Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Department of Medicine, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2023 Feb 10;18(2):e0281508. doi: 10.1371/journal.pone.0281508. eCollection 2023.
Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.
雄激素剥夺疗法（ADT）是治疗局部晚期和转移性前列腺癌患者的基石，它与许多不良反应相关，包括骨质疏松、性功能障碍、疲劳和血管舒缩症状。它还与肌肉质量减少和脂肪增加有关。这种身体成分的变化可能是导致胰岛素抵抗的起因，而胰岛素抵抗是糖尿病和心血管疾病的独立危险因素。尽管已经报道了 ADT 期间发生胰岛素抵抗，但仍不清楚这种胰岛素抵抗主要是肝脏还是肌肉引起的。同样，导致胰岛素抵抗的机制也尚不清楚。ADT & Metabolism 研究旨在解决这些知识空白，因为阐明胰岛素抵抗的主要部位将允许在接受 ADT 的患者中预防策略和使用靶向、组织特异性胰岛素增敏剂。这是一项前瞻性、机制性、单中心、24 周、观察性队列研究，将招募即将接受至少 24 周手术或药物 ADT 的初治成年前列腺癌男性（ADT 组，n=50）和接受根治性前列腺切除术且处于缓解期的男性对照组（非 ADT 组，n=25）。主要结局是使用基线和 ADT 开始后 12 和 24 周（ADT 组）或入组后（非 ADT 组）进行频繁采样口服葡萄糖耐量试验，确定胰岛素抵抗的部位（骨骼肌或肝脏）。次要结局将评估肝内和肌内脂肪（使用磁共振波谱）、炎症标志物、脂肪因子、游离脂肪酸的变化以及身体成分的变化（使用双能 X 射线吸收法评估）及其与胰岛素抵抗发展的相关性。探索性结局将包括肌肉性能、身体功能、身体活动、活力和性驱动的变化。
