Pathways of Insulin Resistance in Ovarian Granulosa Cells of Polycystic Ovary Syndrome Patients

doi:10.12280/gjszjk.20230330

Abstract

Abstract:

Insulin resistance (IR) is associated with the genesis and development of polycystic ovary syndrome (PCOS). The abnormity of insulin-related signaling pathways causes metabolism disorder, which affects follicle development and quality. In ovarian granulosa cells of PCOS, the classical pathways of insulin include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). The pathways related with inflammation include Toll-like receptor (TLR)/nuclear factor-κB (NF-κB), and the pathways of oxidative stress include nuclear factor-erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) and GTPase of immunity-associated protein 7 (GIMAP7)/ sonic hedgehog (SHH). There are multiple pathways related with metabolism, such as the lipid metabolism-related pathway of activating transcription factor 4 (ATF4). Therefore, clarifying the IR-related signal transduction pathway and molecular mechanism in ovarian granulosa cells of PCOS patients can supplement the knowledge of PCOS pathogenesis, and further provide new ideas for the treatment of PCOS.

Key words: Polycystic ovary syndrome, Insulin resistance, Intracellular signaling peptides and proteins, Signal transduction, Granulosa cells

REN Lu-lu, REN Wen-chao, ZHANG Xiao-xuan, REN Chun-e. Pathways of Insulin Resistance in Ovarian Granulosa Cells of Polycystic Ovary Syndrome Patients[J]. Journal of International Reproductive Health/Family Planning, 2024, 43(1): 32-37.

