Japanese quince (Chaenomeles japonica L.) fruit polyphenolic extract modulates carbohydrate metabolism in HepG2 cells via AMP-activated protein kinase

  • Małgorzata Zakłos-Szyda Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Institute of Technical Biochemistry, Stefanowskiego 4/10, 90-924 Lodz, Poland
  • Nina Pawlik Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Institute of Technical Biochemistry, Stefanowskiego 4/10, 90-924 Lodz, Poland


Scope: Type 2 diabetes mellitus is a chronic diet-related disease which has become a prominent health problem of the world and there is a need of research of natural agents with preventive activities against that metabolic disorder and present in food matrixes. Thus the aim of the study was to explore the in vitro activity of Japanese quince fruit polyphenolic extract as modulator of carbohydrates metabolism.

Methods and results: The study was designed to investigate the effect of Japanese quince polyphenolic extract on glucose metabolism in human hepatoma HepG2 cell line. Pretreatment of the cells with JQ preparation caused decrease of intracellular ROS generation and influenced mitochondrial membrane polarization which seems to lead to AMPK activation. Further effects observed in HepG2 cells were associated with activation of the enzyme: elevation of glucose uptake and glycogen content, and alleviation of gluconeogenesis through modulation of PEPCK, PTP1B, FOXO1 and GLUT4 mRNA expression.

Conclusion: These findings suggest that JQ polyphenols exhibit hypoglycemic effects via modulation of AMPK signaling.


Bahadoran, Z., Mirmiran, P., Azizi, F. (2013). Dietary polyphenols as potential nutraceuticals in management of diabetes: a review. J Diabetes Metab Disorders Disorders 12: 43. doi: 10.1186/2251-6581-12-43

Boucher, J., Kleinridders, A., Kahn, C. R. (2014). Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 6: a009191. doi: 10.1101/cshperspect.a009191

Brereton, M.F., Rohm, M., Ashcroft, F.M. (2016). β-Cell dysfunction in diabetes: a crisis of identity? Diabetes Obes Metab 18 Supplement 1:102-109. doi: 10.1111/dom.12732

Cardaci, S., Filomeni, G., Ciriolo, M.R. (2012). Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Science 125: 2115–2125. doi: 10.1242/jcs.095216

Collins, Q. F., Liu, H. Y., Pi, J., Liu, Z., Quon, M. J. et al. (2007). Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5’-AMP-activated protein kinase. J Biol Chem 282: 30143–30149.

Coughlan, K. A., Valentine, R. J., Ruderman, N., B., Saha, A. K. (2014). AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Met Syndrome Obesity 7: 241–253. doi: 10.2147/DMSO.S43731

Crescenti, A., del Bas, J. M., Arola-Arnal, A., Oms-Oliu, G., et al. (2015). Grape seed procyanidins administered at physiological doses to rats during pregnancy and lactation promote lipid oxidation and up-regulate AMPK in the muscle of male offspring in adulthood. J Nutr Biochem 26: 912-920. doi: 10.1016/j.jnutbio.2015.03.003

Doan, K. V., Ko, C. M., Kinyua, A. W., Yang, D. J., Choi, Y-H., et al. (2015). Gallic acid regulates body weight and glucose homeostasis through AMPK activation. Endocrinol 156: 157–168. doi: 10.1210/en.2014-1354

Du, H.; Wu, J.; Li, H. (2013). Polyphenols and triterpenes from Chaenomeles fruits: Chemical analysis and antioxidant activities assessment. Food Chem 141: 4260-4268. doi: 10.1016/j.foodchem.2013.06.109

Gorlach, S., Wagner, W., Podsędek, A., Szewczyk, K., Koziołkiewicz, M., et al. (2011). Procyanidins from Japanese quince (Chaenomeles japonica) fruit induce apoptosis in human colon cancer Caco-2 cells in a degree of polymerization-dependent manner. Nutr Cancer 63: 1348–1360. doi: 10.1080/01635581.2011.608480

Hardie, D. G. (2016). Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharmacol Sin B 6: 1–19. doi: 10.1016/j.apsb.2015.06.002

Hardie, D. G. (2014). AMPK--sensing energy while talking to other signaling pathways. Cell Metab 20: 939-52. doi: 10.1016/j.cmet.2014.09.013

Hardie, D. G., Carling, D., Gamblin, S. J. (2011). AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci 36: 470-477. doi: 10.1016/j.tibs.2011.06.004

Jitrapakdee, S. (2012). Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. Int J Biochem Cell Biol 44: 33– 45. doi: 10.1016/j.biocel.2011.10.001

Julian, D., April, K. L., Patel, S., Stein, J. R., Wohlgemuth, S. E. (2005). Mitochondrial depolarization following hydrogen sulfide exposure in erythrocytes from a sulfide-tolerant marine invertebrate, J Exp Biol 208: 4109-4122.

