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: 9924534
• 负责人: PAMELA U FREDA
• 金额: $ 58.56万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924534
• 关键词: Acromegaly; Adipocytes; Adipose tissue; Aftercare; Biochemical; Biopsy; Body Composition; Body Patterning; Cardiovascular Diseases; Cells; Cessation of life; Chronic Disease; Clinical; Cohort Studies; Data; Deposition; Development; Disease; Dissociation; Drug or chemical Tissue Distribution; Energy Metabolism; Evaluation; Fatty acid glycerol esters; Funding; Future; Gene Expression; General Population; Glucagon; Glucose Intolerance; Guidelines; HIV; Hepatic; Immune; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Knowledge; Link; Lipids; Lipodystrophy; Liver; Longevity; Longitudinal cohort; Measures; Medical; Metabolic; Metabolic Diseases; Methods; Modeling; Modernization; Molecular; Morbidity - disease rate; Muscle; Obesity; Operative Surgical Procedures; Outcome; Pancreatic Hormones; Patients; Pattern; Phenotype; Pituitary Neoplasms; Population; Process; Prospective Studies; Prospective cohort study; Rare Diseases; Recovery; Risk; Role; Somatostatin Analog Therapy; Somatotropin; Somatotropin-Releasing Hormone; Techniques; Testing; United States National Institutes of Health; Visceral; Work; analog; base; cardiovascular risk factor; clinically relevant; cohort; comparison group; falls; follow-up; ghrelin; glucose tolerance; improved; insight; lipid metabolism; macrophage; monocyte; mortality; novel; novel strategies; prospective; receptor; somatostatin analog

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.

概括 该项目建立在我们由 NIH 资助的新颖、独特的前瞻性研究的基础上，该研究对 330 名肢端肥大症患者进行了研究。 源自分泌 GH 的垂体肿瘤的疾病，其特征是循环中 GH 和 IGF-1 过多 以及它们产生的多系统发病率和死亡率增加。肢端肥大症提供了一个模型 我们可以提高我们对 GH 和 IGF-1 对脂肪组织 (AT)、身体成分和 在这种情况和其他临床情况下，肝脏和肌肉的脂质积累。肢端肥大症死亡的主要原因， 心血管疾病可能与普遍的代谢异常有关，特别是胰岛素抵抗。我们的工作 然而，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。该项目建议，或者，一部小说 肢端肥大症特异性脂肪营养不良是代谢异常的基础，可能影响长期结果。 根据我们的初步数据，我们假设脂肪营养不良会产生独特的 AT 模式 尽管胰岛素抵抗和增加，但重新分布，内脏脂肪组织质量和肝脂质减少 导致胰岛素抵抗的肌间脂肪组织量。了解这个过程很重要 因为肢端肥大症的药物治疗可能无法一致逆转这种脂肪营养不良。利用最先进的技术 身体成分方法目标 1 测试从我们的数据中出现的新假设，包括 GH 是 肝脏脂肪和生长抑素类似物（SSA）的负调节剂会增加肌肉脂质。这些将通过测试 与特别匹配的对照以及患有 GH 缺乏症和 HIV 脂肪营养不良 (HIVLD) 的患者进行比较， 两种疾病会导致 GH 分泌减少以及 VAT 和 CV 风险增加。 GHD 和 HIVLD 患者将 分别在 GH 或 GHRH 类似物治疗之前和之后检查身体成分模式 变化与 GH 降低相反。我们将评估心外膜脂肪组织，这是一个具有重要作用的仓库。 与心血管疾病有关，但对肢端肥大症和 HIVLD 的研究还不够。目标 2 研究机制 治疗特定的身体成分变化，特别是生长素释放肽、肠道和胰腺激素的作用 SSA 治疗期间异位脂质积累和未来 DM 风险的变化。肢端肥大症的一部分 脂肪营养不良及其与胰岛素抵抗的联系是 GH 在 AT 中的作用。目标 3 研究活检 AT、测试 肢端肥大症产生炎症和免疫细胞表型的新分离的假设 肢端肥大症治疗可逆转，可能与胰岛素抵抗以及脂质和能量改变有关 AT 中的代谢。循环单核细胞的炎症特征可能与心血管风险相关，也将受到影响。 进行了肢端肥大症、GHD 和 HIVLD 测试。目标 4 分析与以下相关的死亡率和发病率结果 使用现代 GH 和 IGF-1 测量方法，我们在特征明确的纵向队列中发现了脂肪营养不良。这个项目 为肢端肥大症治疗提供重要指南。了解这种脂肪营养不良、其后果以及 逆转，对于优化治疗患者、纠正代谢异常和过高的心血管风险至关重要。

项目成果

A Pituitary Society update to acromegaly management guidelines.

垂体协会更新了肢端肥大症管理指南。

• 发表时间: 2021-02
• 影响因子: 3.8
• 作者: Fleseriu, Maria;Biller, Beverly M K;Freda, Pamela U;Gadelha, Monica R;Giustina, Andrea;Katznelson, Laurence;Molitch, Mark E;Samson, Susan L;Strasburger, Christian J;van der Lely, A J;Melmed, Shlomo
• 通讯作者: Melmed, Shlomo

Multidisciplinary management of acromegaly: A consensus.

肢端肥大症的多学科治疗：共识。

• 发表时间: 2020-12
• 影响因子: 8.2
• 作者: Giustina, Andrea;Barkhoudarian, Garni;Beckers, Albert;Ben;Biermasz, Nienke;Biller, Beverly;Boguszewski, Cesar;Bolanowski, Marek;Bollerslev, Jens;Bonert, Vivien;Bronstein, Marcello D;Buchfelder, Michael;Casanueva, Felipe;Chanson
• 通讯作者: Chanson