Skip to main content

Advertisement

SpringerLink
Log in

Irisin alleviates FFA induced β-cell insulin resistance and inflammatory response through activating PI3K/AKT/FOXO1 signaling pathway

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Type 2 diabetes mellitus is characterized by insulin resistance and β-cell dysfunction. Elevated free fatty acids-induced lipotoxicity may play a vital role in the pathogenesis of β-cell insulin resistance. Exercise-stimulated myokine irisin has been reported to be closely related to T2DM. However, its function on β-cell insulin signaling and the underlying mechanisms are only partially elucidated as yet.

Methods

High-fat diet-fed C57BL/6J mice and palmitic acid-treated MIN6 cell models were utilized as lipotoxic models. Factors associated with β-cell insulin signaling transduction and inflammatory responses were assessed in these models. Furthermore, the role of irisin in β-cells and the underlying mechanisms were also explored.

Results

Irisin effectively decreased lipid levels in HFD mice, enhanced glucose-stimulated insulin secretion and nullified the expressions of inflammatory cytokines in vivo and in vitro experiments. Moreover, irisin improved PI3K/AKT insulin signaling pathway and inhibited TLR4/NF-κB inflammatory signaling pathway in both islets of HFD mice and PA-treated MIN6 cells. Mechanistic analysis indicated that FOXO1 might serve as a bridge between the two pathways.

Conclusion

Irisin alleviates lipotoxicity-induced β-cell insulin resistance and inflammatory response through the activation of PI3K/AKT/FOXO1 signaling pathways and the inhibition of TLR4/NF-κB signaling pathways. Irisin might provide a novel therapeutic strategy for T2DM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. D. Accili, Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67(9), 1701–1709 (2018)

    Article  CAS  Google Scholar 

  2. R.N. Kulkarni, J.C. Bruning, J.N. Winnay, C. Postic, M.A. Magnuson, C.R. Kahn, Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96(3), 329–339 (1999)

    Article  CAS  Google Scholar 

  3. M.I. McCarthy, Genomics, type 2 diabetes, and obesity. N. Engl. J. Med 363(24), 2339–2350 (2010)

    Article  CAS  Google Scholar 

  4. T. Kubota, N. Kubota, T. Kadowaki, Imbalanced insulin actions in obesity and type 2 diabetes: key mouse models of insulin signaling pathway. Cell Metab. 25(4), 797–810 (2017)

    Article  CAS  Google Scholar 

  5. Y.X. Li, T.T. Han, Y. Liu, S. Zheng, Y. Zhang, W. Liu, Y.M. Hu, Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice. Atherosclerosis 239(1), 276–282 (2015)

    Article  CAS  Google Scholar 

  6. S. Zheng, X. Ren, T. Han, Y. Chen, H. Qiu, W. Liu, Y. Hu, Fenofibrate attenuates fatty acid-induced islet beta-cell dysfunction and apoptosis via inhibiting the NF-kappaB/MIF dependent inflammatory pathway. Metabolism 77, 23–38 (2017)

    Article  CAS  Google Scholar 

  7. A. Sampath Kumar, A.G. Maiya, B.A. Shastry, K. Vaishali, N. Ravishankar, A. Hazari, S. Gundmi, R. Jadhav, Exercise and insulin resistance in type 2 diabetes mellitus: a systematic review and meta-analysis. Ann. Phys. Rehabil. Med 62(2), 98–103 (2019)

    Article  CAS  Google Scholar 

  8. P. Bostrom, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach, E.A. Bostrom, J.H. Choi, J.Z. Long, S. Kajimura, M.C. Zingaretti, B.F. Vind, H. Tu, S. Cinti, K. Hojlund, S.P. Gygi, B.M. Spiegelman, A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481(7382), 463–468 (2012)

    Article  Google Scholar 

  9. T. Kurdiova, M. Balaz, M. Vician, D. Maderova, M. Vlcek, L. Valkovic, M. Srbecky, R. Imrich, O. Kyselovicova, V. Belan, I. Jelok, C. Wolfrum, I. Klimes, M. Krssak, E. Zemkova, D. Gasperikova, J. Ukropec, B. Ukropcova, Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies. J. Physiol. 592(5), 1091–1107 (2014)

    Article  CAS  Google Scholar 

  10. J.J. Liu, M.D. Wong, W.C. Toy, C.S. Tan, S. Liu, X.W. Ng, S. Tavintharan, C.F. Sum, S.C. Lim, Lower circulating irisin is associated with type 2 diabetes mellitus. J. Diabetes Complications 27(4), 365–369 (2013)

    Article  Google Scholar 

  11. C. Zhang, Z. Ding, G. Lv, J. Li, P. Zhou, J. Zhang, Lower irisin level in patients with type 2 diabetes mellitus: a case-control study and meta-analysis. J. Diabetes 8(1), 56–62 (2016)

    Article  CAS  Google Scholar 

  12. B. Garcia-Fontana, R. Reyes-Garcia, S. Morales-Santana, V. Avila-Rubio, A. Munoz-Garach, P. Rozas-Moreno, M. Munoz-Torres, Relationship between myostatin and irisin in type 2 diabetes mellitus: a compensatory mechanism to an unfavourable metabolic state? Endocrine 52(1), 54–62 (2016)

    Article  CAS  Google Scholar 

  13. B.L. Guilford, J.C. Parson, C.W. Grote, S.N. Vick, J.M. Ryals, D.E. Wright, Increased FNDC5 is associated with insulin resistance in high fat-fed mice. Physiol. Rep. 5, 13 (2017)

    Article  Google Scholar 

  14. A. Natalicchio, N. Marrano, G. Biondi, R. Spagnuolo, R. Labarbuta, I. Porreca, A. Cignarelli, M. Bugliani, P. Marchetti, S. Perrini, L. Laviola, F. Giorgino, The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic beta-Cell Survival and Insulin Secretion. Diabetes 66(11), 2849–2856 (2017)

    Article  CAS  Google Scholar 

  15. Y. Zhang, R. Li, Y. Meng, S. Li, W. Donelan, Y. Zhao, L. Qi, M. Zhang, X. Wang, T. Cui, L.J. Yang, D. Tang, Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63(2), 514–525 (2014)

    Article  CAS  Google Scholar 

  16. J.E. Dominy, P. Puigserver, Nuclear FoxO1 inflames insulin resistance. EMBO J. 29(24), 4068–4069 (2010)

    Article  CAS  Google Scholar 

  17. Y. Mirdamadi, A. Thielitz, A. Wiede, A. Goihl, E. Papakonstantinou, R. Hartig, C.C. Zouboulis, D. Reinhold, L. Simeoni, U. Bommhardt, S. Quist, H. Gollnick, Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase/Akt/FoxO1 pathway in SZ95 sebocytes in vitro. Mol. Cell Endocrinol. 415, 32–44 (2015)

    Article  CAS  Google Scholar 

  18. J.C. Ansarullah, F.F. Far, S. Homberg, K. Wissmiller, F.G. von Hahn, A. Raducanu, S. Schirge, M. Sterr, S. Bilekova, J. Siehler, J. Wiener, L. Oppenlander, A. Morshedi, A. Bastidas-Ponce, G. Collden, M. Irmler, J. Beckers, A. Feuchtinger, M. Grzybek, C. Ahlbrecht, R. Feederle, O. Plettenburg, T.D. Muller, M. Meier, M.H. Tschop, U. Coskun, H. Lickert, Inceptor counteracts insulin signalling in beta-cells to control glycaemia. Nature 590(7845), 326–331 (2021)

    Article  CAS  Google Scholar 

  19. J. Bai, S. Zheng, D. Jiang, T. Han, Y. Li, Y. Zhang, W. Liu, Y. Cao, Y. Hu, Oxidative stress contributes to abnormal glucose metabolism and insulin sensitivity in two hyperlipidemia models. Int J. Clin. Exp. Pathol. 8(10), 13193–13200 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. K. Eguchi, I. Manabe, Y. Oishi-Tanaka, M. Ohsugi, N. Kono, F. Ogata, N. Yagi, U. Ohto, M. Kimoto, K. Miyake, K. Tobe, H. Arai, T. Kadowaki, R. Nagai, Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab. 15(4), 518–533 (2012)

    Article  CAS  Google Scholar 

  21. L. Marselli, M. Bugliani, M. Suleiman, F. Olimpico, M. Masini, M. Petrini, U. Boggi, F. Filipponi, F. Syed, P. Marchetti, beta-Cell inflammation in human type 2 diabetes and the role of autophagy. Diabetes Obes. Metab. 15(Suppl 3), 130–136 (2013)

    Article  CAS  Google Scholar 

  22. J.A. Ehses, A. Perren, E. Eppler, P. Ribaux, J.A. Pospisilik, R. Maor-Cahn, X. Gueripel, H. Ellingsgaard, M.K. Schneider, G. Biollaz, A. Fontana, M. Reinecke, F. Homo-Delarche, M.Y. Donath, Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9), 2356–2370 (2007)

    Article  CAS  Google Scholar 

  23. M.J. Butcher, D. Hallinger, E. Garcia, Y. Machida, S. Chakrabarti, J. Nadler, E.V. Galkina, Y. Imai, Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes. Diabetologia 57(3), 491–501 (2014)

    Article  CAS  Google Scholar 

  24. J.J. Kim, D.D. Sears. TLR4. and Insulin Resistance. Gastroenterol Res Pract. 2010, 212563 (2010)

  25. W. Link, Introduction to FOXO Biology. Methods Mol. Biol. 1890, 1–9 (2019)

    Article  CAS  Google Scholar 

  26. T. Kitamura, J. Nakae, Y. Kitamura, Y. Kido, W.H. Biggs III, C.V. Wright, M.F. White, K.C. Arden, D. Accili, The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J. Clin. Investig. 110(12), 1839–1847 (2002)

