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03.11.2023 | Original Article

Androgen-induced upregulation of CFTR in pancreatic β-cell contributes to hyperinsulinemia in PCOS model

verfasst von: Mengzhu Sun, Yong Wu, Chun Yuan, Jingya Lyu, Xinyi Zhao, Ye Chun Ruan, Jinghui Guo, Hui Chen, Wen Qing Huang

Erschienen in: Endocrine | Ausgabe 1/2024

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Abstract

Purpose

Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5–10% of reproductive-aged women and characterized by hyperandrogenism, insulin resistance (IR), and hyperinsulinemia. CFTR is known to be regulated by steroid hormones, and our previous study has demonstrated an essential role of CFTR in β-cell function. This study aims to investigate the contribution of androgen and CFTR to hypersecretion of insulin in PCOS and the underlying mechanism.

Methods

We established a rat PCOS model by subcutaneously implanting silicon tubing containing Dihydrotestosterone (DHT). Glucose tolerance test with insulin levels was performed at 9 weeks after implantation. A rat β-cell line RINm5F, a mouse β-cell line β-TC-6, and mouse islets were treated with DHT, and with or without the androgen antagonist flutamide for CFTR and insulin secretion-related functional assays or mRNA/protein expression measurement. The effect of CFTR inhibitors on DHT-promoted membrane depolarization, glucose-stimulated intracellular Ca²⁺ oscillation and insulin secretion were examined by membrane potential imaging, calcium imaging and ELISA, respectively.

Results

The DHT-induced PCOS model showed increased body weight, impaired glucose tolerance, and higher blood glucose and insulin levels after glucose stimulation. CFTR was upregulated in islets of PCOS model and DHT-treated cells, which was reversed by flutamide. The androgen receptor (AR) could bind to the CFTR promoter region, which was enhanced by DHT. Furthermore, DHT-induced membrane depolarization, enhanced glucose-stimulated Ca²⁺ oscillations and insulin secretion, which could be abolished by CFTR inhibitors.

Conclusions

Excessive androgen enhances glucose-stimulating insulin secretion through upregulation of CFTR, which may contribute to hyperinsulinemia in PCOS.

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Titel: Androgen-induced upregulation of CFTR in pancreatic β-cell contributes to hyperinsulinemia in PCOS model
verfasst von: Mengzhu Sun
Yong Wu
Chun Yuan
Jingya Lyu
Xinyi Zhao
Ye Chun Ruan
Jinghui Guo
Hui Chen
Wen Qing Huang
Publikationsdatum: 03.11.2023
Verlag: Springer US
Erschienen in: Endocrine / Ausgabe 1/2024
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-023-03516-2

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Androgen-induced upregulation of CFTR in pancreatic β-cell contributes to hyperinsulinemia in PCOS model