New Approaches to the Evaluation and Treatment of Acromegaly

摘要 该项目建立在我们对330名肢端肥大症患者进行的新型、独特的由NIH资助的前瞻性研究的基础上， 起源于生长激素分泌性垂体瘤的疾病，其特征是循环中的生长激素和IGF-1过多 以及它们所产生的多系统发病率和增加的死亡率。肢端肥大症提供了一个模型，通过 我们可以提高对生长激素和胰岛素样生长因子-1对脂肪组织(AT)、身体成分和 肝脏和肌肉的脂肪堆积，在这种和其他临床环境中。肢端肥大症死亡的主要原因， 心血管疾病，可能与普遍存在的代谢异常，特别是胰岛素抵抗有关。我们的工作 然而，这表明，将代谢和身体成分异常与心血管疾病联系起来的范式 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营养不良是代谢异常的基础，并可能影响长期预后。 根据我们的初步数据，我们假设脂肪营养不良会产生一种独特的AT模式 重新分布，内脏脂肪组织质量和肝脏脂肪减少，尽管胰岛素抵抗和增加 导致胰岛素抵抗的肌肉间脂肪组织块。了解这一过程很重要 因为肢端肥大症的药物治疗可能不会完全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测试从我们的数据中出现的新假设，包括生长激素是一种 肝脂肪负调节因子和生长抑素类似物(SSA)可增加肌肉脂肪。这些将通过以下方式进行测试 与特殊配对的对照组和GH缺乏症和HIV脂营养不良(HIVLD)患者进行比较， 两种疾病，生长激素分泌减少，VAT和心血管风险增加。GHD和HIVLD患者将 分别在生长激素或促生长激素释放激素类似物治疗前后检查身体成分模式 与生长激素降低的变化相反。我们将评估心外膜脂肪组织，这是一个重要的 与心血管疾病有关，但在肢端肥大症和HIVLD中研究不足。AIM 2研究了 治疗特定的身体成分改变，特别是胃促生长素、肠道和胰腺激素的作用 SSA治疗期间异位脂肪堆积和糖尿病未来风险的变化。肢端肥大症的组成部分 脂肪营养不良及其与胰岛素抵抗的联系是生长激素在AT中的作用。AIM 3调查AT，检测活组织检查 肢端肥大症导致炎症和免疫细胞表型的新分离的假说 这与肢端肥大症的治疗相反，这可能与胰岛素抵抗和血脂和能量改变有关。 AT的新陈代谢。循环单核细胞的炎症情况，可能与心血管疾病的风险有关，也将是 在肢端肥大症、GHD和HIVLD中进行了测试。目标4分析与以下因素相关的死亡率和发病率 利用现代生长激素和胰岛素样生长因子-1的方法，在我们特征良好的纵向队列中发现脂肪营养不良。这个项目 为肢端肥大症的治疗提供重要指南。了解这种脂肪营养不良，它的后果和 逆转，对于最佳治疗患者至关重要，纠正他们的代谢异常和额外的简历风险。

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.