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，其特征是生长激素和IGF-I过量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联系起来，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心血管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成分。相反，正如我们新的初步数据所表明的那样，我们假设GH-IGF-I过量特异性脂肪组织失调（AT）和脂肪营养不良发生。我们认为，这种脂肪营养不良包括中心AT库减少而肌肉中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，最终增加活动性肢端肥大症的心血管风险。肢端肥大症的生化控制应能逆转这些异常。然而，我们已经确定了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的正常化，脂肪营养不良的逆转显著增加中枢AT、巨噬细胞浸润和AT中的炎症和全身炎症。炎症是否持续，这些患者的最终身体组成以及治疗后胃饥饿素水平的增加在刺激体重增加中的作用需要确定。我们将通过在治疗前和治疗期间研究活动性肢端肥大症患者来验证这些假设，使用研究肢端肥大症和GH/IGF-I轴的新技术，包括通过MRI和1HMRS检查肌肉脂质，通过1HMRS检查肝脏脂质，脂肪组织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肢端肥大症的现代生化标志物联系起来，从而建立临床验证的肢端肥大症治疗生化指南。了解这种脂肪营养不良的后果及其逆转是至关重要的，因为肢端肥大症的新有效医学疗法现在允许我们滴定治疗特定的生化目标，甚至在正常范围内的igf - 1靶标，这可能对心血管结果具有长期的临床意义。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，唯一一个由美国国立卫生研究院资助的肢端肥大症，提供了新的重要数据在肢端肥大症的一些方面，特别是其生化标志物。当前应用中研究的终点和结果只能通过对一个独特的、连续的、特征良好的队列进行长期随访来实现，我们正在进行这项研究。肢端肥大症提供了一个模型，通过这个模型，我们可以提高我们对生长激素和IGF-I过量对脂肪组织、全身炎症、内皮功能障碍和心血管风险的影响的认识，这也适用于我们对生长激素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：肢端肥大症是一种罕见的疾病，由于生长激素产生垂体瘤，与发病率和死亡率增加有关。在这个项目中，我们将利用现代生化方法、新技术和一项独特的、正在进行的前瞻性肢端肥大症队列研究来描述肢端肥大症的新特征，包括可能导致其发病率和死亡率增加的异常脂肪分布。我们的研究将使我们了解生长激素和igf - 1对身体成分、脂肪组织炎症、内皮功能障碍和心血管风险的影响，这也适用于我们对其他临床环境中生长激素使用和过度使用的影响的理解。

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.