New Approaches to the Evaluation and Treatment of Acromegaly

总结 该项目建立在我们新颖的，独特的NIH资助的前瞻性研究330例肢端肥大症， 一种起源于GH分泌性垂体瘤的疾病，其特征为循环中GH和IGF-1过量 以及它们所产生的多系统发病率和死亡率的增加。肢端肥大症提供了一个模型， 我们可以提高我们的知识生长激素和IGF-1对脂肪组织（AT），身体成分和 肝脏和肌肉脂质积聚，在这种和其他临床环境中。肢端肥大症死亡的主要原因， CV疾病可能与普遍的代谢异常有关，特别是胰岛素抵抗。我们的工作 然而，这表明将代谢和身体组成异常与CV疾病联系起来的范例， 一般人群不适用于肢端肥大症。这个项目提出，或者，一部小说 肢端肥大症特异性脂肪营养不良是代谢异常的基础，并可能影响长期结果。 根据我们的初步数据，我们假设脂肪代谢障碍产生了一种独特的AT模式， 尽管存在胰岛素抵抗，但内脏脂肪组织质量和肝脏脂质减少， 导致胰岛素抵抗的肌肉间脂肪组织质量。理解这个过程很重要 因为肢端肥大症的药物治疗可能不会均匀地逆转这种脂肪营养不良。利用最先进的技术 身体组成方法目标1测试新的假设出现从我们的数据，包括生长激素是一个 肝脏脂肪的负调节剂和生长抑素类似物（SSA）增加肌肉脂质。这些将由 与特别匹配的对照组和GH缺乏和HIV脂肪营养不良（HIVLD）患者进行比较， 两种疾病GH分泌减少，VAT和CV风险增加。GHD和HIVLD患者将 分别在GH或GHRH类似物治疗前后检查身体组成模式 与GH降低时相反。我们将评估心外膜脂肪组织，一个重要的储存库， 与CV疾病相关，但在肢端肥大症和HIVLD中研究不足。目标2研究了 治疗特定的身体组成变化，特别是ghrelin，肠道和胰腺激素的作用 SSA治疗期间异位脂质积聚和未来糖尿病风险的变化。肢端肥大症的组成部分 脂肪代谢障碍及其与胰岛素抵抗的联系是GH在AT中的作用。目的3研究活检AT，测试 肢端肥大症产生一种新的炎性和免疫细胞表型分离的假说 这种情况可通过肢端肥大症治疗逆转，可能与胰岛素抵抗和脂质及能量改变有关 AT代谢还将评估可能与CV风险相关的循环单核细胞的炎症特征。 在肢端肥大症，生长激素缺乏症和艾滋病方面进行了测试目的4分析与治疗相关的死亡率和发病率结局。 在我们的充分表征，纵向队列使用现代GH和IGF-1措施脂肪营养不良。这个项目 为肢端肥大症的治疗提供了重要的指导方针。了解这种脂肪代谢障碍，其后果和 逆转，是至关重要的最佳治疗患者，纠正他们的代谢异常和过度的CV风险。

SUMMARY This project builds on our novel, uniquely NIH-funded prospective study of 330 patients with acromegaly, a disease originating in a GH secreting pituitary tumor that is characterized by excess circulating GH and IGF-1 and the multi-system morbidity and increased mortality they produce. Acromegaly provides a model through which we can improve our knowledge of GH and IGF-1 effects on adipose tissue (AT), body composition and liver and muscle lipid accumulation, in this and other clinical settings. The leading cause of acromegaly death, CV disease, likely relates to the prevalent metabolic abnormalities, in particular insulin resistance. Our work suggests, however, that the paradigm linking metabolic and body composition abnormalities to CV disease in the general population does not apply in acromegaly. This project proposes, alternatively, that a novel acromegaly-specific lipodystrophy underlies the metabolic abnormalities and may impact long-term outcome. Based on our preliminary data, we hypothesize that the lipodystrophy produces a unique pattern of AT redistribution, reduced visceral adipose tissue mass and hepatic lipid despite insulin resistance and increased inter-muscular adipose tissue mass that cause insulin resistance. Understanding this process is important because acromegaly medical therapies may not uniformly reverse this lipodystrophy. Utilizing state of the art body composition methods Aim 1 tests new hypotheses emerging from our data, including that GH is a negative regulator of liver fat and somatostatin analogs (SSA) increase muscle lipid. These will be tested by comparisons to specially matched controls and to patients with GH deficiency and HIV lipodystrophy (HIVLD), two disorders with reduced GH secretion and increased VAT and CV risk. GHD and HIVLD patients will be examined before and after GH or GHRH analogue therapy, respectively, for a pattern of body composition change opposite to that with GH lowering. We will assess epicardial adipose tissue, a depot with important links to CV disease, but is understudied in acromegaly and HIVLD. Aim 2 investigates mechanisms for therapy-specific body composition changes, specifically the roles of ghrelin, gut and pancreatic hormone changes during SSA therapy on ectopic lipid accumulation and future risk of DM. Integral to the acromegaly lipodystrophy and its link with insulin resistance are GH's effects in AT. Aim 3 investigates biopsied AT, testing the hypothesis that acromegaly produces a novel dissociation of inflammatory and immune cell phenotypes that reverses with acromegaly treatment and that may relate to insulin resistance and altered lipid and energy metabolism in AT. The inflammatory profile of circulating monocytes, which may relate to CV risk, will also be tested in acromegaly, GHD and HIVLD. Aim 4 analyzes mortality and morbidity outcomes related to the lipodystrophy in our well-characterized, longitudinal cohort using modern GH and IGF-1 measures. This project provides important guidelines for acromegaly therapy. Understanding this lipodystrophy, its consequences and reversal, is crucial to optimally treating patients, correcting their metabolic abnormalities and excess CV risk.