胰岛素对女性脂肪组织中 AKR1C3 表达的影响：多囊卵巢综合征脂肪雄激素生成的体内和体外研究。

Effect of insulin on AKR1C3 expression in female adipose tissue: in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome.

机构信息

Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK.

出版信息

Lancet. 2015 Feb 26;385 Suppl 1:S16. doi: 10.1016/S0140-6736(15)60331-2.

DOI:10.1016/S0140-6736(15)60331-2

PMID:26312838

Abstract

BACKGROUND

Insulin resistance and hyperandrogenism are the cardinal features of polycystic ovary syndrome (PCOS). Women with insulin receptor (INSR) mutations develop severe hyperandrogenism secondary to hyperinsulinaemia. We hypothesised that insulin might drive adipose testosterone generation from androstenedione through aldoketoredutase type 3 (AKR1C3) in women with insulin resistance. Here we assessed the effect of insulin on AKR1C3 activity in vivo and in vitro.

METHODS

Ten women with PCOS, ten healthy controls, and three women with INSR mutations underwent dehydroepiandrosterone (DHEA) challenge; serum androgens were measured every 30 min for 4 h after ingestion of 100 mg DHEA. Additionally, paired subcutaneous and omental fat samples were obtained during abdominal surgery from 38 women. AKR1C3 expression was measured by real-time PCR. Serum steroids and cultured cell media androgens were measured with liquid chromatography tandem mass spectrometry.

FINDINGS

Women with PCOS had higher androstenedione concentrations than did controls and women with INSR mutations (p=0·01 and p=0·005, respectively). However, area under the curve for testosterone was higher in women with INSR mutations after DHEA than in women with PCOS and controls (874·2 [SE 242] vs 425 [136] and 375·2 [109], p<0·001 for both). AKR1C3 mRNA expression was significantly higher in subcutaneous than in omental adipose tissue (p=0·004). AKR1C3 expression correlated positively with body-mass index in subcutaneous fat (Spearman correlation=0·51, p=0·006). Insulin significantly increased AKR1C3 expression in differentiated subcutaneous adipocytes (p=0·04). Incubation with insulin significantly increased testosterone generation from androstenedione in cultured subcutaneous cell media compared with controls (p<0·001).

INTERPRETATION

We have found in-vivo and in-vitro evidence of modulation of AKR1C3 activity by insulin in PCOS and in women with INSR mutations. Insulin seems to drive adipose androgen generation by increasing AKR1C3 activity in female subcutaneous adipose tissue. Selective AKR1C3 inhibition might offer a novel therapeutic target to reduce androgen burden and improve metabolic phenotype in PCOS.

FUNDING

Wellcome Trust.

摘要

背景

胰岛素抵抗和高雄激素血症是多囊卵巢综合征（PCOS）的主要特征。胰岛素受体（INSR）突变的女性由于高胰岛素血症而导致严重的高雄激素血症。我们假设胰岛素可能通过醛酮还原酶 3（AKR1C3）将雄烯二酮转化为睾酮，从而驱动胰岛素抵抗女性的脂肪产生睾酮。在此，我们评估了胰岛素对体内和体外 AKR1C3 活性的影响。

方法

10 名 PCOS 女性、10 名健康对照者和 3 名 INSR 突变女性接受脱氢表雄酮（DHEA）挑战；在摄入 100mg DHEA 后，每 30 分钟测量一次血清雄激素，共 4 小时。此外，在腹部手术期间，从 38 名女性中获得了配对的皮下和网膜脂肪样本。通过实时 PCR 测量 AKR1C3 表达。使用液相色谱串联质谱法测量血清类固醇和培养细胞培养基中的雄激素。

结果

PCOS 女性的雄烯二酮浓度高于对照组和 INSR 突变女性（分别为 p=0.01 和 p=0.005）。然而，DHEA 后 INSR 突变女性的睾酮曲线下面积高于 PCOS 女性和对照组（874.2[SE 242]vs.425[136]和 375.2[109]，两者均 p<0.001）。AKR1C3mRNA 表达在皮下脂肪中明显高于网膜脂肪（p=0.004）。AKR1C3 表达与皮下脂肪的体重指数呈正相关（Spearman 相关系数=0.51，p=0.006）。胰岛素显著增加分化的皮下脂肪细胞中 AKR1C3 的表达（p=0.04）。与对照组相比，胰岛素孵育显著增加了培养的皮下细胞培养基中从雄烯二酮生成睾酮（p<0.001）。