DOI QR코드

DOI QR Code

A Review on the Role of Irisin in Insulin Resistance and Type 2 Diabetes Mellitus

  • Gizaw, Mamo ;
  • Anandakumar, Pandi ;
  • Debela, Tolessa
  • Received : 2017.10.10
  • Accepted : 2017.11.03
  • Published : 2017.12.31

Abstract

Irisin is a novel hormone like polypeptide that is cleaved and secreted by an unknown protease from fibronectin type III domain-containing protein 5 (FNDC5), a membrane-spanning protein and which is highly expressed in skeletal muscle, heart, adipose tissue, and liver. Since its discovery in 2012, it has been the subject of many researches due to its potent physiological role. It is believed that understanding irisin's function may be the key to comprehend many diseases and their development. Irisin is a myokine that leads to increased energy expenditure by stimulating the 'browning' of white adipose tissue. In the first description of this hormone, increased levels of circulating irisin, which is cleaved from its precursor fibronectin type III domain-containing protein 5, were associated with improved glucose homeostasis by reducing insulin resistance. Irisin is a powerful messenger, sending the signal to determine the function of specific cells, like skeletal muscle, liver, pancreas, heart, fat and the brain. The action of irisin on different targeted tissues or organs in human being has revealed its physiological functions for promoting health or executing the regulation of variety of metabolic diseases. Numerous studies focus on the association of irisin with metabolic diseases which has gained great interest as a potential new target to combat type 2 diabetes mellitus and insulin resistance. Irisin is found to improve insulin resistance and type 2 diabetes by increasing sensitization of the insulin receptor in skeletal muscle and heart by improving hepatic glucose and lipid metabolism, promoting pancreatic ${\beta}$ cell functions, and transforming white adipose tissue to brown adipose tissue. This review is a thoughtful attempt to summarize the current knowledge of irisin and its effective role in mediating metabolic dysfunctions in insulin resistance and type 2 diabetes mellitus.

Keywords

Irisin;insulin receptor;insulin resistance;metabolic diseases;metabolic dysfunctions;type 2 diabetes

