Effects Of Androgen Deficiency on Glucose Homeostasis

最近，我们与约翰霍普金斯医学院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。前列腺癌患者接受雄激素剥夺疗法（ADT）作为治疗计划的一部分，不仅会产生胰岛素抵抗，而且超过50%的患者会患上多发性硬化症。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的多发性硬化症与更常见的多发性硬化症不同，因为ADT患者血清中由脂肪组织分泌的脂联素水平升高。通常情况下，脂联素水平在多发性硬化症中下降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胰岛素介导的葡萄糖摄取减少，即加剧胰岛素抵抗，这是多发性硬化症的一贯特征，随着越来越多的患者接受ADT治疗，ADT是一个新的、不断发展的临床研究领域，其他组的数据也证实了我们的代谢发现。我们有一个方案来研究雄激素缺乏的大鼠在低循环水平的雄激素通过性腺切除术和注射两种药物来阻止垂体分泌促性腺激素。到目前为止，我们已经发现来自ADT患者的人体脂联素数据是可重复的，因为循环脂联素水平在性腺功能低下的动物中增加，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，导致脂联素基因的正反馈。我们目前正在研究如何调节脂联素受体，因为以前没有报道过雄激素对脂联素受体的调节。我们相信，我们的研究结果也将适用于前列腺癌患者的ADT。

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.