目的:多囊卵巢综合征(PCOS)是一种内分泌代谢疾病,影响5-10%的育龄女性,其特征是高雄激素血症,胰岛素抵抗(IR),和高胰岛素血症.已知CFTR受类固醇激素调节,我们之前的研究已经证明了CFTR在β细胞功能中的重要作用。本研究旨在探讨雄激素和CFTR在PCOS胰岛素高分泌中的作用及其机制。
方法:我们通过皮下植入含有双氢睾酮(DHT)的硅管建立了大鼠PCOS模型。在植入后9周进行具有胰岛素水平的葡萄糖耐量试验。大鼠β细胞系RINm5F,小鼠β-细胞系β-TC-6和小鼠胰岛用DHT处理,和有或没有雄激素拮抗剂氟他胺用于CFTR和胰岛素分泌相关功能测定或mRNA/蛋白质表达测量。CFTR抑制剂对DHT促进膜去极化的影响,通过膜电位成像检查葡萄糖刺激的细胞内Ca2振荡和胰岛素分泌,钙成像和ELISA,分别。
结果:DHT诱导的PCOS模型显示体重增加,糖耐量受损,葡萄糖刺激后血糖和胰岛素水平升高。CFTR在PCOS模型和DHT处理细胞的胰岛中上调,被氟他胺逆转了.雄激素受体(AR)可以与CFTR启动子区结合,由DHT增强。此外,DHT诱导的膜去极化,增强葡萄糖刺激的Ca2+振荡和胰岛素分泌,可以通过CFTR抑制剂废除。
结论:过量的雄激素通过上调CFTR增强葡萄糖刺激胰岛素分泌,这可能有助于PCOS的高胰岛素血症。
OBJECTIVE: 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.