Study on action mechanism of metformin on insulin resistance in rats with polycystic ovary syndrome

WANG Mingkai; ZHANG Xinhua; LI Wei; QIANG Ping

doi:10.7619/jcmp.20214796

Journal of Clinical Medicine in Practice > 2022 > 26(9): 1-7. > DOI: 10.7619/jcmp.20214796

WANG Mingkai, ZHANG Xinhua, LI Wei, QIANG Ping. Study on action mechanism of metformin on insulin resistance in rats with polycystic ovary syndrome[J]. Journal of Clinical Medicine in Practice, 2022, 26(9): 1-7. DOI: 10.7619/jcmp.20214796

Citation:

PDF (4324 KB)

Study on action mechanism of metformin on insulin resistance in rats with polycystic ovary syndrome

1.
Department of Pharmacy, Division of Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001
2.
Department of Human Anatomy, Medical College of Nantong University, Nantong, Jiangsu, 226001
3.
Department of Renal Endocrinology, Nantong Hospital of Traditional Chinese Medicine of Jiangsu Province, Nantong, Jiangsu, 226001
4.
Department of Obstetrics and Gynecology, Zhangjiagang Hospital Affiliated to Suzhou University, Suzhou, Jiangsu, 215600

More Information

Received Date: December 05, 2021
Available Online: May 06, 2022
Published Date: May 14, 2022

Graphical Abstract

Abstract

Abstract

Objective To explore the action mechanism of metformin in improving insulin resistance of rats with polycystic ovary syndrome (PCOS) by interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway.
Methods A total of 50 SD rats were injected subcutaneously with dehydroepiandrosterone into the back of the neck to establish a PCOS model, and were randomly divided into model group, metformin group, STAT3 inhibitor group, IL-6 activator group, and metformin+IL-6 activator group, with 10 rats per group. Another 10 SD rats (subcutaneously injected with oil 2 mL/kg on the back of the neck) were selected as sham operation group. The levels of blood glucose, testosterone (androgen), insulin level of rats in each group were measured, and the insulin resistance index was calculated; hematoxylin and eosin staining (HE) was performed to observe the ovarian morphology; immunohistochemical method was performed to measure the positive expression of IL-6; real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method was performed to measure the level of microRNA-21 (miR-21); western blot was performed to measure the expressions of IL-6, STAT3, phosphorylated-STAT3 (p-STAT3) and downstream insulin receptor substrate-2 (IRS-2), signal transduction pathway inhibitor protein 3 (SOCS-3), peroxisome proliferator activation receptor γ (PPARγ) proteins.
Results Compared with the sham operation group, the insulin resistance index[(40.88±3.74) versus (15.23±1.00)] and androgen secretion level[(1.73±0.19) ng/mL versus(1.10±0.10) ng/mL] in the model group were increased, the follicles cystic changes, the disappearance of the oocyte radiation crown, the decrease of the corpus luteum and the granulosa cells and other pathological damages in the ovarian tissue were serious, the IL-6/STAT3 pathway was in an active state, leading to inflammation, insulin resistance, androgen secretion-related proteins and genes mediated increased (P<0.05). Compared with the model group, IL-6/STAT3 pathway activation in both metformin group and STAT3 inhibitor group were inhibited, and insulin resistance index[(20.39±2.41), (20.89±2.54) versus (40.88±3.74)] and androgen secretion level[(1.29±0.11) ng/mL, (1.29±0.11) ng/mL versus (1.73±0.19) ng/mL](P<0.05). Compared with the metformin group, insulin resistance index[(39.87±3.88) versus (20.39±2.41)], androgen secretion level[(1.70±0.18) versus (1.29±0.11)ng/mL] in the metformin+IL-6 activator group increased, and the recovery of ovarian pathological injury was slow, the differences were statistically significant (P<0.05).
Conclusion Metformin can inhibit IL-6/STAT3 activation to improve insulin resistance, androgen secretion and ovarian morphology changes of PCOS rats.
- metformin,
- polycystic ovary syndrome,
- interleukin-6,
- signal transducer and activator of transcription 3,
- insulin resistance

FullText(HTML)

References (23)