References 47

[1]	Zeng X, Xie YJ, Liu YT, et al. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity[J]. Clin Chim Acta, 2020, 502:214-221. doi: 10.1016/j.cca.2019.11.003. pmid: 31733195
[2]	Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome[J]. Hum Reprod, 2018, 33(9):1602-1618. doi: 10.1093/humrep/dey256.
[3]	Li M, Chi X, Wang Y, et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy[J]. Signal Transduct Target Ther, 2022, 7(1):216. doi: 10.1038/s41392-022-01073-0.
[4]	Tong C, Wu Y, Zhang L, et al. Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway[J]. Front Endocrinol(Lausanne), 2022, 13:1091147. doi: 10.3389/fendo.2022.1091147.
[5]	杨蕾, 陶仕英, 王继峰, 等. PI3k/Akt通路参与二仙汤抑制顺铂所致卵巢颗粒细胞凋亡的作用[J]. 世界科学技术-中医药现代化, 2016, 18(8):1362-1367. doi: 10.11842/wst.2016.08.020.
[6]	Qiu Z, Dong J, Xue C, et al. Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway[J]. J Ethnopharmacol, 2020, 250:111965. doi: 10.1016/j.jep.2019.111965.
[7]	Huang Y, Zhang X. Luteolin alleviates polycystic ovary syndrome in rats by resolving insulin resistance and oxidative stress[J]. Am J Physiol Endocrinol Metab, 2021, 320(6):E1085-E1092. doi: 10.1152/ajpendo.00034.2021. pmid: 33900851
[8]	Wang C, Ding C, Hua Z, et al. Cangfudaotan Decoction Alleviates Insulin Resistance and Improves Follicular Development in Rats with Polycystic Ovary Syndrome via IGF-1-PI3K/Akt-Bax/Bcl-2 Pathway[J]. Mediators Inflamm, 2020, 2020:8865647. doi: 10.1155/2020/8865647.
[9]	Guo R, Zheng H, Li Q, et al. Melatonin alleviates insulin resistance through the PI3K/AKT signaling pathway in ovary granulosa cells of polycystic ovary syndrome[J]. Reprod Biol, 2022, 22(1):100594. doi: 10.1016/j.repbio.2021.100594.
[10]	Liu J, Wu DC, Qu LH, et al. The role of mTOR in ovarian Neoplasms, polycystic ovary syndrome, and ovarian aging[J]. Clin Anat, 2018, 31(6):891-898. doi: 10.1002/ca.23211. pmid: 29752839
[11]	Zhu Y, Li Y, Liu M, et al. Guizhi Fuling Wan, Chinese Herbal Medicine, Ameliorates Insulin Sensitivity in PCOS Model Rats With Insulin Resistance via Remodeling Intestinal Homeostasis[J]. Front Endocrinol(Lausanne), 2020, 11:575. doi: 10.3389/fendo.2020.00575.
[12]	Fazel Torshizi F, Chamani M, Khodaei HR, et al. Therapeutic effects of organic zinc on reproductive hormones, insulin resistance and mTOR expression, as a novel component, in a rat model of Polycystic ovary syndrome[J]. Iran J Basic Med Sci, 2020, 23(1):36-45. doi: 10.22038/IJBMS.2019.36004.8586. pmid: 32405346
[13]	Tan M, Cheng Y, Zhong X, et al. LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway[J]. Aging(Albany NY), 2021, 13(3):4617-4633. doi: 10.18632/aging.202421.
[14]	Shi L, Liu S, Zhao W, et al. miR-483-5p and miR-486-5p are down-regulated in cumulus cells of metaphase Ⅱ oocytes from women with polycystic ovary syndrome[J]. Reprod Biomed Online, 2015, 31(4):565-572. doi: 10.1016/j.rbmo.2015.06.023.
[15]	Yang X, Wang K, Lang J, et al. Up-regulation of miR-133a-3p promotes ovary insulin resistance on granulosa cells of obese PCOS patients via inhibiting PI3K/AKT signaling[J]. BMC Womens Health, 2022, 22(1):412. doi: 10.1186/s12905-022-01994-6. pmid: 36209087
[16]	Li T, Mo H, Chen W, et al. Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome[J]. Reprod Sci, 2017, 24(5):646-655. doi: 10.1177/1933719116667606. pmid: 27613818
[17]	Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications[J]. Endocr Rev, 2012, 33(6):981-1030. doi: 10.1210/er.2011-1034. pmid: 23065822
[18]	Walters KA, Moreno-Asso A, Stepto NK, et al. Key signalling pathways underlying the aetiology of polycystic ovary syndrome[J]. J Endocrinol, 2022, 255(1):R1-R26. doi: 10.1530/JOE-22-0059. pmid: 35980384
[19]	Belani M, Deo A, Shah P, et al. Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells-A study in PCOS patients[J]. J Steroid Biochem Mol Biol, 2018, 178:283-292. doi: 10.1016/j.jsbmb.2018.01.008.
[20]	任文超, 刘建新, 祁秀娟, 等. 二甲双胍对卵巢颗粒细胞IRS-1及ERK-2基因表达的影响[J]. 国际生殖健康/计划生育杂志, 2013, 32(3):154-156,171.
[21]	赵粉琴, 赵艳, 刘洁颖, 等. 黄连素对PCOS模型大鼠LPS/NF-κB、MAPK信号通路的影响[J]. 中国应用生理学杂志, 2022, 38(2):181-186,192. doi: 10.12047/j.cjap.6229.2022.029.
[22]	Wang Z, Zhai D, Zhang D, et al. Quercetin Decreases Insulin Resistance in a Polycystic Ovary Syndrome Rat Model by Improving Inflammatory Microenvironment[J]. Reprod Sci, 2017, 24(5):682-690. doi: 10.1177/1933719116667218. pmid: 27634381
[23]	Zhu Q, Yao Y, Xu L, et al. Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome[J]. Reprod Biol Endocrinol, 2022, 20(1):4. doi: 10.1186/s12958-021-00873-3.
[24]	Tan W, Zhang J, Dai F, et al. Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets[J]. Mol Cell Biochem,2023 Apr 25. doi: 10.1007/s11010-023-04736-w.
[25]	Hu M, Zhang Y, Guo X, et al. Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance[J]. Life Sci, 2019, 232:116681. doi: 10.1016/j.lfs.2019.116681.
