Paeoniflorin attenuates gestational diabetes via Akt/mTOR pathway in a rat model
Abstract
Background: Gestational diabetes mellitus (GDM) is a type of diabetes associated with pregnancy and may impose risks on both mother and fetus. Akt paeoniflorin was shown to have anti-inflammatory and anti-hyperglycemia properties and has a potential ability to suppress mammalian target of rapamycin (mTOR) signaling. The current study aimed to study the effect of paeoniflorin on GDM maternal, fetal, and placental characteristics in vivo.
Methods: Streptozotocin (STZ)-induced gestational diabetes rat model was used in our study. The expression levels of phosphorylation (p-) and total protein expression levels of protein kinase B (Akt), mTOR, serum/ glucocorticoid regulated kinase 1 (SGK1), and eIF4E-binding protein 1 (4E-BP1) in the placenta were determined by Western blot assay. The blood glucose, insulin, and leptin levels were assessed using enzyme-linked immunosorbent assay (ELISA).
Results: We found that placental Akt/mTOR signaling was substantially upregulated in GDM patients compared with healthy donors. Paeoniflorin administration alleviates the dysregulation of blood glucose, leptin, and insulin levels in both maternal and fetal GDM rats. Paeoniflorin treatment suppressed the overactivation of Akt/mTOR signaling in placental tissues. More importantly, administration of paeoniflorin was beneficial for normalization of fetal size and body weight in the GDM rats.
Conclusion: Our study suggested that application of paeoniflorin may serve as a potential therapeutical strategy for patients with GDM.
Downloads
References
- Alfadhli EM. Gestational diabetes mellitus. Saudi Med J 2015; 36(4): 399–406. doi: 10.15537/smj.2015.4.10307
- Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci 2018; 19(11): 3342. doi: 10.3390/ijms19113342
- Damm P, Houshmand-Oeregaard A, Kelstrup L, Lauenborg J, Mathiesen ER, Clausen TD. Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark. Diabetologia 2016; 59(7): 1396–9. doi: 10.1007/s00125-016-3985-5
- Carreiro MP, Nogueira AI, Ribeiro-Oliveira A. Controversies and advances in gestational diabetes-an update in the era of continuous glucose monitoring. J Clin Med 2018; 7(2): 11. doi: 10.3390/jcm7020011
- Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat Rev Endocrinol 2012; 8(11): 639–49. doi: 10.1038/nrendo.2012.96
- Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol 2009; 36 (Suppl 3): S3–17. doi: 10.1053/j.seminoncol.2009.10.011
- Weichhart T. Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol 2012; 821: 1–14. doi: 10.1007/978-1-61779-430-8_1
- Marshall S. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Science’s STKE: Signal Trans Knowl Environ 2006; 2006(346): re7. doi: 10.1126/stke.3462006re7
- Yang X, Yang C, Farberman A, Rideout TC, de Lange CF, France J, et al. The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth. J Anim Sci 2008; 86(14 Suppl): E36–50. doi: 10.2527/jas.2007-0567
- Burton GJ, Fowden AL. The placenta: a multifaceted, transient organ. Philos Trans R Soc Lond B, Biol Sci 2015; 370(1663): 20140066. doi: 10.1098/rstb.2014.0066
- Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res 2004; 114(5–6): 397–407. doi: 10.1016/j.thromres.2004.06.038
- Jansson T, Aye IL, Goberdhan DC. The emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta 2012; 33(Suppl 2): e23–9. doi: 10.1016/j.placenta.2012.05.010
- Jansson N, Rosario FJ, Gaccioli F, Lager S, Jones HN, Roos S, et al. Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. J Clin Endocrinol Metab 2013; 98(1): 105–13. doi: 10.1210/jc.2012-2667
- Fahlbusch FB, Hartner A, Menendez-Castro C, Nogel SC, Marek I, Beckmann MW, et al. The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction? J Dev Origins Health Dis 2015; 6(4): 317–26. doi: 10.1017/S2040174415001154
- Roos S, Powell TL, Jansson T. Placental mTOR links maternal nutrient availability to fetal growth. Biochem Soc Trans 2009; 37(Pt 1): 295–8. doi: 10.1042/BST0370295
