Effects Of Androgen Deficiency on Glucose Homeostasis

雄激素缺乏对血糖稳态的影响

• 批准号: 8736643
• 负责人: Josephine Egan
• 金额: $ 17.14万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736643
• 关键词: Androgens; Animals; Cardiovascular Diseases; Cause of Death; Characteristics; Clinical; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; Elderly man; Fatty acid glycerol esters; Feedback; Gene Expression; Genes; Gonadotropins; Growth; Human; Hypogonadism; Injection of therapeutic agent; Institutes; Insulin; Insulin Resistance; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical; Metabolic; Metabolic syndrome; Modeling; Muscle; Myocardial Infarction; Neoplasm Metastasis; Patients; Pituitary Gland; Protocols documentation; Rattus; Regulation; Reporting; Risk; Serum; Stroke; Tissues; adiponectin; blood glucose regulation; cytokine; deprivation; glucose uptake; interest; men; prevent; receptor; therapy development; treatment planning

Recently, in conjunction with collaborators at Johns Hopkins Medical Institutes, we have been studying the effects of hypogonadism on insulin resistance, diabetes and the metabolic syndrome (MS). Patients with prostate cancer who undergo androgen deprivation therapy (ADT) as part of their treatment plan become not only insulin resistant but more than 50% develop MS. This clearly puts them at risk for strokes and heart attacks, and, in fact, cardiovascular disease is the leading cause of death in patients with prostate cancer. The MS of ADT is not characteristic of the more usual MS, in that serum levels of adiponectin, which is secreted from fat tissue, are elevated in patients with ADT. Typically, adiponectin levels are decreased in MS due to increased secretion of cytokines that down-regulate the adiponectin gene: low circulating adiponectin levels cause reduced insulin-mediated glucose uptake in muscle and liver, that is, exacerbate insulin resistance and are a consistent feature in MS. ADT is a new and evolving field of clinical interest as more and more patients are subjected to ADT, and data is now appearing from other groups confirming our metabolic findings. We have a protocol in place to study androgen deficiency in rats subjected to low circulating levels of androgens by gonadiectomy and injections of 2 pharmacological agents that prevents gonadotropin secretion from pituitary. So far, we have found that the human adiponectin data from ADT patients is reproducible in that circulating adiponectin levels are increased in the hypogonadal animals, and interestingly, adiponectin gene expression is actually increased in fat tissue. We therefore conclude the ADT therapy leads to down-regulation of adiponectin receptors in liver and muscle, causing a positive feedback to the adiponectin gene. We are currently studying how adiponectin receptors might be regulated because androgen regulation of adiponectin receptors has not been previously reported. We are confident that our findings will be also applicable to ADT in patients with prostate cancer.

最近，我们与约翰霍普金斯医学研究所的合作者一起研究了性腺功能减退对胰岛素抵抗、糖尿病和代谢综合征（MS）的影响。接受雄激素剥夺治疗（ADT）作为其治疗计划的一部分的前列腺癌患者不仅会产生胰岛素抵抗，而且超过50%会发展为MS。这显然使他们面临中风和心脏病发作的风险，事实上，心血管疾病是前列腺癌患者死亡的主要原因。ADT的MS不是更常见的MS的特征，因为ADT患者中从脂肪组织分泌的脂联素的血清水平升高。通常，MS中脂联素水平降低是由于下调脂联素基因的细胞因子分泌增加：低循环脂联素水平导致肌肉和肝脏中胰岛素介导的葡萄糖摄取减少，即加剧胰岛素抵抗，并且是MS的一致特征。ADT是临床感兴趣的新的和不断发展的领域，因为越来越多的患者经受ADT，其他研究小组的数据也证实了我们的代谢发现。我们有一个适当的方案，研究雄激素缺乏症的大鼠受到低循环水平的雄激素通过性腺切除术和注射2种药物，防止促性腺激素分泌垂体。到目前为止，我们已经发现，来自ADT患者的人脂联素数据是可重复的，因为在性腺功能减退的动物中循环脂联素水平增加，有趣的是，脂联素基因表达实际上在脂肪组织中增加。因此，我们得出结论，ADT治疗导致肝脏和肌肉中脂联素受体的下调，引起脂联素基因的正反馈。由于雄激素对脂联素受体的调节以前没有报道，我们目前正在研究脂联素受体是如何被调节的。我们相信，我们的研究结果也将适用于前列腺癌患者的ADT。