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: 10371018
• 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/10371018
• 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，老化的患有睾丸激素缺乏症的男性和雄激素部署的男性 前列腺癌治疗的患者患2型糖尿病（T2D）的风险增加。虽然研究 研究这个问题的重点是睾丸激素缺乏症作为胰岛素的危险因素 抗性，这种方法忽略了睾丸激素缺乏作为胰腺β -Cell的潜在原因 男性功能障碍。尽管已经确定睾丸激素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中AR在β细胞功能障碍中的作用 未知。用于解决雄激素的新工作的治疗应用具有巨大的潜力 在衰老的大部分地区，T2D背景下的缺陷。新的深远的初步数据 我们的实验室表明，在β细胞中有条件缺失的雄性小鼠暴露于β细胞（βARKO）降低 葡萄糖刺激的胰岛素分泌（GSI）并发展为β细胞未能补偿高脂饮食 诱导胰岛素抵抗。睾丸激素-AR轴的胰岛素功能在培养 男性人类小岛。最重要的是，在β细胞中，AR是核外的，AR对AR的刺激作用 GSIS涉及营地产生和蛋白激酶A（PKA）激活。最后，睾丸激素放大器 GSIS在啮齿动物胰岛中增强胰高血糖素样肽-1（GLP-1）。根据这个目的 应用是：1）探索一种新型范式，其中睾丸激素对AR的作用增强了GLP-1的作用 在β细胞和2）中阐明在核外室中维持AR的分子确定剂 扩增GLP-1受体作用的β细胞。这笔赠款将产生的知识将填写密钥 我们对男性细胞功能障碍的基本机制的理解差距。这些信息将 为开发以组织特异性调节AR的方法提供基础 没有前列腺或心血管副作用的糖尿病。那就是拟议的工作将具有重要的科学 对退伍军人医疗体系人口的影响和开放临床相关的途径。

项目成果

The impact of androgen actions in neurons on metabolic health and disease.

• DOI: 10.1016/j.mce.2017.09.001
• 发表时间: 2018-04-15
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Morford JJ;Wu S;Mauvais-Jarvis F
• 通讯作者: Mauvais-Jarvis F

Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis.

雌二醇和睾酮对人成纤维细胞和内皮细胞增殖、生物能学和血管生成的性别特异性作用。

• DOI: 10.1101/2023.07.23.550236
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Martier,AshleyT;Maurice,YasminV;Conrad,KMichael;Mauvais-Jarvis,Franck;Mondrinos,MarkJ
• 通讯作者: Mondrinos,MarkJ

Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.

• DOI: 10.1016/j.jdiacomp.2017.03.002
• 发表时间: 2017-05
• 期刊: Journal of diabetes and its complications
• 影响因子: 3
• 作者: Xu W;Niu T;Xu B;Navarro G;Schipma MJ;Mauvais-Jarvis F
• 通讯作者: Mauvais-Jarvis F

Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes.

• DOI: 10.1016/j.xcrm.2022.100598
• 发表时间: 2022-04-19
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Fuselier, Taylor;de Sa, Paula Mota;Qadir, M. M. Fahd;Xu, Beibei;Allard, Camille;Meyers, Mathew M.;Tiano, Joseph P.;Yang, Bin S.;Gelfanov, Vasily;Lindsey, Sarah H.;Dimarchi, Richard D.;Mauvais-Jarvis, Franck
• 通讯作者: Mauvais-Jarvis, Franck

Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol.

• DOI: 10.1097/gme.0000000000001195
• 发表时间: 2019-03
• 期刊: Menopause (New York, N.Y.)
• 作者: Zimmerman MA;Hutson DD;Mauvais-Jarvis F;Lindsey SH
• 通讯作者: Lindsey SH