Role of the Androgen Receptor in Insulin Secretion in the Male

雄激素受体在男性胰岛素分泌中的作用

• 批准号: 10488954
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488954
• 关键词: Adenylate Cyclase; Aging; Agonist; Androgen Receptor; Androgens; Award; B-Lymphocytes; Beta Cell; Binding; Cardiovascular system; Cell membrane; Cell physiology; Complex; Cyclic AMP; Data; Dendrimers; Development; Diabetes Mellitus; Docking; Drug Targeting; Endosomes; Epidemic; Estrogen Nuclear Receptor; Exhibits; FRAP1 gene; Failure; Foundations; Functional disorder; Funding; GLP-I receptor; Genetic; Glucagon; Glucose; Goals; Grant; Healthcare Systems; Human; Insulin; Insulin deficiency; Investigation; Islet Cell; Laboratories; Ligands; Maps; Mediating; Membrane; Methods; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Phosphatidylinositols; Phosphotransferases; Physiological; Production; Prostate; Publishing; Qualifying; Receptor Activation; Research; Role; Signal Transduction; Stanolone; Structure of beta Cell of islet; Testing; Testosterone; Tissues; Translating; Veterans; Work; base; clinically relevant; glucagon-like peptide 1; human male; in vivo; innovation; insulin secretion; islet; male; men; military veteran; novel; novel therapeutics; pharmacologic; polypeptide; prevent; receptor; recruit; side effect; src-Family Kinases; tool; transcription factor

The goal of this renewal application is to further elucidate the mechanisms by which testosterone action on the androgen receptor (AR) in male insulin-producing pancreatic β-cells enhances insulin secretion by amplifying glucagon-like peptide-1 (GLP-1) actions. The role of testosterone deficiency as a cause of pancreatic β–cell dysfunction predisposing to type 2 diabetes (T2D) in men is poorly studied. While it is established that testosterone action is mediated via the AR, a ligand-activated transcription factor, the role of the AR in β-cell function is still poorly understood. Funded by this Merit Award I01BX003725, the new and recently published far-reaching preliminary data from our laboratory investigating the role of the AR in β-cell function provides the following information: 1) 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 produce enough insulin, leading to T2D; 2) the insulinotropic function of AR is recapitulated in islets from male human donors that have the enzymatic machinery to convert circulating testosterone to the potent AR agonist dihydrotestosterone (DHT); 3) DHT activates an extranuclear AR in mouse and human β-cells that enhances GSIS by amplifying the actions of glucagon-like peptide-1 (GLP-1) on the GLP-1 receptor, increasing cAMP production at the plasma membrane and endosomes; 4) DHT selectively enhances GLP-1-mediated cAMP production and GSIS but not that of glucose-insulinotropic polypeptide (GIP) or glucagon (GCN); 5) DHT amplification of GSIS from islets requires the tyrosine kinase SRC, the mammalian target of rapamycin complex 2 (mTORC2), and the activities of transmembrane (tmAC) and soluble (sAC) adenylate cyclases. Based on this extensive preliminary data and the scientific rigor of previous research presented in the application, our overarching hypothesis is that in male β-cells, DHT action on AR in the vicinity of the plasma membrane binds SRC and phosphoinositide 3-kinase (PI3K), thus recruiting mTORC2 and increasing the activities of tmAC and sAC at the plasma membrane and endosomes. This enhances GLP-1 receptor (GLP-1R) production of cAMP and GSIS. DHT-activated AR is selectively biased toward the GLP-1R, because AR and GLP-1R uniquely converge on mTORC2 signaling to activate tmAC and sAC to produce cAMP in similar microdomains. The proposed work uses genetic, physiological and pharmacological tools in genetically modified mice, as well as in human islets and β-cells. This work is particularly relevant against to the aging and androgen-deficient male Veterans and the T2D epidemic, because the AR is a well-characterized drug target. The goal of the work proposed in this application is to elucidate the molecular bases by which DHT-activated AR stimulates cAMP production and enhances GLP-1 signaling at the plasma membrane and endosomes to increase insulin secretion in males. Accordingly, the specific aims of this application are to 1) Test the hypothesis that AR activation in human β cells enhances GLP-1 insulinotropic action following docking to SRC, recruitment of mTORC2, and activation of tmAC and sAC, which increases cAMP production at the plasma membrane and endosomes; 2) Unmask novel androgen actions on insulin secretion by mapping the AR interactome and functional signaling network in human β cells; 3) Translate the findings of androgen stimulation of insulin secretion in vivo in mice using an androgen dendrimer conjugate that selectively activates AR membrane/extranuclear actions. The proposed work will fill key gaps in our understanding of the fundamental mechanisms of b-cell function and will have a lasting scientific impact and open clinically relevant avenues for androgen-deficient male Veterans with diabetes.

