Ginsenoside Rb3 strengthens the hypoglycemic effect through AMPK for inhibition of hepatic gluconeogenesis

Meng,Fanli; Su,Xiaotian; Li,Wei; Zheng,Yinan

doi:10.3892/etm.2017.4280

Ginsenoside Rb3 strengthens the hypoglycemic effect through AMPK for inhibition of hepatic gluconeogenesis

Authors:
- Fanli Meng
- Xiaotian Su
- Wei Li
- Yinan Zheng
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Affiliations: Department of Agronomy and Horticulture, Liaoning Agricultural Technology College, Yingkou, Liaoning 115009, P.R. China, Department of Biological Technology, Liaoning Agricultural Technology College, Yingkou, Liaoning 115009, P.R. China, College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin 130118, P.R. China
Published online on: March 29, 2017 https://doi.org/10.3892/etm.2017.4280
Pages: 2551-2557

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Abstract

Ginsenoside Rb3 is one of the major active components in protopanaxdiol type ginsenosides, and has demonstrated anti‑diabetic activity. However, the mechanism of this action has yet to be elucidated. The present study investigated the effects of ginsenoside Rb3 on the AMP‑activated protein kinase (AMPK) gluconeogenesis pathway. The present study involved the use of HepG2 cells and western blot analysis to systematically evaluate the effect of ginsenoside Rb3 on AMPK signaling proteins and key factors of gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK), glucose‑6‑phosphatase, forkhead transcription factor 1 (FOXO1) and hepatic nuclear receptor 4α (HNF4α)]. The results indicated that 25 µM ginsenoside Rb3 significantly activated AMPK activity, increased the ratio of p‑AMPK/total‑AMPK, and had synergistic effects with the activator of AICAR on the activation of AMPK. Further analysis indicated that the expression of the transcription factor FOXO1 and HNF4α protein, two important factors in the pathway of HepG2 cell gluconeogenesis, was significantly suppressed by ginsenoside Rb3. PEPCK and G6Pase were subsequently inhibited, which led to the suppression of gluconeogenesis. These effects were partially blocked by the AMPK inhibitor, Compound C, which indicated that the inhibition effects of ginsenoside Rb3 on hepatic gluconeogenesis were predominantly due to the activation of the AMPK signaling pathway. These data suggested that ginsenoside Rb3 can suppress hepatic gluconeogenesis, at least partially through stimulation of AMPK activity.

