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image of Inhibition of Circular RNA 006029 Alleviates Pancreatic β-Cell Injury Through the AKT/mTOR Signaling Pathway
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Abstract

Introduction

Type 1 Diabetes Mellitus (T1DM) is characterized by the damage of pancreatic β-cells induced by autoimmune responses. Circular RNAs (circRNAs) play important regulatory roles in the pathogenesis of T1DM, but the underlying mechanisms require further substantiation.

Methods

This study focused on a novel circRNA, circ006029, to investigate its regulation on β-cell damage. The potential involvement of circ006029 in β-cell proliferation, apoptosis, autophagy, and inflammatory responses was investigated using CCK-8, qRT-PCR, and immunoblot assays. The utilization of a cytokine mixture, and specific molecular blockers Rapamycin and Capivasertib, was applied to investigate the pathway by which circ006029 regulates β-cell damage. Transcriptome sequencing and bioinformatics analysis were conducted to explore differentially expressed mRNAs related to circ006029 regulation.

Results

The expression of circ006029 was observed to increase in damaged MIN6 cells. The inhibition of circ006029 serves a protective role in MIN6 β-cells by promoting β- cell proliferation and attenuating apoptosis. circ006029-knockdown could augment β- cell autophagy and attenuate apoptosis through the AKT/mTOR signaling pathway. Moreover, circ006029 might be involved in the inflammatory response of MIN6 cells.

Discussion

The knockdown of circ006029 was demonstrated to alleviate β-cell inflammation and reduce cell apoptosis. The promotion of β-cell proliferation and heightened autophagy also substantiated the protective effects of circ006029 silence. Furthermore, we also proved that circ006029 might contribute to autophagy the AKT/mTOR signaling pathway. All the results implied that the presence of circ006029 may drive a detrimental regulatory role in pancreatic β-cells. This may provide valuable evidence that circ006029 might be a potential target for alleviating β-cell damage in T1DM and rebuilding β-cell function.

Conclusion

These findings suggest that circ006029 may serve a detrimental role in β- cell damage, which provides new ideas for exploring the mechanism of β-cell damage in early insulitis in T1DM.

© 2026 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2026-02-04
2026-02-19

