New Approaches to the Evaluation and Treatment of Acromegaly

描述（由申请人提供）：肢端肥大症是一种罕见的疾病，其特征是过量的GH和IGF-I及其多系统不良反应。流行病学数据将肢端肥大症与主要由心血管原因引起的发病率和死亡率增加相关联，这通常归因于肢端肥大症相关的代谢异常，包括胰岛素抵抗。然而，这些异常的病因和对CV风险增加的贡献不一定等同于其他人群中类似代谢综合征组分的病因和贡献。相反，我们的新的初步数据表明，我们假设，一个GH-IGF-I过量的脂肪组织（AT）和脂肪营养不良发生特异性失调。我们认为，这种脂肪代谢障碍包括中央AT库减少，但肌肉AT增加，并导致胰岛素抵抗，脂肪因子和食欲激素失调，内皮细胞功能障碍，并最终增加活动性肢端肥大症的CV风险。肢端肥大症的生化控制应该逆转这些异常。然而，我们已经发现一些患者的缓解伴随着显著的体重增加和crp升高。在这些研究中，我们假设随着GH/IGF-I正常化，脂肪代谢障碍的逆转显著增加了中央AT、AT中的巨噬细胞浸润和炎症以及全身炎症。炎症是否持续，这些患者的最终身体组成以及治疗后生长激素释放肽水平增加在刺激体重增加中的作用需要确定。我们将利用肢端肥大症和GH/IGF-I轴研究的新技术，通过研究活动性肢端肥大症患者的治疗前和治疗期间来验证这些假设，包括通过MRI和1HMRS检查肌肉脂质，通过1HMRS检查肝脏脂质，检查脂肪组织中的巨噬细胞浸润和炎症以及活检内皮细胞的功能。我们还将这些临床终点与我们的现代肢端肥大症的生化标志物，从而建立临床验证的肢端肥大症治疗的生化指南。了解这种脂肪代谢障碍及其逆转的后果是至关重要的，因为肢端肥大症的新的有效药物治疗现在允许我们将治疗滴定到特定的生化目标，甚至是在正常范围内的IGF-I目标，这可能对心血管结局具有长期临床意义。我们独特的、正在进行的前瞻性肢端肥大症队列研究的继续加强了这一建议。这项研究是唯一一项由NIH资助的肢端肥大症研究，为肢端肥大症的许多方面提供了新的重要数据，特别是其生化标志物。本申请中研究的终点和结局只能通过对一个独特的大型、连续、特征良好的队列进行长期随访来实现，我们正在进行中。肢端肥大症提供了一个模型，通过该模型，我们可以提高我们对GH和IGF-I过量对脂肪组织、全身炎症、内皮功能障碍和CV风险的影响的认识，这也适用于我们对GH使用和过度使用在其他临床环境中的影响的理解。公共卫生相关性：肢端肥大症，一种罕见的疾病，由于生长激素产生的垂体瘤，是与发病率和死亡率增加。在这个项目中，我们将利用现代生物化学方法，新技术和独特的大型，正在进行的前瞻性肢端肥大症队列研究，以表征肢端肥大症的新特征，包括异常脂肪分布，可能会显着增加其发病率和死亡率。我们的研究将导致重要的知识GH和IGF-I对身体组成，脂肪组织炎症，内皮功能障碍和心血管风险的影响，这也适用于我们的GH使用和过度使用在其他临床环境中的影响的理解。

DESCRIPTION (provided by applicant): Acromegaly is a rare disease characterized by excess GH and IGF-I and their multi-system adverse effects. Epidemiological data associate acromegaly with increased morbidity and mortality primarily from cardiovascular causes, which are often attributed to acromegaly's associated metabolic abnormalities including insulin resistance. However, these abnormalities' etiology and contribution to increased CV risk cannot necessarily be equated with those of similar metabolic syndrome components in other populations. Rather, as our novel preliminary data suggest, we hypothesize that a GH-IGF-I excess specific dysregulation of adipose tissue (AT) and lipodystrophy occur. This lipodystrophy, we propose, includes reduced central AT depots yet increased AT in muscle and contributes to insulin resistance, adipokine and appetite hormone dysregulation, endothelial cell dysfunction and ultimately increased CV risk in active acromegaly. Biochemical control of acromegaly should reverse these abnormalities. However, we have identified some patients whose remission is accompanied by significant weight gain and a rise in crp. In them, we hypothesize that as GH/IGF-I normalize, reversal of the lipodystrophy markedly increases central AT, macrophage infiltration and inflammation in AT and systemic inflammation. Whether inflammation persists and these patients' ultimate body composition as well as the role of post-therapy increases in ghrelin levels in stimulating weight gain need to be determined. We will test these hypotheses by studying patients with active acromegaly before and during therapies utilizing techniques novel to the study of acromegaly and the GH/IGF-I axis including examinations of muscle lipid by MRI and 1HMRS, hepatic lipid by 1HMRS, adipose tissue for macrophage infiltration and inflammation and function of biopsied endothelial cells. We will also relate these clinical endpoints to our modern biochemical markers of acromegaly and thereby establish clinically validated biochemical guidelines for acromegaly therapy. Understanding the consequences of this lipodystrophy and its reversal are crucial because new potent medical therapies for acromegaly now allow us to titrate therapy to particular biochemical goals and even a target for IGF-I within the spectrum of the normal range which may have long term clinical significance with regard to cardiovascular outcomes. This proposal is strengthened by its continuation of our unique, ongoing prospective acromegaly cohort study. This study, the only one on acromegaly funded by the NIH, has provided novel important data on a number of aspects of acromegaly in particular its biochemical markers. The endpoints and outcomes studied in the current application can only be achieved with long term follow up of a uniquely large, consecutive, well-characterized cohort, which we have well underway. Acromegaly provides a model through which we can improve our knowledge about the effects of GH and IGF-I excess on adipose tissue, systemic inflammation, endothelial dysfunction and CV risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings. PUBLIC HEALTH RELEVANCE: Acromegaly, a rare disease due to a growth hormone producing pituitary tumor, is associated with increased morbidity and mortality. In this project we will utilize modern biochemical methods, novel techniques and a uniquely large, ongoing prospective acromegaly cohort study to characterize novel features of acromegaly including an abnormal fat distribution that may contribute significantly to its increased morbidity and mortality. Our study will lead to important knowledge about the effects GH and IGF-I on body composition, adipose tissue inflammation, endothelial dysfunction and cardiovascular risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings.