European Food Research and Technology

, Volume 234, Issue 5, pp 873–881 | Cite as

Myricetin attenuates hyperinsulinemia-induced insulin resistance in skeletal muscle cells

  • Ye Ding
  • Xiao-qian Dai
  • Zhao-feng Zhang
  • Yong LiEmail author
Original Paper


Previous studies have shown that hyperinsulinemia is not only a marker of insulin resistance, but also the causative factor of peripheral tissue insulin resistance. It also has been suggested that prolonged high-dose insulin treatment can mimic the effects of hyperinsulinemia and exacerbate insulin resistance in skeletal muscle cells. However, how to prevent or reverse insulin resistance induced by hyperinsulinemia remains largely unclear. In the past few decades, the use of myricetin as an anti-diabetic agent has gained much attention, but little information is available regarding the effects of myricetin on glucose uptake and hyperinsulinemia-induced insulin resistance in skeletal muscle cells. The present study focuses on the effect of myricetin on insulin signaling in skeletal muscle cell line C2C12 myotubes. Initially, the effect of myricetin under normal condition was determined. We found that myricetin’s enhancement in glucose uptake coincided with both protein kinase B (Akt) and AMP-activated protein kinase (AMPK) activities. After that, the role of hyperinsulinemia was investigated. It was showed that prolonged high-dose insulin treatment inhibited both Akt and AMPK activities. As the results, the low-dose insulin stimulation of glucose uptake was inhibited by hyperinsulinemia. However, the treatment of myricetin improved low-dose insulin-stimulated glucose uptake in the hyperinsulinemic state, and this effect essentially depended on the AMPK signal pathway. Together, our data suggest a putative link between hyperinsulinemia and insulin resistance in C2C12 myotubes, and the myricetin treatment stimulates glucose uptake and attenuates insulin resistance.


Myricetin Hyperinsulinemia Insulin resistance AMP-activated protein kinase Protein kinase B 



The present study was supported by the foundation (No. 2006BAD27B01) from the Ministry of Science and Technology of PR China.