- Tu J, Guo Y, Hong W, Fang Y, Han D, Zhang P, et al. The regulatory effects of paeoniflorin and its derivative paeoniflorin-6’-O-benzene sulfonate CP-25 on inflammation and immune diseases. Front Pharmacol 2019; 10: 57. doi: 10.3389/fphar.2019.00057
- Zheng YQ, Wei W, Zhu L, Liu JX. Effects and mechanisms of paeoniflorin, a bioactive glucoside from paeony root, on adjuvant arthritis in rats. Inflamm Res 2007; 56(5): 182–8. doi: 10.1007/s00011-006-6002-5
- Shu JL, Zhang XZ, Han L, Zhang F, Wu YJ, Tang XY, et al. Paeoniflorin-6’-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-kappaB signaling: comparison with biological agents. Acta Pharmacol Sinica 2019; 40(6): 801–13. doi: 10.1038/s41401-018-0169-5
- Zhao Y, Ma X, Wang J, Zhu Y, Li R, Wang J, et al. Paeoniflorin alleviates liver fibrosis by inhibiting HIF-1alpha through mTOR-dependent pathway. Fitoterapia 2014; 99: 318–27. doi: 10.1016/j.fitote.2014.10.009
- Sati L, Soygur B, Celik-Ozenci C. Expression of mammalian target of rapamycin and downstream targets in normal and gestational diabetic human term placenta. Reprod Sci 2016; 23(3): 324–32. doi: 10.1177/1933719115602765
- Mao Z, Zhang W. Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 2018; 19(7); 2043. doi: 10.3390/ijms19072043
- Ali M, Bukhari SA, Ali M, Lee HW. Upstream signalling of mTORC1 and its hyperactivation in type 2 diabetes (T2D). BMB Rep 2017; 50(12): 601–9. doi: 10.5483/BMBRep.2017.50.12.206
- Reifsnyder PC, Flurkey K, Te A, Harrison DE. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging 2016; 8(11): 3120–30. doi: 10.18632/aging.101117
- Kezic A, Popovic L, Lalic K. mTOR inhibitor therapy and metabolic consequences: where do we stand? Oxid Med Cell Longevity 2018; 2018: 2640342. doi: 10.1155/2018/2640342
- Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274–93. doi: 10.1016/j.cell.2012.03.017
- Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic beta-cells and a review of the underlying molecular mechanisms. Diabetes 2013; 62(8): 2674–82. doi: 10.2337/db13-0106
- Jia Z, He J. Paeoniflorin ameliorates rheumatoid arthritis in rat models through oxidative stress, inflammation and cyclooxygenase 2. Exp Therap Med 2016; 11(2): 655–9. doi: 10.3892/etm.2015.2908
- Zhao J, Di T, Wang Y, Wang Y, Liu X, Liang D, et al. Paeoniflorin inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response and cytokine secretion. Eur J Pharmacol 2016; 772: 131–43. doi: 10.1016/j.ejphar.2015.12.040
- Wang S, Zhao X, Qiao Z, Jia X, Qi Y. Paeoniflorin attenuates depressive behaviors in systemic lupus erythematosus mice. Biomed Pharmacother Biomed Pharmacother 2018; 103: 248–52. doi: 10.1016/j.biopha.2018.03.149
- Shao YX, Xu XX, Wang K, Qi XM, Wu YG. Paeoniflorin attenuates incipient diabetic nephropathy in streptozotocin-induced mice by the suppression of the Toll-like receptor-2 signaling pathway. Drug Design Dev Ther 2017; 11: 3221–33. doi: 10.2147/DDDT.S149504
- Wang JS, Huang Y, Zhang S, Yin HJ, Zhang L, Zhang YH, et al. A protective role of paeoniflorin in fluctuant hyperglycemia-induced ascular endothelial injuries through antioxidative and anti-inflammatory effects and reduction of PKCbeta1. Oxid Med Cell Longevity 2019; 2019: 5647219. doi: 10.1155/2019/5647219
- Li PP, Liu DD, Liu YJ, Song SS, Wang QT, Chang Y, et al. BAFF/BAFF-R involved in antibodies production of rats with collagen-induced arthritis via PI3K-Akt-mTOR signaling and the regulation of paeoniflorin. J Ethnopharmacol 2012; 141(1): 290–300. doi: 10.1016/j.jep.2012.02.034
- Gong WG, Lin JL, Niu QX, Wang HM, Zhou YC, Chen SY, et al. Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation. Int J Biochem Cell Biol 2015; 62: 93–100. doi: 10.1016/j.biocel.2015.02.017
- Hu PF, Chen WP, Bao JP, Wu LD. Paeoniflorin inhibits IL-1beta-induced chondrocyte apoptosis by regulating the Bax/Bcl-2/caspase-3 signaling pathway. Mol Med Rep 2018; 17(4): 6194–200. doi: 10.3892/mmr.2018.8631
![Creative Commons License](http://i.creativecommons.org/l/by/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright of their work, with first publication rights granted to SNF Swedish Nutrition Foundation. Read the full Copyright- and Licensing Statement.