References

[1]	ALBAGHDADI A J H, KAN F W K. Therapeutic potentials of low-dose tacrolimus for aberrant endometrial features in polycystic ovary syndrome[J]. Int J Mol Sci, 2021, 22(6): 2872. doi: 10.3390/ijms22062872
[2]	李慕白, 陈靖馨, 王婷婷, 等. 多囊卵巢综合征子宫内膜胰岛素抵抗的研究进展[J]. 中国医药导报, 2019, 16(29): 49-52. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY201929012.htm
[3]	AZZIZ R. Systemic chronic subclinical inflammation, adipose tissue dysfunction, and polycystic ovary syndrome: three major forces intertwined[J]. Fertil Steril, 2021, 116(4): 1147-1148. doi: 10.1016/j.fertnstert.2021.08.017
[4]	LUO P C, WANG Y N, ZHAO C Q, et al. Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling[J]. Eur J Pharmacol, 2021, 893: 173822. doi: 10.1016/j.ejphar.2020.173822
[5]	KHODARAHMI A, ESHAGHIAN A, SAFARI F, et al. Quercetin mitigates hepatic insulin resistance in rats with bile duct ligation through modulation of the STAT3/SOCS₃/IRS1 signaling pathway[J]. J Food Sci, 2019, 84(10): 3045-3053. doi: 10.1111/1750-3841.14793
[6]	KALININA T S, KONONCHUK V V, YAKOVLEVA A K, et al. Association between lymph node status and expression levels of androgen receptor, miR-185, miR-205, and miR-21 in breast cancer subtypes[J]. Int J Breast Cancer, 2020, 2020: 3259393. https://pubmed.ncbi.nlm.nih.gov/32373367/
[7]	ZHAO Q T, HUANG L, QIN G H, et al. Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma[J]. Cancer Lett, 2021, 518: 35-48. doi: 10.1016/j.canlet.2021.06.009
[8]	刘湾湾, 唐玲丽, 李东海, 等. 二甲双胍对中心性肥胖和非中心性肥胖多囊卵巢综合征患者生殖内分泌及糖脂代谢的影响[J]. 中华生殖与避孕杂志, 2019, 39(1): 57-60. https://www.cnki.com.cn/Article/CJFDTOTAL-JLYX202102041.htm
[9]	王婧. 黄芩苷联合二甲双胍对多囊卵巢综合征大鼠的影响及机制[J]. 中国临床药理学杂志, 2019, 35(14): 1467-1469. https://www.cnki.com.cn/Article/CJFDTOTAL-GLYZ201914015.htm
[10]	CHEN S L, CAI G X, DING H G, et al. JAK/STAT signaling pathway-mediated microRNA-181b promoted blood-brain barrier impairment by targeting sphingosine-1-phosphate receptor 1 in septic rats[J]. Ann Transl Med, 2020, 8(21): 1458. doi: 10.21037/atm-20-7024
[11]	TANAKA T, NARAZAKI M, KISHIMOTO T. IL-6 in inflammation, immunity, and disease[J]. Cold Spring Harb Perspect Biol, 2014, 6(10): a016295. doi: 10.1101/cshperspect.a016295
[12]	HUANG-DORAN I, KINZER A B, JIMENEZ-LINAN M, et al. Ovarian hyperandrogenism and response to gonadotropin-releasing hormone analogues in primary severe insulin resistance[J]. J Clin Endocrinol Metab, 2021, 106(8): 2367-2383. doi: 10.1210/clinem/dgab275
[13]	GONG H, WU W Q, XU J J, et al. Flutamide ameliorates uterine decidualization and angiogenesis in the mouse hyperandrogenemia model during mid-pregnancy[J]. PLoS One, 2019, 14(5): e0217095. doi: 10.1371/journal.pone.0217095
[14]	戚怀钻. 多囊卵巢综合征患者激素与胰岛素抵抗指数相关性研究[J]. 医药前沿, 2018, 8(7): 21-22. doi: 10.3969/j.issn.2095-1752.2018.07.025
[15]	赖雪梅, 黄金园, 张海燕, 等. 个体化营养指导与药物治疗对多囊卵巢综合征的疗效研究[J]. 西南大学学报: 自然科学版, 2020, 42(5): 102-107. https://www.cnki.com.cn/Article/CJFDTOTAL-XNND202005013.htm
[16]	邵洋, 杨婷婷, 张洁, 等. 二甲双胍通过PI3K-AKT-MDm2通路对PCOS患者子宫内膜的影响[J]. 实用药物与临床, 2019, 22(12): 1275-1278. https://www.cnki.com.cn/Article/CJFDTOTAL-LYLC201912012.htm
[17]	曾海霞, 黄艳婷, 吴娟, 等. 吡格列酮二甲双胍对多囊卵巢综合征代谢参数及激素的影响[J]. 现代妇产科进展, 2020, 29(11): 805-808. https://www.cnki.com.cn/Article/CJFDTOTAL-XDFC202011002.htm
[18]	GONZÅLEZ F, CONSIDINE R V, ABDELHADI O A, et al. Inflammation triggered by saturated fat ingestion is linked to insulin resistance and hyperandrogenism in polycystic ovary syndrome[J]. J Clin Endocrinol Metab, 2020, 105(6): e2152-e2167. doi: 10.1210/clinem/dgaa108
[19]	ALISSA E M, ALGARNI S A, KHAFFJI A J, et al. Role of inflammatory markers in polycystic ovaries syndrome: in relation to insulin resistance[J]. J Obstet Gynaecol Res, 2021, 47(4): 1409-1415. doi: 10.1111/jog.14684
[20]	GENDY A M, AMIN M M, AL-MOKADDEM A K, et al. Cilostazol mitigates mesenteric ischemia/reperfusion-induced lung lesion: contribution of PPAR-γ, NF-κB, and STAT3 crosstalk[J]. Life Sci, 2021, 266: 118882. doi: 10.1016/j.lfs.2020.118882
[21]	ABO EL-NASR N M E, SALEH D O, MAHMOUD S S, et al. Olmesartan attenuates type 2 diabetes-associated liver injury: cross-talk of AGE/RAGE/JNK, STAT3/SCOS₃ and RAS signaling pathways[J]. Eur J Pharmacol, 2020, 874: 173010. doi: 10.1016/j.ejphar.2020.173010
[22]	ZHANG Y L, LI C Z, ZHANG W H, et al. Decreased insulin resistance by myo-inositol is associated with suppressed interleukin 6/phospho-STAT3 signaling in a rat polycystic ovary syndrome model[J]. J Med Food, 2020, 23(4): 375-387. doi: 10.1089/jmf.2019.4580
[23]	YANG X, HUANG M, ZHANG Q, et al. Metformin antagonizes ovarian cancer cells malignancy through MSLN mediated IL-6/STAT3 signaling[J]. Cell Transplant, 2021, 30: 9636897211027819.