[26]	Shen H, Xu X, Fu Z, et al. The interactions of CAP and LYN with the insulin signaling transducer CBL play an important role in polycystic ovary syndrome[J]. Metabolism, 2022, 131:155164. doi: 10.1016/j.metabol.2022.155164.
[27]	Cirillo F, Catellani C, Sartori C, et al. CFTR and FOXO1 gene expression are reduced and high mobility group box 1 (HMGB1) is increased in the ovaries and serum of women with polycystic ovarian syndrome[J]. Gynecol Endocrinol, 2019, 35(10):842-846. doi: 10.1080/09513590.2019.1599349.
[28]	Huang Y, Li W, Wang CC, et al. Cryptotanshinone reverses ovarian insulin resistance in mice through activation of insulin signaling and the regulation of glucose transporters and hormone synthesizing enzymes[J]. Fertil Steril, 2014, 102(2):589-596.e4. doi: 10.1016/j.fertnstert.2014.05.012. pmid: 24973798
[29]	Yang Y, Yang L, Qi C, et al. Cryptotanshinone alleviates polycystic ovary syndrome in rats by regulating the HMGB1/TLR4/NF-κB signaling pathway[J]. Mol Med Rep, 2020, 22(5):3851-3861. doi: 10.3892/mmr.2020.11469.
[30]	Almario RU, Karakas SE. Roles of circulating WNT-signaling proteins and WNT-inhibitors in human adiposity, insulin resistance, insulin secretion, and inflammation[J]. Horm Metab Res, 2015, 47(2):152-157. doi: 10.1055/s-0034-1384521. pmid: 25089371
[31]	Zhao Y, Zhang C, Huang Y, et al. Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-κB signaling in the granulosa cells of PCOS patients[J]. J Clin Endocrinol Metab, 2015, 100(1):201-211. doi: 10.1210/jc.2014-2419. pmid: 25303486
[32]	牛群, 石婧婧, 符江. WNT5A基因对卵巢颗粒细胞胰岛素反应性和胰岛素抵抗的调控作用[J]. 山东大学学报(医学版), 2021, 59(6):57-63. doi: 10.6040/j.issn.1671-7554.0.2021.0304.
[33]	Lai Q, Xiang W, Li Q, et al. Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome[J]. Front Med, 2018, 12(5):518-524. doi: 10.1007/s11684-017-0575-y.
[34]	Yu C, Chen H, Du D, et al. β-Glucan from Saccharomyces cerevisiae alleviates oxidative stress in LPS-stimulated RAW264.7 cells via Dectin-1/Nrf2/HO-1 signaling pathway[J]. Cell Stress Chaperones, 2021, 26(4):629-637. doi: 10.1007/s12192-021-01205-5.
[35]	Gharaei R, Alyasin A, Mahdavinezhad F, et al. Randomized controlled trial of astaxanthin impacts on antioxidant status and assisted reproductive technology outcomes in women with polycystic ovarian syndrome[J]. J Assist Reprod Genet, 2022, 39(4):995-1008. doi: 10.1007/s10815-022-02432-0.
[36]	Li Y, Xu J, Li L, et al. Inhibition of Nicotinamide adenine dinucleotide phosphate oxidase 4 attenuates cell apoptosis and oxidative stress in a rat model of polycystic ovary syndrome through the activation of Nrf-2/HO-1 signaling pathway[J]. Mol Cell Endocrinol, 2022, 550:111645. doi: 10.1016/j.mce.2022.111645.
[37]	赵洪强, 时敬爱, 王金权, 等. 大豆异黄酮调节Nrf2/HO-1信号通路对多囊卵巢综合征大鼠卵巢组织损伤的影响[J]. 中国药学杂志, 2023, 58(8):699-707. doi: 10.11669/cpj.2023.08.007.
[38]	Xu A, Fan Y, Liu S, et al. GIMAP7 induces oxidative stress and apoptosis of ovarian granulosa cells in polycystic ovary syndrome by inhibiting sonic hedgehog signalling pathway[J]. J Ovarian Res, 2022, 15(1):141. doi: 10.1186/s13048-022-01092-z. pmid: 36581994
[39]	Ding Y, Jiang Y, Zhu M, et al. Follicular fluid lipidomic profiling reveals potential biomarkers of polycystic ovary syndrome: A pilot study[J]. Front Endocrinol(Lausanne), 2022, 13:960274. doi: 10.3389/fendo.2022.960274.
[40]	Belani MA, Shah P, Banker M, et al. Investigating the potential role of swertiamarin on insulin resistant and non-insulin resistant granulosa cells of poly cystic ovarian syndrome patients[J]. J Ovarian Res, 2023, 16(1):55. doi: 10.1186/s13048-023-01126-0. pmid: 36932437
[41]	郭禹含. YAP1调控PPAR-γ通路在PCOS患者颗粒细胞脂质代谢异常中的作用研究[D]. 郑州: 郑州大学, 2022.
[42]	Di F, Liu J, Li S, et al. Activating transcriptional factor 4 correlated with obesity and insulin resistance in polycystic ovary syndrome[J]. Gynecol Endocrinol, 2019, 35(4):351-355. doi: 10.1080/09513590.2018.1527307. pmid: 30382797
[43]	Liu Q, Jiang J, Shi Y, et al. Apelin/Apelin receptor: A new therapeutic target in Polycystic Ovary Syndrome[J]. Life Sci, 2020, 260:118310. doi: 10.1016/j.lfs.2020.118310.
[44]	Bongrani A, Mellouk N, Ramé C, et al. Vaspin, a novel adipokine in woman granulosa cells physiology and PCOS pathogenesis?[J]. J Endocrinol, 2021, 249(1):57-70. doi: 10.1530/JOE-20-0550. pmid: 33608490
[45]	Li X, Zhu Q, Wang W, et al. Elevated chemerin induces insulin resistance in human granulosa-lutein cells from polycystic ovary syndrome patients[J]. FASEB J, 2019, 33(10):11303-11313. doi: 10.1096/fj.201802829R. pmid: 31311314
[46]	Kumariya S, Ubba V, Jha RK, et al. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective[J]. Autophagy, 2021, 17(10):2706-2733. doi: 10.1080/15548627.2021.1938914.
[47]	Xiong W, Lin Y, Xu L, et al. Circulatory microRNA 23a and microRNA 23b and polycystic ovary syndrome (PCOS): the effects of body mass index and sex hormones in an Eastern Han Chinese population[J]. J Ovarian Res, 2017, 10(1):10. doi: 10.1186/s13048-016-0298-8. pmid: 28193283