References

  1. Liu JJ, Wong MD, Toy WC, Tan CS, Liu S, Ng XW, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications 2013; 27(4):365-9. https://doi.org/10.1016/j.jdiacomp.2013.03.002
  2. Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung KE, Tsoukas MA, et al. CS. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab. 2013; 98(12): 4899-907. https://doi.org/10.1210/jc.2013-2373
  3. Park MJ, Kim D Il, Choi JH, Heo YR, Park SH. New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro. Cell Signal 2015; 27(9):1831-9. https://doi.org/10.1016/j.cellsig.2015.04.010
  4. Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi, et al. Irisin stimulates browning of white adipocytes through mitogen activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 2014; 63(2):514-25. https://doi.org/10.2337/db13-1106
  5. Liu S, Du F, Li X, Wang M, Duan R, Zhang J, et al. Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic $\beta$ cells. PLoS One 2017; 12(4):e0175498. https://doi.org/10.1371/journal.pone.0175498
  6. Bostrom P, Wu J, Jedrychowski M.P, Korde A, Ye L, Lo J.C, et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463-8. https://doi.org/10.1038/nature10777
  7. Kozakova M, Balkau B, Morizzo C. Physical activity, adiponectin, and cardiovascular structure and function. Heart Vessels 2013; 28(1): 91-100. https://doi.org/10.1007/s00380-011-0215-4
  8. Chen N, Li Q, Liu J, Jia S. Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review. Diabetes Metab Res Rev. 2016;32(1):51-9. https://doi.org/10.1002/dmrr.2660
  9. Roca-Rivada A, Castelao C, Senin LL. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One 2013; 8(4): e60563. https://doi.org/10.1371/journal.pone.0060563
  10. Schumacher MA, Chinnam N, Ohashi T, Shah RS, Erickson HP. The structure of irisin reveals a novel intersubunit $\beta$-sheet fibronectin (FNIII) dimer: implications for receptor activation. J Biol Chem. 2013;22:288(47):33738-44. https://doi.org/10.1074/jbc.M113.516641
  11. Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, et al. The effects of acute and chronic exercise on PGC-1alpha, irisin and browning of subcutaneous adipose tissue in humans. FEBS J. 2014; 281(3): 739–49. https://doi.org/10.1111/febs.12619
  12. Xu B. BDNF (I)rising from exercise. Cell Metab. 2013; 18(5): 612–4. https://doi.org/10.1016/j.cmet.2013.10.008
  13. Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F, et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab. 2013; 98(4): 769–78. https://doi.org/10.1210/jc.2012-2270
  14. Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, et al. Irisin Stimulates Browning of White Adipocytes through Mitogen-Activated Protein Kinase p38 MAP Kinase and ERK MAP Kinase Signaling. Diabetes 2014;63(2):514-25. https://doi.org/10.2337/db13-1106
  15. Rizk FH, Elshweikh SA, Abd El-Naby AY. Irisin levels in relation to metabolic and liver functions in Egyptian patients with metabolic syndrome. Can J Physiol Pharmacol. 2016; 94(4):359-62. https://doi.org/10.1139/cjpp-2015-0371
  16. Jung, UJ, Choi, MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci.2014; 15 (4): 6184–6223. https://doi.org/10.3390/ijms15046184
  17. Liu JJ, Wong MD, Toy WC, Tan CS, Liu S, Ng XW, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications. 2013; 27(4):365-9. https://doi.org/10.1016/j.jdiacomp.2013.03.002
  18. Gouni-Berthold I, Berthold HK, Huh JY, Berman R, Spenrath N, Krone W, et al. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One 2013; 8:e72858. https://doi.org/10.1371/journal.pone.0072858
  19. Kurdiova T, Balaz M, Vician M, Maderova D, Vlcek M, Valkovic L, et al. 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. 2014; 592 (5):1091–107. https://doi.org/10.1113/jphysiol.2013.264655
  20. Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008; 9(5):367–77 https://doi.org/10.1038/nrm2391
  21. Castillo-Quan JI. From white to brown fat through the $PGC-1{\alpha}$-dependent myokine irisin: implications for diabetes and obesity. Dis Model Mech. 2012; 5(3): 293-5. https://doi.org/10.1242/dmm.009894
  22. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Belen CA. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One.2013; 8(4):e60563. https://doi.org/10.1371/journal.pone.0060563
  23. Yan B, Shi X, Zhang H, Pan L, Ma Z, Liu S, et al. Association of serum irisin with metabolic syndrome in obese Chinese adults. PLoS One 2014; 9(4):e94235. https://doi.org/10.1371/journal.pone.0094235
  24. Xiong XQ, Chen D, Sun HJ, Ding L, Wang JJ, Chen Q, et al. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochim et Biophysica Acta. 2015; 1867-75.
  25. Chen JQ, Huang YY, Gusdon AM, Qu S. Irisin: a new molecular marker and target in metabolic disorder. Lipids in Health and Disease 2015; 14(2): 1476-511.
  26. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates $PGC-1{\alpha}$ and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012; 26: 271-81. https://doi.org/10.1101/gad.177857.111
  27. Liu JJ, Liu S, Wong MD, Tan CS, Tavintharan S, Sum CF, et al. Relationship between circulating irisin, renal function and body composition in type 2 diabetes. J Diabetes Complications 2014; 28(2):208-13. https://doi.org/10.1016/j.jdiacomp.2013.09.011
  28. Park KH, Zaichenko L, Brinkoetter M, Thankkar B, Shain-Efe A, Joung KE, et al Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab. 2013; 98 (12):4899-907. https://doi.org/10.1210/jc.2013-2373
  29. Tang H, Yu R, Liu S, Huwatibieke B, Li Z, et al. Irisin inhibits hepatic cholesterol synthesis via AMPK-SREBP2 signaling. EBioMedicine 2016;139-48.
  30. Liu TY, Shi CX, Gao R, Sun HJ, Xiong XQ, Ding L, et al. Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin Sci(Lond). 2015; 129: 839–50. https://doi.org/10.1042/CS20150009
  31. Liu S, Du F, Li X, Wang M, Duan R Zhang J, et al. Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic $\beta$ cells. PLoS One.2017; 12(4):e0175498 https://doi.org/10.1371/journal.pone.0175498
  32. Song H, Wu F, Zhang Y, Zhang Y, Wang F, Jiang M, et al. Irisin promotes human umbilical vein endothelial cell proliferation through the ERK signaling pathway and partly suppresses high glucose-induced apoptosis. PLoS One 2014; 9(10): e110273. https://doi.org/10.1371/journal.pone.0110273
  33. Moon HS, Dincer F, Mantzoros CS. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism. 2013; 62(8): 1131-6. https://doi.org/10.1016/j.metabol.2013.04.007
  34. Lu J, Xiang G, Liu M, Mei W, Xiang L, Dong J. Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice. Atherosclerosis. 2015; 243(2):438-48. https://doi.org/10.1016/j.atherosclerosis.2015.10.020
  35. Qiao X, Nie Y, Ma Y, Chen Y, Cheng R, Yin W, et al. Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci Rep. 2016; 6: 18732 https://doi.org/10.1038/srep18732
  36. Zhu D, Wang H, Zhang J, Zhang X, Xin C, Zhang F et al. Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. J Mol Cell Cardiol. 2015; 87: 138-47. https://doi.org/10.1016/j.yjmcc.2015.07.015
  37. Kuloglu T, Aydin S, Eren MN, Yilmaz M, Sahin I, Kalayci M, et al. Irisin: a potentially candidate marker for myocardial infarction. Peptides 2014; 55:85-91. https://doi.org/10.1016/j.peptides.2014.02.008
  38. Emanuele E, Minoretti P, Pareja-Galeano H, Sanchis-Gomar F, Garatachea N, Lucia A. Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity. Am J Med 2014; 127 (9):888-90. https://doi.org/10.1016/j.amjmed.2014.04.025
  39. Aronis KN, Moreno M, Polyzos SA, Moreno-Navarrete JM, Ricart W, Delgado E, et al. Circulating irisin levels and coronary heart disease: association with future acute coronary syndrome and major adverse cardiovascular events. Int J Obes (Lond) 2015; 39(1):156-61. https://doi.org/10.1038/ijo.2014.101
  40. Aydin S, Kuloglu T, Aydin S, Eren MN, Celik A, Yilmaz M, et al Cardiac, skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: cardiac muscle produces more irisin than skeletal muscle. Peptides 2014; 52:68-73. https://doi.org/10.1016/j.peptides.2013.11.024
  41. Qiao X, Nie Y, Ma Y, Chen Y, Cheng R, Yao Yinrg W. Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci Rep. 2016; 6: 18732. https://doi.org/10.1038/srep18732
  42. Wu F, Song H, Zhang Y, Zhang Y, Mu Q, Jiang M, et al Irisin Induces Angiogenesis in Human Umbilical Vein Endothelial Cells In Vitro and in Zebrafish Embryos In Vivo via Activation of the ERK Signaling Pathway. PLoS One. 2015; 10(8): e0134662. https://doi.org/10.1371/journal.pone.0134662
  43. Zhu D, Wang H, Zhang J, Zhang X, Xin C, Zhang F, et al. Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. J Mol cell Cardiol. 2015; 87: 138-147. https://doi.org/10.1016/j.yjmcc.2015.07.015