[1]	ZHOU Lina, HAN Yanhua, GENG Tiantian, LIU Li. Research progress in effects of hyperandrogenin and insulin resistance on placental pathology of polycystic ovary syndrome [J]. Journal of Clinical Medicine in Practice, 2023, 27(11): 137-141. DOI: 10.7619/jcmp.20223478
[2]	WANG Yaning, CUI Liye, CHEN Yilin, JIA Hongchao. Correlations of serum interleukin-6, Janus kinase/signal transducers and activators of transcription protein with immune function in children with viral bronchiolitis[J]. Journal of Clinical Medicine in Practice, 2022, 26(7): 78-81. DOI: 10.7619/jcmp.20214423
[3]	XIE Yu, WANG Chun, JIANG Ming. Effects of different doses of Caltrate D supplementation on insulin resistance in patients with impaired glucose tolerance and vitamin D deficiency[J]. Journal of Clinical Medicine in Practice, 2017, (19): 59-62. DOI: 10.7619/jcmp.201719017
[4]	XU Zhengrong, LIU Ming, SUN Haifeng, HU Limei, ZUO Lijuan, ZHANG Qiuzi. Influencing factors and prevention of insulin resistance in first-degree relatives of Graves disease patients with abnormal glucose metabolism[J]. Journal of Clinical Medicine in Practice, 2015, (15): 41-43. DOI: 10.7619/jcmp.201515012
[5]	JIN Shilu, QU Dongdong. Changes of serum tumor necrosis factor-α and interlukin-6 levels in patients with non-alcoholic fatty liver and its correlation with insulin resistance[J]. Journal of Clinical Medicine in Practice, 2015, (5): 48-50. DOI: 10.7619/jcmp.201505015
[6]	YANG Zhiqin, ZHANG Xuehui, TANG Xinsheng. Effects of metformin on serum lipid metabolism and insulin resistance in patients with polycystic ovary syndrome[J]. Journal of Clinical Medicine in Practice, 2014, (23): 63-66. DOI: 10.7619/jcmp.201423021
[7]	BAI Xiaogang, LI Xia, LI Wei. Relationship between fasting serum resistin level and insulin resistance in the elderly type 2 diabetic patients with metabolic syndrome[J]. Journal of Clinical Medicine in Practice, 2014, (15): 4-7,24. DOI: 10.7619/jcmp.201415002
[8]	YANG Yongbi. Changes of serum adiponectin in hypertensive disorder complicating pregnancy patients with hypertension and its relationship with insulin resistance[J]. Journal of Clinical Medicine in Practice, 2014, (3): 124-126. DOI: 10.7619/jcmp.201403044
[9]	ZHU Dan. Comparison of effects of early intensive therapy and conventional therapy on β-cell function and insulin resistance in patients with preliminary diagnostic type 2 diabetes[J]. Journal of Clinical Medicine in Practice, 2013, (24): 10-12. DOI: 10.7619/jcmp.201324003
[10]	LI Caihui, JIA Xueqin. Study on the relationship between uric acid and insulin resistance in patients with gestational diabetes mellitus[J]. Journal of Clinical Medicine in Practice, 2013, (16): 113-114,119. DOI: 10.7619/jcmp.201316044