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References

  1. Bottazzo G. Florin-Christensen A. Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 1974 304 7892 1279 1283 10.1016/S0140‑6736(74)90140‑8 4139522
    [Google Scholar]
  2. Maccuish A.C. Irvine W.J. Barnes E.W. Duncan L.J.P. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet 1974 304 7896 1529 1531 10.1016/S0140‑6736(74)90281‑5 4140978
    [Google Scholar]
  3. Tomita T. Apoptosis of pancreatic β-cells in type 1 diabetes. Bosn. J. Basic Med. Sci. 2017 17 3 183 193 10.17305/bjbms.2017.1961 28368239
    [Google Scholar]
  4. Pan X. Kaminga A.C. Kinra S. Wen S.W. Liu H. Tan X. Liu A. Chemokines in type 1 diabetes mellitus. Front. Immunol. 2022 12 690082 10.3389/fimmu.2021.690082 35242125
    [Google Scholar]
  5. Levine B. Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008 132 1 27 42 10.1016/j.cell.2007.12.018 18191218
    [Google Scholar]
  6. Lambelet M. Terra L.F. Fukaya M. Meyerovich K. Labriola L. Cardozo A.K. Allagnat F. Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis. Cell Death Dis. 2018 9 2 96 10.1038/s41419‑017‑0121‑5 29367588
    [Google Scholar]
  7. Motterle A. Gattesco S. Caille D. Meda P. Regazzi R. Involvement of long non-coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice. Diabetologia 2015 58 8 1827 1835 10.1007/s00125‑015‑3641‑5 26037202
    [Google Scholar]
  8. Huang Y.N. Chiang S.L. Lin Y.J. Liu S.C. Li Y.H. Liao Y.C. Lee M.R. Su P.H. Tsai F.J. Hung H.C. Wang C.H. Long, noncoding RNA SRA induces apoptosis of β-cells by promoting the IRAK1/LDHA/lactate pathway. Int. J. Mol. Sci. 2021 22 4 1720 10.3390/ijms22041720 33572095
    [Google Scholar]
  9. Pang H. Fan W. Shi X. Li J. Wang Y. Luo S. Lin J. Huang G. Li X. Xie Z. Zhou Z. Characterization of lncRNA profiles of plasma-derived exosomes from type 1 diabetes mellitus. Front. Endocrinol. 2022 13 822221 10.3389/fendo.2022.822221 35634499
    [Google Scholar]
  10. Roggli E. Gattesco S. Caille D. Briet C. Boitard C. Meda P. Regazzi R. Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice. Diabetes 2012 61 7 1742 1751 10.2337/db11‑1086 22537941
    [Google Scholar]
  11. Guay C. Kruit J.K. Rome S. Menoud V. Mulder N.L. Jurdzinski A. Mancarella F. Sebastiani G. Donda A. Gonzalez B.J. Jandus C. Bouzakri K. Pinget M. Boitard C. Romero P. Dotta F. Regazzi R. Lymphocyte-derived exosomal micrornas promote pancreatic β cell death and may contribute to type 1 diabetes development. Cell Metab. 2019 29 2 348 361.e6 10.1016/j.cmet.2018.09.011 30318337
    [Google Scholar]
  12. Zheng Y. Wang Z. Tu Y. Shen H. Dai Z. Lin J. Zhou Z. miR-101a and miR-30b contribute to inflammatory cytokine-mediated β-cell dysfunction. Lab. Invest. 2015 95 12 1387 1397 10.1038/labinvest.2015.112 26367486
    [Google Scholar]
  13. Stoll L. Sobel J. Rodriguez-Trejo A. Guay C. Lee K. Venø M.T. Kjems J. Laybutt D.R. Regazzi R. Circular RNAs as novel regulators of β-cell functions in normal and disease conditions. Mol. Metab. 2018 9 69 83 10.1016/j.molmet.2018.01.010 29396373
    [Google Scholar]
  14. Zhang C. Han X. Yang L. Fu J. Sun C. Huang S. Xiao W. Gao Y. Liang Q. Wang X. Luo F. Lu W. Zhou Y. Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus. Theranostics 2020 10 24 10908 10924 10.7150/thno.48264 33042261
    [Google Scholar]
  15. Wang Z. Deng C. Zheng Y. Involvement of circRNAs in proinflammatory cytokines-mediated β-cell dysfunction. Mediators Inflamm. 2021 2021 1 5566453 10.1155/2021/5566453 34054343
    [Google Scholar]
  16. Huang K. Inhibition of circular RNA 006029 alleviates pancreatic β-cell injury through the AKT/mTOR signaling pathway. Res. Sq. 2024 10.21203/rs.3.rs‑4851054/v1
    [Google Scholar]
  17. Wang Z. Huang K. Xu J. Liu J. Zheng Y. Insights from dysregulated mRNA expression profile of β-cells in response to proinflammatory cytokines. J. Immunol. Res. 2022 2022 1 9 10.1155/2022/4542487 35103245
    [Google Scholar]
  18. Kim Y.C. Guan K.L. mTOR: A pharmacologic target for autophagy regulation. J. Clin. Invest. 2015 125 1 25 32 10.1172/JCI73939 25654547
    [Google Scholar]
  19. Wang S. Zhang Y. Wang M. Zhai Z. Tan Y. Xu W. Ren X. Hu X. Mo J. Liu J. Yang Y. Chen D. Jiang B. Huang H. Huang J. Xiong K. Noncanonical feedback loop between "RIP3-MLKL" and "4EBP1-eIF4E" promotes neuronal necroptosis. MedComm 2025 6 3 e70107 10.1002/mco2.70107 39974664
    [Google Scholar]