    Article  CAS  Google Scholar 

  27. S.J. Mutt, G.S. Raza, M.J. Makinen, S. Keinanen-Kiukaanniemi, M.R. Jarvelin, K.H. Herzig, Vitamin D deficiency induces insulin resistance and re-supplementation attenuates hepatic glucose output via the PI3K-AKT-FOXO1 mediated pathway. Mol. Nutr. Food Res. 64(1), e1900728 (2020)

    Article  Google Scholar 

  28. A. Clark, M.R. Nilsson, Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes? Diabetologia 47(2), 157–169 (2004)

    Article  CAS  Google Scholar 

  29. L. Chen, B. Gao, Y. Zhang, H. Lu, X. Li, L. Pan, L. Yin, X. Zhi, PAR2 promotes M1 macrophage polarization and inflammation via FOXO1 pathway. J. Cell Biochem. 120(6), 9799–9809 (2019)

    Article  CAS  Google Scholar 

  30. Y. Akgul Balaban, N. Yilmaz, M. Kalayci, M. Unal, T. Turhan, Irisin and Chemerin Levels in Patients with Type 2 Diabetes Mellitus. Acta Endocrinol. 15(4), 442–446 (2019)

    CAS  Google Scholar 

  31. M.P. Jedrychowski, C.D. Wrann, J.A. Paulo, K.K. Gerber, J. Szpyt, M.M. Robinson, K.S. Nair, S.P. Gygi, B.M. Spiegelman, Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metab. 22(4), 734–740 (2015)

    Article  CAS  Google Scholar 

  32. M. Yang, P. Chen, H. Jin, X. Xie, T. Gao, L. Yang, X. Yu, Circulating levels of irisin in middle-aged first-degree relatives of type 2 diabetes mellitus—correlation with pancreatic beta-cell function. Diabetol. Metab. Syndr. 6(1), 133 (2014)

    Article  Google Scholar 

  33. X.Q. Xiong, D. Chen, H.J. Sun, L. Ding, J.J. Wang, Q. Chen, Y.H. Li, Y.B. Zhou, Y. Han, F. Zhang, X.Y. Gao, Y.M. Kang, G.Q. Zhu, FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochim Biophys. Acta. 1852(9), 1867–1875 (2015)

    Article  CAS  Google Scholar 

  34. M.J. Park, D.I. Kim, J.H. Choi, Y.R. Heo, S.H. Park, New role of irisin in hepatocytes: the protective effect of hepatic steatosis in vitro. Cell Signal 27(9), 1831–1839 (2015)

    Article  CAS  Google Scholar 

  35. D. Zhu, H. Wang, J. Zhang, X. Zhang, C. Xin, F. Zhang, Y. Lee, L. Zhang, K. Lian, W. Yan, X. Ma, Y. Liu, L. Tao, Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. J. Mol. Cell Cardiol. 87, 138–147 (2015)

    Article  CAS  Google Scholar 

  36. J.Y. Huh, F. Dincer, E. Mesfum, C.S. Mantzoros, Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J. Obes. 38(12), 1538–1544 (2014)

    Article  CAS  Google Scholar 

  37. N. Marrano, G. Biondi, A. Borrelli, A. Cignarelli, S. Perrini, L. Laviola, F. Giorgino, A. Natalicchio, Irisin and incretin hormones: similarities, differences, and implications in type 2 diabetes and obesity. Biomolecules 11, 2 (2021)

    Article  Google Scholar 

Download references

Funding

This study was supported by Shanghai Sailing Program (19YF1428600), China Postdoctoral Science Foundation (2019M651588) and Cultivation Program for the National Natural Science Foundation of China from Shanghai Tenth People’s Hospital (04. 03. 18. 081).

Author information

Authors and Affiliations

  1. School of Medicine, Shanghai University, Shanghai, 200444, China

    Shuang Zheng

  2. Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China

    Shuang Zheng, Ningxin Chen & Yaomin Hu

  3. School of Stomatology, Wenzhou Medical University, Wenzhou, 325000, China

    Xingjian Kang

  4. Department of Orthopedics, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China

    Sheng Shi

Authors
  1. Shuang Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ningxin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xingjian Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yaomin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sheng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SZ and SS contributed to the conception and design of the study; SZ, NC and XK contributed to perform the experiments and analyzed data. YH edited the manuscript. SZ, NC and SS contributed to the analysis and interpretation of the data. All authors revised and approved the final manuscript.

Corresponding author

Correspondence to Sheng Shi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

All experiments were approved by the Ethics Committee of Shanghai University (ECSHU).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, S., Chen, N., Kang, X. et al. Irisin alleviates FFA induced β-cell insulin resistance and inflammatory response through activating PI3K/AKT/FOXO1 signaling pathway. Endocrine 75, 740–751 (2022). https://doi.org/10.1007/s12020-021-02875-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02875-y

Keywords

Search

Navigation