该更新应用的目的是进一步阐明睾丸激素对睾丸激素作用的机制 雄性胰岛素产生胰腺β细胞中的雄激素受体（AR）通过扩增来增强胰岛素分泌 胰高血糖素样肽-1（GLP-1）作用。睾丸激素缺乏作为胰腺β -Cell的原因 男性的2型糖尿病（T2D）的功能障碍较差。虽然确定 睾丸激素的作用是通过AR（AR）（一种配体激活的转录因子）介导的，AR在β细胞中的作用 功能仍然很了解。由该优点奖I01BX003725资助，新的和最近出版 来自我们实验室研究AR在β细胞功能中的作用的深远初步数据提供了 以下信息：1）在β细胞（βARKO）中有条件缺失的雄性小鼠暴露的雄性小鼠降低 葡萄糖刺激的胰岛素分泌（GSI）并产生β细胞未能产生足够的胰岛素，导致 t2d; 2）AR的胰岛素功能在具有的男性供体的胰岛中概括 酶促机制将循环睾丸激素转换为潜在的AR型激动剂二氢睾丸激素（DHT）； 3）DHT激活小鼠和人β细胞中的核外A，通过扩增来增强GSI 胰高血糖素样肽-1（GLP-1）在GLP-1受体上的作用，增加了血浆的营地产生 膜和内体； 4）DHT有选择地增强了GLP-1介导的营地生产和GSI，但不能 葡萄糖 - 胰岛素多肽（GIP）或胰高血糖素（GCN）的葡萄糖； 5）从胰岛进行GSI的DHT扩增 需要酪氨酸激酶SRC，雷帕霉素复合物2（MTORC2）的哺乳动物靶标，并且活动 跨膜（TMAC）和固体（SAC）腺苷酸循环。基于此广泛的初步数据和 应用程序中提出的先前研究的科学严谨性，我们的总体假设是男性 β细胞，质膜附近AR的DHT作用结合SRC和磷酸肌醇3-激酶 （PI3K），因此招募MTORC2并增加TMAC和SAC在质膜上的活动 内体。这增强了CAMP和GSIS的GLP-1受体（GLP-1R）产生。 DHT激活的AR是 有选择地偏向GLP-1R，因为AR和GLP-1R在MTORC2信号上唯一收敛到 激活TMAC和SAC以在类似的微区中产生cAMP。提出的工作使用遗传， 基因修饰的小鼠以及人类胰岛和β细胞中的生理和药物工具。 这项工作与缺乏老化和雄激素的男性退伍军人和T2D尤其重要 流行病，因为AR是一个良好的药物靶标。本申请中提出的工作的目标 是为了阐明DHT激活的AR刺激cAMP的产生并增强的分子碱基 质膜和内体的GLP-1信号传导增加男性的胰岛素分泌。根据， 本应用的具体目的是1）检验以下假设：人β细胞中AR激活增强 对接SRC后的GLP-1胰岛素动作，MTORC2的募集以及TMAC的激活和激活 SAC，增加了质膜和内体的营地产量； 2）揭露新颖的雄激素 通过绘制人β细胞中的AR相互作用组和功能信号网络对胰岛素分泌的作用； 3）使用雄激素转化小鼠体内胰岛素分泌的雄激素刺激的发现 树枝状聚合物偶联物，可有选择地激活AR膜/核外作用。拟议的工作将填补 我们对B细胞功能基本机制的理解的关键差距，并将具有持久的 科学影响和开放式临床相关途径，用于患有糖尿病的雄激素缺陷型男性退伍军人。