  20. Davies B.R. Greenwood H. Dudley P. Crafter C. Yu D.H. Zhang J. Li J. Gao B. Ji Q. Maynard J. Ricketts S.A. Cross D. Cosulich S. Chresta C.C. Page K. Yates J. Lane C. Watson R. Luke R. Ogilvie D. Pass M. Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 2012 11 4 873 887 10.1158/1535‑7163.MCT‑11‑0824‑T 22294718
    [Google Scholar]
  21. Zhang Q. Lenardo M.J. Baltimore D. 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell 2017 168 1-2 37 57 10.1016/j.cell.2016.12.012 28086098
    [Google Scholar]
  22. Brain O. Allan P. Simmons A. NOD2-mediated autophagy and Crohn disease. Autophagy 2010 6 3 412 414 10.4161/auto.6.3.11389 20212355
    [Google Scholar]
  23. Jia J. Claude-Taupin A. Gu Y. Choi S.W. Peters R. Bissa B. Mudd M.H. Allers L. Pallikkuth S. Lidke K.A. Salemi M. Phinney B. Mari M. Reggiori F. Deretic V. Galectin-3 coordinates a cellular system for lysosomal repair and removal. Dev. Cell 2020 52 1 69 87.e8 10.1016/j.devcel.2019.10.025 31813797
    [Google Scholar]
  24. Wu J.L. Wu H.Y. Tsai D.Y. Chiang M.F. Chen Y.J. Gao S. Lin C.C. Lin C.H. Khoo K.H. Chen Y.J. Lin K.I. Temporal regulation of Lsp1 O-GlcNAcylation and phosphorylation during apoptosis of activated B cells. Nat. Commun. 2016 7 1 12526 10.1038/ncomms12526 27555448
    [Google Scholar]
  25. Quan W. Jo E.K. Lee M.S. Role of pancreatic β-cell death and inflammation in diabetes. Diabetes Obes. Metab. 2013 15 s3 141 151 10.1111/dom.12153 24003931
    [Google Scholar]
  26. FDA approves first cellular therapy to treat patients with type 1 diabetes. 2023 Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first- cellular-therapy-treat-patients-type-1-diabetes
  27. FDA approves first drug that can delay onset of type 1 diabetes. 2023 Available from: https://www.fda.gov/media/164864/download
  28. Yin D. Zhang E. You L. Wang N. Wang L. Jin F. Zhu Y. Cao L. Yuan Q. De W. Tang W. Downregulation of lncRNA TUG1 affects apoptosis and insulin secretion in mouse pancreatic β cells. Cell. Physiol. Biochem. 2015 35 5 1892 1904 10.1159/000373999 25871529
    [Google Scholar]
  29. Li Z. Hao S. Yin H. Gao J. Yang Z. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice. Behav. Brain Res. 2016 305 265 277 10.1016/j.bbr.2016.03.023 26971628
    [Google Scholar]
  30. Salas-Pérez F. Codner E. Valencia E. Pizarro C. Carrasco E. Pérez-Bravo F. MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology 2013 218 5 733 737 10.1016/j.imbio.2012.08.276 22999472
    [Google Scholar]
  31. Lee Y. Kim J. Park K. Lee M.S. β-cell autophagy: Mechanism and role in β-cell dysfunction. Mol. Metab. 2019 27 S92 S103 10.1016/j.molmet.2019.06.014 31500836
    [Google Scholar]
  32. He Z. Cai K. Zeng Z. Lei S. Cao W. Li X. Autophagy-associated circRNA circATG7 facilitates autophagy and promotes pancreatic cancer progression. Cell Death Dis. 2022 13 3 233 10.1038/s41419‑022‑04677‑0 35288538
    [Google Scholar]
  33. Bai C Yang W Lu Y Wei W Li Z Zhang L Identification of circular RNAs regulating islet β-cell autophagy in type 2 diabetes mellitus. Biomed Res Int 2019 2019 4128315 10.1155/2019/4128315 31815137
    [Google Scholar]
  34. Xu J. Xia Y. Zhang H. Guo H. Feng K. Zhang C. Overexpression of long non-coding RNA H19 promotes invasion and autophagy via the PI3K/AKT/mTOR pathways in trophoblast cells. Biomed. Pharmacother. 2018 101 691 697 10.1016/j.biopha.2018.02.134 29522949
    [Google Scholar]
  35. Gao W. Guo H. Niu M. Zheng X. Zhang Y. Xue X. Bo Y. Guan X. Li Z. Guo Y. He L. Zhang Y. Li L. Cao J. Wu Y. circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway. Mol. Cancer 2020 19 1 166 10.1186/s12943‑020‑01279‑2 33234130
    [Google Scholar]
  36. Lawlor M.A. Alessi D.R. PKB/Akt: A key mediator of cell proliferation, survival and insulin responses? J. Cell Sci 2001 114 Pt 16 2903 2910 10.1242/jcs.114.16.2903 11686294
    [Google Scholar]
  37. Hahn-Windgassen A. Nogueira V. Chen C.C. Skeen J.E. Sonenberg N. Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. 2005 280 37 32081 32089 10.1074/jbc.M502876200 16027121
    [Google Scholar]
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Inhibition of Circular RNA 006029 Alleviates Pancreatic β-Cell Injury Through the AKT/mTOR Signaling Pathway
Bentham Science Publishers ; https://doi.org/10.2174/0109298673401334251201092718
/content/journals/cmc/10.2174/0109298673401334251201092718
/content/journals/cmc/10.2174/0109298673401334251201092718
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  • Article Type:     Research Article
Keywords: Rapamycin ; mTOR ; AKT ; Type 1 diabetes ; pancreatic β-cell injury ; circular RNA 006029

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