Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
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DOI：
10.1016/j.cmet.2016.03.015
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发表时间：
2016-05-10
期刊：
影响因子：
29
通讯作者：
Mauvais-Jarvis F
中科院分区：
文献类型：
--
作者：
Navarro G;Xu W;Jacobson DA;Wicksteed B;Allard C;Zhang G;De Gendt K;Kim SH;Wu H;Zhang H;Verhoeven G;Katzenellenbogen JA;Mauvais-Jarvis F
虽然睾酮缺乏的男性患2型糖尿病（T2D）的风险增加，但以前的研究忽略了睾酮和雄激素受体（AR）在胰腺β细胞中的作用。我们发现，在β-细胞（βARKO）中缺乏AR的雄性小鼠表现出葡萄糖刺激胰岛素分泌（GSIS）减少，导致葡萄糖耐受不良。AR激动剂双氢睾酮（DHT）增强了培养的男性胰岛的GSIS，这一作用在βARKO−/y胰岛和用AR拮抗剂治疗的人胰岛中被消除。在β-细胞中，DHT激活的AR主要位于核外，并通过增加胰岛cAMP和激活蛋白激酶a来增强GSIS。在小鼠和人胰岛中，DHT的促胰岛素作用依赖于胰高血糖素样肽-1 （GLP-1）受体的激活，因此DHT放大了GLP-1的促胰岛素作用。本研究确定AR是一种增强β细胞功能的新型受体，这一发现对老年男性预防T2D具有重要意义。
Although men with testosterone deficiency are at increased risk of type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β–cells. We show that male mice lacking AR in β-cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO−/y islets and human islets treated with an AR antagonist. In β-cells, DHT-activated AR is predominantly extranuclear and enhances GSIS by increasing islet cAMP and activating the protein kinase A. In mouse and human islets, the insulinotropic effect of DHT depends on activation of the glucagon like peptide-1 (GLP-1) receptor and accordingly, DHT amplifies the incretin effect of GLP-1. This study identifies AR as a novel receptor that enhances β-cell function, a finding with implications for prevention of T2D in aging men.