Androgens impair β-cell function in a mouse model of polycystic ovary syndrome by activating endoplasmic reticulum stress

Zhu, Bo; Chen, Yumei; Xu, Fang; Shen, Xiaojuan; Chen, Xuanyu; Lv, Jieqiang

doi:10.1530/ec-20-0608

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…Hyperinsulinemia can lead to the exhaustion of β-cells. Misfolded proteins of proinsulin accumulate in the cisternae of the endoplasmic reticulum of pancreatic β cells, resulting in ER stress, apoptosis as well as inflammation (39) .…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin, Myoinositol and Metformin Modulate Insulin Sensitivity Indices, Pancreatic Beta Cell Mass and Hepatocellular Changes in a Rat Model of Polycystic Ovary Syndrome

mohammed

Elhaliem

Fanous

et al. 2022

Ain Shams Medical Journal

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Background: Polycystic ovary syndrome (PCOS) is a common health problem in females throughout their reproductive age. Common symptoms of PCOS are hyperandrogenemia, menstrual disorders, and infertility. Metabolic disorders like insulin resistance and steatotic liver are also common. Metformin is most commonly used in the management of hyperglycemia. Erythropoietin and myoinositol were reported to improve insulin sensitivity.Objective: This study aimed to compare the potential therapeutic role of erythropoietin, myoinositol, and the widely used metformin drug against hyperinsulinemia and hepatic injury of the letrozole-induced PCOS model in rats. Materials and methods:Fifty female Wistar rats were classified equally into five groups: The control group and the PCO model group. PCO model was induced by letrozole in a dose of 0.5 mg/kg daily for 3 weeks. Then rats with PCO were administrated: erythropoietin in (EPO/PCO) group, myoinositol in (MYO/PCO) group, or metformin in (MET/PCO) group for the following 21 days. Biochemical and histological studies on the liver and pancreas were done. Immunohistochemical staining with GLUT-1 and insulin was done.Results: PCO rats developed insulin resistance with pancreatic β cell degeneration, hepatocellular injury, and upregulation of hepatic GLUT-1. Metformin, erythropoietin, and myoinositol restored β-cell mass, decreased hyperinsulinemia, and attenuated hepatocellular degeneration via the reduction of stress-induced hepatic GLUT-1. However, erythropoietin was the most effective one of them. Conclusion:Erythropoietin was more effective than metformin and myoinositol in decreasing hyperinsulinemia and attenuation of hepatocellular injury associated with the letrozole-induced model of PCOS.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin, Myoinositol and Metformin Modulate Insulin Sensitivity Indices, Pancreatic Beta Cell Mass and Hepatocellular Changes in a Rat Model of Polycystic Ovary Syndrome

mohammed

Elhaliem

Fanous

et al. 2022

Ain Shams Medical Journal

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“…Both ER stress and the levels of proapoptotic factors are high in the pancreatic islets of mice with PCOS ( 59 ). Testosterone induces both of these abnormalities and the apoptosis of cultured islet cells, while the ER stress inhibitors TUDCA and 4-phenylbutylic acid (4-PBA), and the androgen receptor antagonist flutamide, ameliorate testosterone-induced ER stress and apoptosis in these cells ( 60 ).…”

Section: Pathophysiological Role Of Er Stress In Pcosmentioning

confidence: 99%

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome

Koike

Harada²,

Kusamoto³

et al. 2023

Front. Endocrinol.

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

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“…Reduced expression of glucose transporter type 4 (GLUT-4) in lipocytes might also be a reason of impaired insulin responsiveness [ 66 , 70 ]. β-cell dysfunction is another culprit of IR which militates against proinsulin maturation and insulin secretion [ 71 ]. However, as IR has a genetic predisposition in PCOS, it remains dubious whether the defects in β-cell function precede IR or develop after it [ 72 – 74 ].…”

Section: Il-22 and Irmentioning

confidence: 99%

Opportunities and challenges: interleukin-22 comprehensively regulates polycystic ovary syndrome from metabolic and immune aspects

Geng,

Liu,

et al. 2023

J Ovarian Res

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Polycystic ovary syndrome (PCOS) is known as a prevalent but complicated gynecologic disease throughout the reproductive period. Typically, it is characterized by phenotypic manifestations of hyperandrogenism, polycystic ovary morphology, and persistent anovulation. For now, the therapeutic modality of PCOS is still a formidable challenge. Metabolic aberrations and immune challenge of chronic low-grade inflammatory state are significant in PCOS individuals. Recently, interleukin-22 (IL-22) has been shown to be therapeutically effective in immunological dysfunction and metabolic diseases, which suggests a role in the treatment of PCOS. In this review, we outline the potential mechanisms and limitations of IL-22 therapy in PCOS-related metabolic disorders including its regulation of insulin resistance, gut barrier, systemic inflammation, and hepatic steatosis to generate insights into developing novel strategies in clinical practice.

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Androgens impair β-cell function in a mouse model of polycystic ovary syndrome by activating endoplasmic reticulum stress

Cited by 5 publications

References 39 publications

Erythropoietin, Myoinositol and Metformin Modulate Insulin Sensitivity Indices, Pancreatic Beta Cell Mass and Hepatocellular Changes in a Rat Model of Polycystic Ovary Syndrome

Erythropoietin, Myoinositol and Metformin Modulate Insulin Sensitivity Indices, Pancreatic Beta Cell Mass and Hepatocellular Changes in a Rat Model of Polycystic Ovary Syndrome

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome

Opportunities and challenges: interleukin-22 comprehensively regulates polycystic ovary syndrome from metabolic and immune aspects

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