Antihyperglycemic Effect of Ginsenoside Rh2 by Inducing Islet β-cell Regeneration in Mice

Abstract

The present study was designed to determine the antihyperglycemic function of ginsenoside Rh2 (GS-Rh2) by the regeneration of β-cells in mice that underwent 70% partial pancreatectomy (PPx), and to explore the mechanisms of GS-Rh2-induced β-cell proliferation. Adult C57BL/6J mice were subjected to PPx or a sham operation. Within 14 days post-PPx, mice that underwent PPx received GS-Rh2 (1 mg/kg body weight) or saline injection. GS-Rh2-treated mice exhibited an improved glycemia and glucose tolerance, an increased serum insulin levels, and β-cell hyperplasia. Meanwhile, increased β-cell proliferation percentages and decreased β-cell apoptosis percentages were also observed in GS-Rh2-treated mice. Further studies on the Akt/Foxo1/PDX-1 signaling pathway revealed that GS-Rh2 probably induced β-cell proliferation via activation of Akt and PDX-1 and inactivation of Foxo1. Studies on the abundance and activity of cell cycle proteins suggested that GS-Rh2-induced β-cell proliferation may ultimately be achieved through the regulation of cell cycle proteins. These findings demonstrate that GS-Rh2 administration could inhibit the tendency of apoptosis, and reverse the impaired β-cell growth potential by modulating Akt/Foxo1/PDX-1 signaling pathway and regulating cell cycle proteins. Induction of islet β-cell proliferation by GS-Rh2 suggests its therapeutic potential in the treatment of diabetes.

Key words

islet regeneration - partial pancreatectomy - ginsenoside Rh2 (GS-Rh2) - cyclin D-Cdk4 complex - Akt/Foxo1/PDX-1 signaling pathway

