New Approaches to the Evaluation and Treatment of Acromegaly

肢端肥大症评估和治疗的新方法

• 批准号: 7879364
• 负责人: PAMELA U FREDA
• 金额: $ 47.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879364
• 关键词: Accounting; Acromegaly; Adipose tissue; Adverse effects; Affect; Biochemical; Biochemical Markers; Biological Assay; Biopsy; Body Composition; Cardiovascular system; Cell physiology; Clinical; Cohort Studies; Data; Deposition; Desire for food; Disease; Disease remission; Endothelial Cells; Energy Metabolism; Epidemiology; Etiology; Evaluation; Fatty acid glycerol esters; Functional disorder; Funding; Goals; Guidelines; Hepatic; Hormones; Infiltration; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Knowledge; Lead; Link; Lipids; Lipodystrophy; Lipolysis; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medical; Metabolic; Metabolic syndrome; Methods; Modeling; Morbidity - disease rate; Muscle; Normal Range; Operative Surgical Procedures; Outcome; Outcome Study; Patients; Pattern; Pituitary Gland; Pituitary Neoplasms; Play; Population; Postoperative Period; Prospective Studies; Protons; Rare Diseases; Recovery; Risk; Risk Marker; Role; Serum; Serum Markers; Somatotropin; System; Techniques; Testing; United States National Institutes of Health; Visceral; Weight Gain; adipokines; base; cardiovascular risk factor; clinically significant; cohort; follow-up; ghrelin; improved; increased appetite; inflammatory marker; insulin sensitivity; macrophage; meetings; mortality; novel; novel strategies; prospective; public health relevance; subcutaneous

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.

描述（由申请人提供）：肢端肥大是一种罕见的疾病，其特征是过量的GH和IGF-I及其多系统不良反应。流行病学数据使肢端肥大症与发病率和死亡率增加主要来自心血管原因，这通常归因于肢端肥大症的相关代谢异常，包括胰岛素抵抗。但是，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的代谢综合征成分。相反，正如我们新颖的初步数据所表明的那样，我们假设GH-IGF-I过多的脂肪组织（AT）和脂肪营养不良的非特异性失调。我们提出，这种脂肪营养不良包括减少仓库中的中心，但在肌肉中增加，并有助于胰岛素抵抗，脂肪因子和食欲激素失调，内皮细胞功能障碍，并最终增加了活跃的肢端肿瘤的CV风险。肢端肥大的生化控制应扭转这些异常。但是，我们已经确定了一些患者的缓解伴随着大量体重增加和CRP的增加。在其中，我们假设随着GH/IGF-I的正常化，脂肪营养不良的逆转显着增加了AT的中心，巨噬细胞浸润和AT和系统性炎症中的炎症。炎症是否持续以及这些患者的最终身体组成以及疗法后疗法的作用在刺激体重增加中的提高需要确定。我们将通过研究疗法之前和期间研究这些假设的方法，利用新颖的技术来研究骨膜肥大和GH/IGF-I轴，包括MRI和1HMR对肌肉脂质的检查，1HMR，肝脂质的肝脂质，由1HMRS通过1HMR进行脂肪组织，对型细胞和肥大的Intopration and Sumpropation and Warigamsation和功能。我们还将将这些临床终点与我们的现代肢端肥大性生化标记联系起来，从而确立临床验证的肢端肥大疗法的生化指南。了解这种脂肪营养不良及其逆转的后果至关重要，因为现在的新的有效医疗疗法可以使我们能够将治疗滴定到特定的生化目标，甚至是在正常范围内IGF-I的目标，这些疗法在正常范围内可能具有长期的临床意义，这对于心血管均未发生。通过继续我们持续不断的前瞻性互冲肥大队列研究来加强该提议。这项研究是由NIH资助的唯一一项关于肢端肥大的研究，它提供了有关其生化标志物的许多方面的新重要数据。在当前应用中研究的终点和结果只能通过长期跟进一个独特的大型，连续的，良好的人群的随访，我们正在进行中。肢端肥大提供了一个模型，我们可以通过该模型来提高人们对GH和IGF-I过量对脂肪组织的影响，全身性炎症，内皮功能障碍和CV风险的影响，这也适用于我们对其他临床环境中GH使用和过度使用的影响的理解。公共卫生相关性：由于产生垂体肿瘤的生长激素而引起的一种罕见疾病，与发病率和死亡率增加有关。在这个项目中，我们将利用现代化的生化方法，新颖的技术以及一个独特的，持续的前瞻性肢端肥大队列研究来表征肢端肥大的新特征，包括异常脂肪分布，可能会对其发病率提高和死亡率产生重大贡献。我们的研究将导致有关GH和IGF-I对人体组成，脂肪组织炎症，内皮功能障碍和心血管风险的影响的重要知识，这也适用于我们对其他临床环境中GH使用和过度使用的影响的理解。