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）：肢端肥大症是一种罕见疾病，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与其他人群中类似代谢综合征的病因和贡献等同。相反，正如我们新的初步数据表明的那样，我们假设脂肪组织 (AT) 的 GH-IGF-I 过度特异性失调和脂肪营养不良发生。我们认为，这种脂肪营养不良包括中枢 AT 库减少，但肌肉中 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，并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该可以逆转这些异常。然而，我们发现一些病情缓解的患者伴有体重显着增加和 CRP 升高。其中，我们假设随着 GH/IGF-I 正常化，脂肪营养不良的逆转会显着增加中枢 AT、巨噬细胞浸润和 AT 炎症以及全身炎症。需要确定炎症是否持续存在、这些患者的最终身体成分以及治疗后生长素释放肽水平增加在刺激体重增加中的作用。我们将通过在治疗前和治疗期间研究患有活动性肢端肥大症的患者来检验这些假设，利用肢端肥大症和 GH/IGF-I 轴研究的新颖技术，包括通过 MRI 和 1HMRS 检查肌肉脂质、通过 1HMRS 检查肝脂质、通过脂肪组织检查巨噬细胞活检内皮细胞的浸润、炎症和功能。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，从而建立经过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及其逆转的后果至关重要，因为针对肢端肥大症的新的有效药物疗法现在使我们能够根据特定的生化目标，甚至在正常范围内调整 IGF-I 的治疗目标，这可能具有长期的临床意义关于心血管结局。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提议。这项研究是美国国立卫生研究院 (NIH) 资助的唯一一项关于肢端肥大症的研究，提供了关于肢端肥大症许多方面的新的重要数据，特别是其生化标志物。当前申请中研究的终点和结果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，我们已经在进行中。肢端肥大症提供了一个模型，通过它我们可以提高我们对 GH 和 IGF-I 过量对脂肪组织、全身炎症、内皮功能障碍和心血管风险的影响的了解，这也适用于我们对 GH 使用和过度使用的影响的理解在其他临床环境中。公共卫生相关性：肢端肥大症是一种由生长激素产生的垂体瘤引起的罕见疾病，与发病率和死亡率增加有关。在这个项目中，我们将利用现代生化方法、新技术和一项独特的大型、持续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，包括异常的脂肪分布，这可能会导致其发病率和死亡率的增加。我们的研究将带来关于 GH 和 IGF-I 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的重要知识，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。