foundation of China (973 Program, 81,390,354, 30971389, 81270493, 2012CB517700, 81400786)
- Major State Basic Research Development Program of China (2012CB517700, 973Program, 2012CB517500)
- National Key Research and Development Program of China (2012CB517500, 2012CB517700)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- rapamycin, insulin resistance, inflammatory stress, IRS-1 serine phosphorylation, insulin signaling, Akt phosphorylation, TNF-α, interleukin-6, pancreatic beta-cell apoptosis, hepatic gluconeogenesis, impaired glucose tolerance, hyperglycemia, hepatocytes, myoblasts, adipocytes
- MeSH terms
- Animals, Cell Line, Humans, Immunosuppressive Agents, Inflammation, Insulin Resistance, Male, Mice, Inbred C57BL, Phosphorylation, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Interleukin-6, Apoptosis, Ribosomal Protein S6 Kinases, Sirolimus, 3T3-L1 Cells, Insulin-Secreting Cells, Proto-Oncogene Proteins c-akt, Mice, Insulin Receptor Substrate Proteins, Hep G2 Cells, TOR Serine-Threonine Kinases
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