Cited By

Cited by

Periodical cited type(11)

1.	刘盈，刘劲松，吴猛. 孕晚期经会阴超声联合血清弹性蛋白对产后盆底功能障碍的预测价值. 中国计划生育和妇产科. 2025(01): 78-83 .
2.	周锋，李晓彦，岳丽，康华. 盆底超声参数联合血生化指标对产后早期压力性尿失禁的诊断效能. 中国超声医学杂志. 2025(03): 308-312 .
3.	刘英，于水昌，杨红芳. 经会阴盆底超声联合血清sMFAP4、LTBP-2对产后盆底功能障碍性疾病的临床诊断价值. 检验医学与临床. 2025(06): 773-777 .
4.	姜玉华，刘传金，王冰芝，王琳娜. 基于盆底超声参数及血清学指标建立的列线图模型预测初产妇压力性尿失禁的临床价值. 临床超声医学杂志. 2024(03): 244-248 .
5.	张莹莹，梁琛，李晓燕，张艳玲，酒卫莉. 盆底功能障碍性疾病患者血清miR-4429和miR-19-3p水平表达及临床价值研究. 现代检验医学杂志. 2024(02): 119-123 .
6.	杨博，石克威，李亚楠，尚芯羽. 初产妇产后血清25-（OH）D、OPN、TGF-β1水平对产后盆底功能障碍的预测价值. 分子诊断与治疗杂志. 2024(04): 725-729 .
7.	张馨，安慧，蔡敏，张红菊. 生物电反馈刺激联合心理护理治疗对产后女性性功能障碍的作用. 空军军医大学学报. 2024(05): 563-566 .
8.	郭倩倩，孟君艳，李斌. 盆底超声参数联合血清elafin、TGF-β1水平在预测产后压力性尿失禁中的应用价值. 国际泌尿系统杂志. 2024(06): 1083-1087 .
9.	高鑫，贾红娥，李倩，康旺旺. 盆底三维超声参数联合血清基质金属蛋白酶-1、骨桥蛋白、结缔组织生长因子水平对压力性尿失禁疾病严重程度的预测价值. 陕西医学杂志. 2023(02): 149-153 .
10.	林婕，白丽娟，沈秋妮，傅晓冬. 血清TIMP-1联合elafin水平对自然分娩初产妇产后压力性尿失禁的预测价值. 临床和实验医学杂志. 2023(15): 1628-1632 .
11.	肖华，杨静，崔佑萍，杜欣. 针灸联合补中益气汤加减治疗产后盆底功能障碍的效果. 广西医学. 2022(16): 1885-1889 .

Other cited types(0)

Get Citation

PDF

XML

Article views (398) PDF downloads (48) Cited by(11)

Turn off MathJax

Article Contents

Abstract

References

Study on action mechanism of metformin on insulin resistance in rats with polycystic ovary syndrome