• References

• 1 Bonner-Weir S, Sharma A. Are there pancreatic progenitor cells from which new islets form after birth?. Nat Clin Pract Endocrinol Metab 2006; 2: 240-241
• 2 De Leon DD, Deng S, Madani R, Ahima RS, Drucker DJ, Stoffers DA. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 2003; 52: 365-371
• 3 Tews D, Lehr S, Hartwig S, Osmers A, Paslack W, Eckel J. Anti-apoptotic action of exendin-4 in INS-1 beta cells: comparative protein pattern analysis of isolated mitochondria. Horm Metab Res 2009; 41: 294-301
• 4 Kawasaki Y, Harashima S, Sasaki M, Mukai E, Nakamura Y, Harada N, Toyoda K, Hamasaki A, Yamane S, Yamada C, Yamada Y, Seino Y, Inagaki N. Exendin-4 protects pancreatic beta cells from the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation. Horm Metab Res 2010; 42: 311-317
• 5 Attele AS, Zhou YP, Xie JT, Wu JA, Zhang L, Dey L, Pugh W, Rue PA, Polonsky KS, Yuan CS. Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 2002; 51: 1851-1858
• 6 Xie JT, Wu JA, Mehendale S, Aung HH, Yuan CS. Anti-hyperglycemic effect of the polysaccharides fraction from American ginseng berry extract in ob/ob mice. Phytomedicine 2004; 11: 182-187
• 7 Reeds DN, Patterson BW, Okunade A, Holloszy JO, Polonsky KS, Klein S. ­Ginseng and ginsenoside Re do not improve beta-cell function or insulin sensitivity in overweight and obese subjects with impaired glucose tolerance or diabetes. Diabetes Care 2011; 34: 1071-1076
• 8 Lee WK, Kao ST, Liu IM, Cheng JT. Increase of insulin secretion by ginsenoside Rh2 to lower plasma glucose in Wistar rats. Clin Exp Pharmacol Physiol 2006; 33: 27-32
• 9 Lai DM, Tu YK, Liu IM, Chen PF, Cheng JT. Mediation of beta-endorphin by ginsenoside Rh2 to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med 2006; 72: 9-13
• 10 Lee WK, Kao ST, Liu IM, Cheng JT. Ginsenoside Rh2 is one of the active principles of Panax ginseng root to improve insulin sensitivity in fructose-rich chow-fed rats. Horm Metab Res 2007; 39: 347-354
• 11 Alonso LC, Yokoe T, Zhang P, Scott DK, Kim SK, O’Donnell CP, Garcia-Ocana A. Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes 2007; 56: 1792-1801
• 12 Georgia S, Hinault C, Kawamori D, Hu J, Meyer J, Kanji M, Bhushan A, Kulkarni RN. Cyclin D2 is essential for the compensatory beta-cell hyperplastic response to insulin resistance in rodents. Diabetes 2010; 59: 987-996
• 13 Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994; 14: 2066-2076
• 14 Fatrai S, Elghazi L, Balcazar N, Cras-Meneur C, Krits I, Kiyokawa H, Bernal-Mizrachi E. Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 2006; 55: 318-325
• 15 Park SY, Bell GI. Noninvasive monitoring of changes in pancreatic beta-cell mass by bioluminescent imaging in MIP-luc transgenic mice. Horm Metab Res 2009; 41: 1-4
• 16 Jung HS, Ahn YR, Oh SH, Kim YS, No H, Lee MK, Kim KW. Enhancement of beta-cell regeneration by islet transplantation after partial pancreatectomy in mice. Transplantation 2009; 88: 354-359
• 17 Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 2004; 114: 828-836
• 18 Brazil DP, Yang ZZ, Hemmings BA. Advances in protein kinase B signaling. AKTion on multiple fronts. Trends Biochem Sci 2004; 29: 233-242
• 19 Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 2001; 21: 893-901
• 20 Tuttle RL, Gill NS, Pugh W, Lee JP, Koeberlein B, Furth EE, Polonsky KS, Naji A, Birnbaum MJ. Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha. Nat Med 2001; 7: 1133-1137
• 21 Rao P, Roccisana J, Takane KK, Bottino R, Zhao A, Trucco M, Garcia-Ocana A. Gene transfer of constitutively active Akt markedly improves human islet transplant outcomes in diabetic severe combined immunodeficient mice. Diabetes 2005; 54: 1664-1675
• 22 Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs 3rd WH, Wright CV, White MF, Arden KC, Accili D. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 2002; 110: 1839-1847
• 23 Aoki M, Jiang H, Vogt PK. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc Natl Acad Sci USA 2004; 101: 13613-13617
• 24 Ziegler P, Teller S, Ha NH, Giese B, Fraunholz M, Walther R. Phosphoproteomic identification of a PDX-1/14-3-3epsilon interaction in pancreatic beta cells. Horm Metab Res 2011; 43: 165-170
• 25 Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2002; 2: 81-91
• 26 Georgia S, Hinault C, Kawamori D, Hu J, Meyer J, Kanji M, Bhushan A, Kulkarni RN. Cyclin D2 is essential for the compensatory beta-cell hyperplastic response to insulin resistance in rodents. Diabetes 2010; 59: 987-996
• 27 Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 1999; 22: 44-52
• 28 Xie JT, Wang CZ, Wang AB, Wu J, Basila D, Yuan CS. Antihyperglycemic effects of total ginsenosides from leaves and stem of Panax ginseng. Acta Pharmacol Sin 2005; 26: 1104-1110
• 29 Park S, Ahn IS, Kwon DY, Ko BS, Jun WK. Ginsenosides Rb1 and Rg1 suppress triglyceride accumulation in 3T3-L1 adipocytes and enhance beta-cell insulin secretion and viability in Min6 cells via PKA-dependent pathways. Biosci Biotechnol Biochem 2008; 72: 2815-2823
• 30 Hwang JT, Lee MS, Kim HJ, Sung MJ, Kim HY, Kim MS, Kwon DY. Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR-gamma signal pathways. Phytother Res 2009; 23: 262-266
• 31 Lee OH, Lee HH, Kim JH, Lee BY. Effect of ginsenosides Rg3 and Re on glucose transport in mature 3T3-L1 adipocytes. Phytother Res 2011; 25: 768-773
• 32 Xiong Y, Shen L, Liu KJ, Tso P, Xiong Y, Wang G, Woods SC, Liu M. Antiobesity and antihyperglycemic effects of ginsenoside Rb1 in rats. Diabetes 2010; 59: 2505-2512
• 33 Shang W, Yang Y, Jiang B, Jin H, Zhou L, Liu S, Chen M. Ginsenoside Rb1 promotes adipogenesis in 3T3-L1 cells by enhancing PPARgamma2 and C/EBPalpha gene expression. Life Sci 2007; 80: 618-625
• 34 Lee KT, Jung TW, Lee HJ, Kim SG, Shin YS, Whang WK. The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. Arch Pharm Res 2011; 34: 1201-1208
• 35 Xie JT, Mehendale SR, Li X, Quigg R, Wang X, Wang CZ, Wu JA, Aung HH, P AR Bell GI, Yuan CS. Anti-diabetic effect of ginsenoside Re in ob/ob mice. Biochim Biophys Acta 2005; 1740: 319-325
• 36 Zhang Z, Li X, Lv W, Yang Y, Gao H, Yang J, Shen Y, Ning G. Ginsenoside Re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-kappaB. Mol Endocrinol 2008; 22: 186-195