Karim, S., Adams, D. H., Lalor, P. F. (2012). Hepatic expression and cellular distribution of the glucose transporter family. World J Gastroenterol 18 :6771–6781. doi: 10.3748/wjg.v18.i46.6771

Kim, J. J. Y., Tan, Y., Xiao, L., Sun, Y. L., Qu, X. (2013). Green Tea Polyphenol Epigallocatechin-3-Gallate enhances glycogen synthesis and inhibits lipogenesis in hepatocytes. Biom Res Int doi: 10.1155/2013/920128

Kurimoto, Y., Shibayama, Y., Inoue, S., Soga, M., Takikawa, M. et al. (2013). Black soybean seed coat extract ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase in diabetic mice. J Agric Food Chem 12: 5558-5564. doi: 10.1021/jf401190y

Lewandowska, U., Szewczyk, K., Owczarek, K., Hrabec, Z., Podsędek, A. et al. (2013). Flavanols from Japanese quince (Chaenomeles japonica) fruit inhibit human prostate and breast cancer cell line invasiveness and cause favorable changes in Bax/Bcl-2 mRNA ratio. Nutr Cancer 65: 273–285. doi: 10.1080/01635581.2013.749292

Liu, X., Chhipa, R. R., Nakano, I., Dasgupta B. (2014). The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol Cancer Ther 13: 596–605. doi: 10.1158/1535-7163.MCT-13-0579

O-Sullivan, I. S., Zhang, W., Wasserman, D. H., Liew, C. W., Liu, J., et al. (2015). FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6, 7079. doi: 10.1038/ncomms8079

Scott, J. W., Ling, N. M., Issa, S. M. A., Dite, T. A., O’Brien, M. T. et al. (2014). Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem Biol 21: 619–627. doi: 10.1016/j.chembiol.2014.03.006

Snoussi, C., Ducroc, R., Hamdaoui, M. H., Dhaouadi, K., Abaidi, H., et al. (2014). Green tea decoction improves glucose tolerance and reduces weight gain of rats fed normal and high-fat diet. J Nutr Biochem 25: 557-64. doi: 10.1016/j.jnutbio.2014.01.006

Strek, M., Gorlach, S., Podsedek, A.; Sosnowska, et al. (2007). Procyanidin oligomers from Japanese quince (Chaenomeles japonica) fruit inhibit activity of MMP-2 and MMP-9 metalloproteinases. J Agric Food Chem 55: 6447-6452.

Strugała, P., Cyboran-Mikołajczyk, S., Dudra, A., Mizgier, P., et al. (2016). Biological activity of Japanese quince extract and its interactions with lipids, erythrocyte membrane, and human albumin. J Membr Biol 249: 393–410. doi: 10.1007/s00232-016-9877-2

Tarko, T., Duda-Chodak, A., Satora, P., Sroka, P. et al. (2014). Chaenomeles japonica, Cornus mas, Morus nigra fruits characteristics and their processing potential. J Food Sci Technol 51: 3934-41. doi: 10.1007/s13197-013-0963-5

Ueda, M., Furuyashiki, T., Yamada, K., Aoki, Y. et al. (2010). Tea catechins modulate the glucose transport system in 3T3-L1 adipocytes. Food Funct 1: 167-73. doi: 10.1039/c0fo00105h

World Health Organization, 2016, http://apps.who.int/iris/bitstream/10665/204871/1/ 9789241565257_eng.pdf?ua=1 (accessed 10.01.17)

Vetterli, L., Brun, T., Giovannoni, L., Bosco, D. et al. (2011). Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through Sirt1 dependent mechanism. J Biol Chem 286: 6049–6060. doi: 10.1074/jbc.M110.176842

Viollet, B., Guigas, B., Garcia, N.S., Leclerc, J., Fore, M. (2012). Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122: 253–270. doi: 10.1042/CS20110386

von Wilamowitz-Moellendorff, A., Hunter, R. W., García-Rocha, M., Kang, L., López-Soldado, I. et al. (2013). Glucose-6-Phosphate–mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. Diabetes 62: 4070–4082. doi: 10.2337/db13-0880

Yamashita, Y., Wang, L., Nanba, F., Ito, C., et al. (2016). Procyanidin promotes translocation of glucose transporter 4 in muscle of mice through activation of insulin and AMPK signaling pathways. PLoS One 11:e0161704. doi: 10.1371/journal.pone.0161704

Yamashita, Y., Okabe, M., Natsume, M., Ashida, H. (2012). Cacao liquor procyanidin extract improves glucose tolerance by enhancing GLUT4 translocation and glucose uptake in skeletal muscle. J Nutr Sci 1:e2. doi: 10.1017/jns.2012.2

Zakłos-Szyda, M., Majewska, I., Redzynia, M., Koziołkiewicz, M. (2015). Antidiabetic effect of polyphenolic extracts from selected edible plants as α-amylase, α-glucosidase and PTP1B inhibitors, and β pancreatic cells cytoprotective agents - a comparative study. Curr Top Med Chem 15: 2431-2444. doi: 10.2174/1568026615666150619143051