The role of the androgen receptor in insulin secretion

雄激素受体在胰岛素分泌中的作用

• 批准号: 10045938
• 负责人: Franck Mauvais-Jarvis
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045938
• 关键词: Address; Aging; Androgen Receptor; Androgens; Beta Cell; Cardiovascular system; Cell physiology; Cells; Clinical; Cyclic AMP; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diabetes prevention; Drug Targeting; Epidemic; Estrogen Receptors; Exhibits; Failure; Female; Foundations; Functional disorder; GLP-I receptor; Generations; Genetic; Glucose; Goals; Grant; Healthcare Systems; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; Insulin deficiency; Investigation; Islet Cell; Knowledge; Laboratories; Life Expectancy; Ligands; Mediating; Metabolic; Metabolic dysfunction; Methods; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Peptides; Pharmacology; Physiological; Pilot Projects; Population; Prostate; Prostate Cancer therapy; Publishing; Research; Risk; Risk Factors; Rodent; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Structure of beta Cell of islet; Testosterone; Therapeutic; Time; Tissues; Veterans; Woman; Work; androgen sensitive; base; cardiovascular effects; clinically relevant; design; diabetes risk; estrogenic; glucagon-like peptide 1; human male; innovation; insulin secretion; islet; male; men; military veteran; mouse model; novel; novel strategies; novel therapeutic intervention; prevent; side effect; therapeutic target; tool; transcription factor

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.

在退伍军人医疗保健系统中，患有睾酮缺乏症的老年男性和雄激素耗竭的男性 尽管研究表明，癌症治疗会增加患前列腺 2 型糖尿病 (T2D) 的风险。 研究这个问题的重点是睾酮缺乏作为胰岛素危险因素的作用 抵抗，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 尽管已经确定睾酮作用是通过雄激素介导的。 受体 (AR) - 一种配体激活的转录因子 - AR 在 T2D β 细胞功能障碍中的作用是 未知。针对雄激素的新研究具有巨大的治疗应用潜力。 来自大量老年男性的 T2D 背景下的新的影响深远的初步数据。 我们的实验室表明，条件性删除 β 细胞 AR (β ARKO) 的雄性小鼠表现出下降 葡萄糖刺激胰岛素分泌 (GSIS) 并导致 β 细胞衰竭以补偿高脂肪饮食 - 诱导的胰岛素抵抗。睾酮-AR 轴的促胰岛素功能存在于培养物中。 最重要的是，在β细胞中，AR是核外的，并且AR对β细胞的刺激作用。 GSIS 涉及 cAMP 生成和蛋白激酶 A (PKA) 激活，最后，睾酮放大。 胰高血糖素样肽-1 (GLP-1) 增强啮齿动物胰岛中的 GSIS。 应用包括： 1) 探索一种新的范例，其中睾酮对 AR 的作用增强 GLP-1 的作用 在 β 细胞中，2) 阐明在核外区室中维持 AR 的分子决定因素 放大 GLP-1 受体作用的 β 细胞将由这项资助产生的知识填补关键。 我们对男性  细胞功能障碍的基本机制的理解存在差距。 为开发以组织特异性方式调节 AR 的方法奠定基础，以防止 糖尿病没有前列腺或心血管副作用因此，拟议的工作将具有重大科学意义。 影响并为退伍军人医疗系统人群开辟临床相关途径。