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1	Biadgo B, Melku M, Abebe SM and Abebe M: Hematological indices and their correlation with fasting blood glucose level and anthropometric measurements in type 2 diabetes mellitus patients in Gondar, Northwest Ethiopia. Diabetes Metab Syndr Obes. 9:91–99. 2016. View Article : Google Scholar : PubMed/NCBI
2	Budinsky A, Wolfram R, Oguogho A, Efthimiou Y, Stamatopoulos Y and Sinzinger H: Regular ingestion of opuntia robusta lowers oxidation injury. Prostaglandins Leukot Essent Fatty Acids. 65:45–50. 2001. View Article : Google Scholar : PubMed/NCBI
3	Li Q, Zhou JP and Zhang HB: Research progresses in anti-diabetic drugs. Progress in Pharmaceutical Sciences. 37:417–427. 2013.
4	Lai Yu, Chai Dandan, Niu Rui and Xiaodong S: Study the mechanism of potentilla discolor Bunge extract on blood sugar in diabetic rats. Aisa-Pacific Traditional Medicine. 12:17–19. 2016.
5	Wan Y, Wu J and Wu Q: A review of the hypoglycemic activity of Siraitia Grosvenorii. Food Research and Development. 37:188–191. 2016.
6	Zhang M and Shen Y: Research advances in pharmacological effects of oleanolic acid in hypoglycemia and antidiabetic complications. Anti-infection Pharmacy. 12:801–806. 2015.
7	Ryu GR, Lee MK, Lee E, Ko SH, Ahn YB, Kim JW, Yoon KH and Song KH: Activation of AMP-activated protein kinase mediates acute and severe hypoxic injury to pancreatic beta cells. Biochem Biophys Res Commun. 386:356–362. 2009. View Article : Google Scholar : PubMed/NCBI
8	Magnoni LJ, Vraskou Y, Palstra AP and Planas JV: AMP-activated protein kinase plays an important evolutionary conserved role in the regulation of glucose metabolism in fish skeletal muscle cells. PLoS One. 7:e312192012. View Article : Google Scholar : PubMed/NCBI
9	Viollet B, Guigas B, Leclerc J, Hébrard S, Lantier L, Mounier R, Andreelli F and Foretz M: AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives. Acta Physiol (Oxf). 196:81–98. 2009. View Article : Google Scholar : PubMed/NCBI
10	Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, et al: The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 437:1109–1111. 2005. View Article : Google Scholar : PubMed/NCBI
11	Shi Y, Han B, Yu X, Qu S and Sui D: Ginsenoside Rb3 ameliorates myocardial ischemia-reperfusion injury in rats. Pharm Biol. 49:900–906. 2011. View Article : Google Scholar : PubMed/NCBI
12	Cui J, Jiang L and Xiang H: Ginsenoside Rb3 exerts antidepressant-like effects in several animal models. J Psychopharmacol. 26:697–713. 2012. View Article : Google Scholar : PubMed/NCBI
13	Liu X, Jiang Y, Yu X, Fu W, Zhang H and Sui D: Ginsenoside-Rb3 protects the myocardium from ischemia-reperfusion injury via the inhibition of apoptosis in rats. Exp Ther Med. 8:1751–1756. 2014.PubMed/NCBI
14	Wang T, Yu X, Qu S, Xu H, Han B and Sui D: Effect of ginsenoside Rb3 on myocardial injury and heart function impairment induced by isoproterenol in rats. Eur J Pharmacol. 636:121–125. 2010. View Article : Google Scholar : PubMed/NCBI
15	Rui L, Yi-Nan Z and Wen-Cong L: Inhibitory activity of ginsenoside Rb3 on pancreatic lipase. J Xidian Univ. 23:522–525. 2011.
16	Bu QT, Zhang WY, Chen QC, Zhang CZ, Gong XJ, Liu WC, Li W and Zheng YN: Anti-diabetic effect of ginsenoside Rb(3) in alloxan-induced diabetic mice. Med Chem. 8:934–941. 2012. View Article : Google Scholar : PubMed/NCBI
17	Meng FL, Su XT and Zheng YN: Effects of Ginsenoside Rb3 on antihyperglycemia and antioxidation in diabetic mice. J South Chin Agr Univ. 34:553–557. 2013.
18	Wei S, Li W, Yu Y, Yao F, A L, Lan X, Guan F, Zhang M and Chen L: Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5′monophosphate kinase: A study in vitro and in vivo. Life Sci. 139:8–15. 2015. View Article : Google Scholar : PubMed/NCBI
19	Lee MS, Hwang JT, Kim SH, Yoon S, Kim MS, Yang HJ and Kwon DY: Gimenoside Rc, an active component of Panax ginseng, stimulates glucose uptake in C2C12 myotubes through an AMPK-dependent mechanism. J Ethnopharmacol. 127:771–776. 2010. View Article : Google Scholar : PubMed/NCBI
20	Jin J, Mullen TD, Hou Q, Bielawski J, Bielawska A, Zhang X, Obeid LM, Hannun YA and Hsu YT: AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells. J Lipid Res. 50:2389–2397. 2009. View Article : Google Scholar : PubMed/NCBI
21	Kim YM, Kim MY, Kim HJ, Roh GS, Ko GH, Seo HG, Lee JH and Chang KC: Compound C independent of AMPK inhibits ICAM-1 and VCAM-1 expression in inflammatory stimulants-activated endothelial cells in vitro and in vivo. Atherosclerosis. 219:57–64. 2011. View Article : Google Scholar : PubMed/NCBI
22	Vucicevic L, Misirkic M, Janjetovic K, Vilimanovich U, Sudar E, Isenovic E, Prica M, Harhaji-Trajkovic L, Kravic-Stevovic T, Bumbasirevic V and Trajkovic V: Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. Autophagy. 7:40–50. 2011. View Article : Google Scholar : PubMed/NCBI
23	Martinez-Martin N, Blas-García A, Morales JM, Marti-Cabrera M, Monleón D and Apostolova N: Metabolomics of the effect of AMPK activation by AICAR on human umbilical vein endothelial cells. Int J Mol Med. 29:88–94. 2012.PubMed/NCBI
24	Lee H, Kang R, Bae S and Yoon Y: AICAR, an activator of AMPK, inhibits adipogenesis via the WNT/β-catenin pathway in 3T3-L1 adipocytes. Int J Mol Med. 28:65–71. 2011.PubMed/NCBI
25	Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, Czernin J, Shyy JY, Watson AD, Phelps M, et al: The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA. 106:12932–12937. 2009. View Article : Google Scholar : PubMed/NCBI
26	Langelueddecke C, Jakab M, Ketterl N, Lehner L, Hufnagl C, Schmidt S, Geibel JP, Fuerst J and Ritter M: Effect of the AMP-kinase modulators AICAR, metformin and compound C on insulin secretion of INS-1E rat insulinoma cells under standard cell culture conditions. Cell Physiol Biochem. 29:75–86. 2012. View Article : Google Scholar : PubMed/NCBI
27	Fei F, Xin-rong W, Ming L and Huan L: Effect of bioactive components in mulberry leaves on glucose metabolism in insulinresistant HepG2 cells. J Guang Pharm Col. 27:637–639. 2011.
28	Li XL, He SM, Zhu Y, Feng B, Huang XQ, Chen T and Zheng GJ: Establishment and identify of HepG2 cells model of insulin resistance. Chin J Exp Trad Med Formul. 19:203–207. 2013.
29	Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M and Cantley LC: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 310:1642–1646. 2005. View Article : Google Scholar : PubMed/NCBI
30	Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB and Spiegelman BM: PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem. 278:30843–30848. 2003. View Article : Google Scholar : PubMed/NCBI
31	He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA and Radovick S: Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell. 137:635–646. 2009. View Article : Google Scholar : PubMed/NCBI
32	Caton PW, Kieswich J, Yaqoob MM, Holness MJ and Sugden MC: Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice. Diabetes Obes Metab. 13:1097–1104. 2011. View Article : Google Scholar : PubMed/NCBI