Effects of metformin and Exenatide on insulin resistance and AMPKα-SIRT1 molecular pathway in PCOS rats

Xin, Tao; Cai, Lixin; Chen, Lei; Ge, Shengfang; Deng, Xuanying

doi:10.1186/s13048-019-0555-8

Cited by 36 publications

(32 citation statements)

References 28 publications

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“…In our previous study [7,8], insulin resistance in PCOS rats was associated with the AMPKα-SIRT1 pathway. Furthermore, in our newly study showed that both EX and MET could improve the reproductive and endocrine functions of PCOS mice via the AMPKα-SIRT1 pathway, which may be the molecular mechanism for IR in PCOS and could possibly serve as a therapeutic target [9].…”

Section: Introductionmentioning

confidence: 66%

“…It has been con rmed that MET and EX, extensively applied in metabolic diseases such as T2DM, metabolic syndrome, cardiovascular disease and PCOS, improved patients 'metabolic imbalance and protect patients from corresponding injury. We have investigated the interrelationship between these two drugs and AMPK-SIRT1 pathway in PCOS rat model ovaries, the improved ovarian reservation function has been seen in PCOS rats when intervened by EX or MET [9]. And now, this paper just focused on another side of the same study, the effect of EX on the endometrium of PCOS rat models.…”

Section: Discussionmentioning

confidence: 99%

“…After DHEA pretreatment, the PCOS models were constructed successfully. Details of construction were comprehensively presented in previous paper [9].…”

Section: Construction Of Pcos Model and Its Corresponding Parametersmentioning

confidence: 99%

“…And what is the endometrium morphological images in PCOS rats and what is the endometrium changes after EX treatment? So in this study [9], we have also observed the endometrium change and investigated whether their protective effects were correlated to the pathway of AMPKα-SIRT1.…”

Section: Introductionmentioning

confidence: 99%

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Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1

Cai

et al. 2020

Preprint

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Exenatide can contribute to the therapeutic effect for PCOS patients in restoring menstrual cycles. To exploring endometrial tissue change in PCOS rats and the effects of exenatide on endometrial tissue, we carried out in vivo study of PCOS rat models. Method: PCOS rat models were obtained after DHEA treatment, and the corresponding parameters were measured to confirm the establishment of PCOS models. Hematoxylin-eosin (H&E) staining was performed to observe endometrium morphological change, and western blot and RT-PCR were performed to identify the alteration AMP-activated protein kinase (AMPKα) and SIRT1 proteins and the relative expression of SIRT1 mRNA in endometrial cellular after the intervention of exenatide (EX). Results: The endometrium of PCOS rats appeared to not only the gland number increased but also the gland size enlarged. When the PCOS rats underwent EX treatment, the gland number decreased and the gland size narrowed, the expression of AMPKα and SIRT1 protein increased, and the expression of SIRT1 mRNA level augmented. Conclusion: EX could decrease gland number and narrow gland size in PCOS rat endometrium which may be partly via AMPKα-SIRT1 pathway.

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Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

“…After DHEA pretreatment, the PCOS models were constructed successfully. Details of construction were comprehensively presented in previous paper [9].…”

Section: Construction Of Pcos Model and Its Corresponding Parametersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1

Cai

et al. 2020

Preprint

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“…TXNIP knockout mice had improved insulin sensitivity and increased glucose uptake in both adipose and skeletal muscle [39]. In PCOS, metformin improved insulin resistance in a PCOS rat model via an AMPK alpha-SIRT1 pathway [44].…”

Section: Insulin Resistancementioning

confidence: 98%

New Insight into Metformin Mechanism of Action and Clinical Application

Yan¹,

Kover²,

Moore³

2020

Metformin [Working Title]

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Metformin is the first-line medication for Type 2 diabetes (T2D) treatment, and it is the only US FDA approved oral antidiabetic medication for pediatric patients with T2D 10 years and older. Metformin is also used to treat polycystic ovary syndrome (PCOS), another condition with underlying insulin resistance. The clinical applications of metformin are continuing to expand into other fields including cancer, aging, cardiovascular diseases, and neurodegenerative diseases. Metformin modulates multiple biological pathways. Its novel properties and effects continue to evolve; however, its molecular mechanism of action remains incompletely understood. In this chapter, we focus on the recent translational research and clinical data on the molecular action of metformin and the evidence linking the effects of metformin on insulin resistance, prediabetes, diabetes, aging, cancer, PCOS, cardiovascular diseases, and neurodegenerative diseases. Metformin 2 Mechanisms of actionThe potential mechanisms of metformin action involve several pathways. The AMPK-pathway plays an important role in metformin actions [2, 3]. Metformin inhibits the mitochondrial respiratory chain (complex I), which increases the AMP to ATP ratio, leading to the phosphorylation of AMP-activated protein kinase (AMPK) at Thr-172. We have demonstrated that metformin treatment increases protein level of phosphorylated AMPK in high-glucose-treated endothelial cells [4]. The phosphorylated AMPK subsequently phosphorylates multiple downstream effectors to regulate cellular metabolism and energy homeostasis [5]. These downstream effectors include thioredoxin interacting protein (TXNIP) and TBC1D1, a RAB-GTPase activating protein and a member of the tre-2/BUB2/cdc1 domain family. Phosphorylated TXNIP and TBC1D1 increase the plasma membrane localization of glucose transporter 1 (GLUT1) and GLUT4, respectively [6, 7], and regulate glycogen synthases (GYS1 and GYS2) to prevent the storage of glycogen [8]. Some actions of metformin have been found to be AMPK-independent [9].In diabetic mice, metformin has an effect on gut microbiota by inducing a profound shift in the gut microbial community profile, resulting in an increase in the Akkermansia spp. population [10] and cAMP-induced agmatine production [11], which may decrease absorption of glucose from the gastrointestinal tract and increase lipid metabolism respectively. In addition, metformin decreases insulin-induced suppression of fatty acid oxidation and lowers lipid content of hepatic cells [12].New Insight into Metformin Mechanism of Action and Clinical Application DOI: http://dx.doi.org/10.5772/intechopen.91148 association with insulin resistance. Metformin decreases the level of circulating branched-chain amino acids and reduces insulin resistance in a high-fat diet mouse model [22]. Metformin treatment lowers plasma ADMA which is associated with improved glycemic control in patients with T2D [23].Recent studies indicate that phosphatidylinositol-3-kinase/protein kinase B protein (PI3K/PKB, also known as ...

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Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

Hung

Zhang

Tan

et al. 2021

Medicinal Research Reviews

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Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF‐κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor‐β, Wnt/β‐catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N‐acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti‐inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.

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Effects of metformin and Exenatide on insulin resistance and AMPKα-SIRT1 molecular pathway in PCOS rats

Cited by 36 publications

References 28 publications

Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1

Exenatide Improves Endometrial Glands in PCOS Rats through AMPKα-SIRT1

New Insight into Metformin Mechanism of Action and Clinical Application

Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

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