The role of the androgen receptor in insulin secretion

在退伍军人医疗系统中，患有睾酮缺乏的老年男性和雄激素枯竭的男性 前列腺癌的治疗增加了患2型糖尿病(T2D)的风险。虽然研究 研究这一问题的重点是睾丸激素缺乏作为胰岛素风险因素的作用。 耐药性，这种方法忽略了睾酮缺乏作为胰腺β细胞的潜在原因的作用 男性的功能障碍。尽管已经证实，睾酮的作用是通过雄激素介导的 受体(AR)-配体激活的转录因子-AR在T2D IS的β细胞功能障碍中的作用 未知。解决雄激素问题的新工作具有巨大的治疗应用潜力 大部分老年男性在T2D背景下的缺陷。来自中国的新的影响深远的初步数据 我们的实验室表明，β细胞(βARKO)AR有条件缺失的雄性小鼠表现出减少 葡萄糖刺激的胰岛素分泌(GSI)和β细胞无法补偿高脂肪饮食- 诱导胰岛素抵抗。培养的人体内存在睾酮-AR轴的促胰岛素作用 雄性人类的胰岛。最重要的是，在β-细胞中，AR是核外的，AR对细胞的刺激作用 GSIS涉及cAMP的产生和蛋白激酶A(PKA)的激活。最后，睾丸素会放大 GLP-1促进啮齿动物胰岛GSIS的表达因此，这样做的目的是 应用：1)探索睾丸激素对AR的作用增强GLP-1作用的新范式 在β细胞中和2)阐明在核外区维持AR的分子决定因素 增强β-1受体作用的细胞。这项授权将产生的知识将填补关键 我们对的基本机制--男性细胞功能障碍--的理解存在差距。此信息将 为开发以组织特异性方式调节AR以防止 无前列腺癌或心血管副作用的糖尿病。因此，拟议的工作将具有重大的科学意义 对退伍军人医疗保健系统人群产生影响并开辟临床相关途径。

In the Veterans Healthcare System, aging men with testosterone deficiency and men on androgen depletion therapy for prostate cancer are at increased risk of developing type 2 diabetes (T2D). Although studies examining this issue have focused on the role of testosterone deficiency as a risk factor for insulin resistance, this approach ignores the role of testosterone deficiency as a potential cause of pancreatic β–cell dysfunction in men. Although it has been established that testosterone action is mediated via the androgen receptor (AR) -a ligand-activated transcription factor- the role of the AR in β-cell dysfunction in T2D is unknown. There is tremendous potential for therapeutic application of novel work that addresses androgen deficiency in the context of T2D in large segments of aging men. The new far-reaching preliminary data from our laboratory show that male mice with conditional deletion of the AR in β-cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) and develop β-cell failure to compensate for high fat diet- induced insulin resistance. The insulinotropic function of the testosterone-AR axis is present in cultured male human islets. Most importantly, in β-cells, the AR is extranuclear, and the stimulatory effect of AR on GSIS involves cAMP generation and protein kinase A (PKA) activation. Finally, testosterone amplifies glucagon-like peptide-1 (GLP-1) enhancement of GSIS in rodent islets. Accordingly, the aims of this application are: 1) To explore a novel paradigm in which testosterone action on AR enhances GLP-1 action in β-cells and 2) To elucidate the molecular determinants that maintain AR in an extranuclear compartment of β-cells that amplify GLP-1 receptor action. The knowledge that will be generated by this grant will fill key gaps in our understanding of the fundamental mechanism of -cell dysfunction in men. This information will provide the foundation for development of approaches to modulate AR in a tissue-specific manner to prevent diabetes without prostate or cardiovascular side effects. Thus, the proposed work will have major scientific impact and open clinically relevant avenues for the Veterans Healthcare System population.