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE (2000) A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance. evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 49:2094–2101CrossRefGoogle Scholar
  2. 2.
    Dankner R, Chetrit A, Shanik MH, Raz I, Roth J (2009) Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up. Diabetes Care 32:1464–1466CrossRefGoogle Scholar
  3. 3.
    Morrison JA, Glueck CJ, Umar M, Daniels S, Dolan LM, Wang P (2011) Hyperinsulinemia and metabolic syndrome at mean age of 10 years in black and white schoolgirls and development of impaired fasting glucose and type 2 diabetes mellitus by mean age of 24 years. Metabolism 60:24–31CrossRefGoogle Scholar
  4. 4.
    Kanety H, Moshe S, Shafrir E, Lunenfeld B, Karasik A (1994) Hyperinsulinemia induces a reversible impairment in insulin receptor function leading to diabetes in the sand rat model of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 91:1853–1857CrossRefGoogle Scholar
  5. 5.
    Shafrir E (1996) Development and consequences of insulin resistance: lessons from animals with hyperinsulinaemia. Diabetes Metab 22:122–131Google Scholar
  6. 6.
    Ueno M, Carvalheira JBC, Tambascia RC, Bezerra RMN, Amaral ME, Carneiro EM, Folli F, Franchini KG, Saad MJA (2005) Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia 48:506–518CrossRefGoogle Scholar
  7. 7.
    Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia. Is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl. 2):S262–S268CrossRefGoogle Scholar
  8. 8.
    Pirola L, Bonnafous S, Johnston AM, Chaussade C, Portis F, Obberghen EV (2003) Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. J Biol Chem 278:15641–15651CrossRefGoogle Scholar
  9. 9.
    Gonzaleza E, Fliera E, Mollea D, Accilib D, McGrawa TE (2011) Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor. Proc Natl Acad Sci U S A 108:10162–10167CrossRefGoogle Scholar
  10. 10.
    DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000–1007Google Scholar
  11. 11.
    Saltiel AR, Kahn CR (2001) Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414:799–806CrossRefGoogle Scholar
  12. 12.
    Kraegen EW, Bruce C, Hegarty BD, Ye JM, Turner N, Cooney GJ (2009) AMP-activated protein kinase and muscle insulin resistance. Front Biosci 14:4658–4672CrossRefGoogle Scholar
  13. 13.
    Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ (1998) Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47:1369–1373CrossRefGoogle Scholar
  14. 14.
    Harnly JM, Doherty RF, Beecher GR, Holden JM, Haytowitz DB, Bhagwat S, Gebhardt S (2006) Flavonoid content of US fruits, vegetables, and nuts. J Agric Food Chem 54:9966–9977CrossRefGoogle Scholar
  15. 15.
    Mendez J, Bilia AR, Morelli I (1995) Phytochemical investigations of Licania genus. Flavonoids and triterpenoids from Licania pittieri. Pharm Acta Helv 70:223–226CrossRefGoogle Scholar
  16. 16.
    Barbosa-Filho JM, Vasconcelos THC, Alencar AA, Batista LM, Oliveira RAG, Guedes DN, Falcao HS, Moura MD, Diniz MFFM, Modesto-Filho J (2005) Plants and their active constituents from South, Central, and North America with hypoglycemic activity. Rev Bras Farmacogn 15:392–413CrossRefGoogle Scholar
  17. 17.
    Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliovaara M, Reunanen A, Hakulinen T, Aromaa A (2002) Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 76:560–568Google Scholar
  18. 18.
    Ong KC, Khoo HE (2000) Effects of myricetin on glycemia and glycogen metabolism in diabetic rats. Life Sci 67:1695–1705CrossRefGoogle Scholar
  19. 19.
    Liu IM, Liou SS, Lan TW, Hsu FL, Cheng JT (2005) Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med 71:617–621CrossRefGoogle Scholar
  20. 20.
    Liu IM, Tzeng TF, Liou SS, Lan TW (2007) Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci 81:1479–1488CrossRefGoogle Scholar
  21. 21.
    Liu IM, Tzeng TF, Liou SS, Lan TW (2007) Improvement of insulin sensitivity in obese Zucker rats by myricetin extracted from Abelmoschus moschatus. Planta Med 73:1054–1060CrossRefGoogle Scholar
  22. 22.
    Tzeng TF, Liou SS, Liu IM (2011) Myricetin ameliorates defective post-receptor insulin signaling via β-endorphin signaling in the skeletal muscles of fructose-fed rats. Evid Based Complement Alternat Med 2011:150752CrossRefGoogle Scholar
  23. 23.
    Zhang ZF, Li Q, Liang J, Dai XQ, Ding Y, Wang JB, Li Y (2010) Epigallocatechin-3-O-gallate (EGCG) protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition. Phytomedicine 17:14–18CrossRefGoogle Scholar
  24. 24.
    Ong KC, Khoo HE (1996) Insulinomimetic effects of myricetin on lipogenesis and glucose transportin rat adipocytes but not glucose transport translocation. Biochem Pharmacol 51:423–429CrossRefGoogle Scholar
  25. 25.
    Kwon O, Eck P, Chen S, Corpe CP, Lee JH, Kruhlak M, Levine M (2007) Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J 21:366–377CrossRefGoogle Scholar
  26. 26.
    Yun H, Lee JH, Park CE, Kim MJ, Min BI, Bae H, Choe W, Kang I, Kim SS, Ha J (2009) Inulin increases glucose transport in C2C12 myotubes and HepG2 cells via activation of AMP-activated protein kinase and phosphatidylinositol 3-kinase pathways. J Med Food 12:1023–1028CrossRefGoogle Scholar
  27. 27.
    Park CE, Kim MJ, Lee JH, Min BI, Bae H, Choe W, Kim SS, Ha J (2007) Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp Mol Med 39:222–229Google Scholar
  28. 28.
    Hegarty BD, Turner N, Cooney GJ, Kraegen EW (2009) Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase. Acta Physiol 196:129–145CrossRefGoogle Scholar
  29. 29.
    Sakamoto K, Mccarthy A, Smith D, Green KA, Grahame Hardie D, Ashworth A, Alessi D (2005) Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J 24:1810–1820CrossRefGoogle Scholar
  30. 30.
    Shaw RJ, Lamia KA, Vasquez D, Koo S, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646CrossRefGoogle Scholar
  31. 31.
    Lin CL, Huang HC, Lin JK (2007) Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells. J Lipid Res 48:2334–2343CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ye Ding
    • 1
  • Xiao-qian Dai
    • 1
  • Zhao-feng Zhang
    • 1
  • Yong Li
    • 1
    Email author
  1. 1.Department of Nutrition and Food HygieneSchool of Public Health, Peking UniversityBeijingPeople’s Republic of China

Personalised recommendations