Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hypoinsulinemia and hyperglycemia when challenged with a Western diet. Testosterone activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of glucagon-like peptide-1 (GLP-1). Here, using a combination of βARKO and β cell-selective GLP-1 receptor knockout mice and their islets, we show that AR activation in β cells amplifies the insulinotropic effect of islet-derived GLP-1. In β cell models expressing cAMP sensors, testosterone enhances the ability of GLP-1, but not that of glucose-dependent insulinotropic polypeptide or glucagon, to produce cAMP. Accordingly, testosterone selectively enhances the ability of GLP-1 to potentiate GSIS. Notably, testosterone enhances GLP-1 production of cAMP at the plasma membrane and endosomes. In male mouse and human islets, the insulinotropic effect of testosterone is abolished following inhibition of the membrane and endosomal cAMP-dependent protein kinase A and exchange protein activated by cAMP islet 2 pathways. Thus, membrane localization of AR enhances the ability of the GLP-1 receptor to produce cAMP, thus increasing glucose-stimulated insulin exocytosis.

中文翻译：

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睾丸激素可增强质膜和内体的GLP-1功效，从而增强雄性胰腺β细胞的胰岛素分泌

胰岛β细胞（βARKO）中消除了雄激素受体（AR）的雄性小鼠表现出钝化的葡萄糖刺激的胰岛素分泌（GSIS），在用西方饮食攻击时会导致低胰岛素血症和高血糖症。β细胞中核外AR的睾丸激素活化通过放大胰高血糖素样肽-1（GLP-1）的促胰岛素作用来增强GSIS。在这里，结合使用βARKO和β细胞选择性GLP-1受体基因敲除小鼠及其胰岛的组合，我们显示β细胞中的AR激活可放大胰岛衍生的GLP-1的促胰岛素作用。在表达cAMP传感器的β细胞模型中，睾丸激素可增强GLP-1（而非葡萄糖依赖性促胰岛素多肽或胰高血糖素）产生cAMP的能力。因此，睾丸激素选择性地增强了GLP-1增强GSIS的能力。值得注意的是 睾丸激素可增强质膜和内体的cAMP的GLP-1产生。在雄性小鼠和人类胰岛中，在抑制膜和内体cAMP依赖性蛋白激酶A和cAMP胰岛2途径激活的交换蛋白后，睾丸激素的促胰岛素作用被消除。因此，AR的膜定位增强了GLP-1受体产生cAMP的能力，从而增加了葡萄糖刺激的胰岛素胞吐作用。