Growth hormone and adult physiology

描述(申请人提供)：生长激素(GH)是由脑下垂体前叶的生长激素产生的，并被释放到一般循环中，在那里它刺激多个靶组织产生胰岛素样生长因子I(IGF-I)。GH和IGF-I协同工作，调节细胞功能的各个方面。在正常人中，循环中的GH/IGF-I水平在出生后稳步上升，在青春期周围处于平台期，然后以每十年~14%的速度下降。循环中的生长激素水平也随着体重的增加而下降，与年龄无关。基于人类和动物研究生长激素缺乏(GHD)对代谢的影响，在有或没有GH或IGF-I替代的情况下，很明显GH可以抑制脂肪积累和促进蛋白质积累，而IGF-I的代谢作用类似于胰岛素。GH和IGF-I也被报道对胰腺b细胞功能、心血管功能和骨重建有积极作用。生长激素替代疗法在生长激素缺乏症患者中的代谢益处推动了生长激素在正常健康成人中的非标记性使用和滥用，以改善身体形象和运动表现，并为老年和/或肥胖患者使用生长激素替代疗法以帮助抗击代谢性疾病提供了理论依据。尽管生长激素对成人有潜在的积极作用，但在生理水平上，生长激素是否会降低胰岛素敏感性、加剧癌症和缩短寿命仍在争论中。内源性GH在成人维持健康或促进疾病中的真正重要性仍有待阐明，因为我们的大部分知识基于以下研究：1)在正常受试者中急性或长期给予GH，1)发育性GHD，这可能不反映性成熟后GH下降的后果，2)成人型GHD(AOGHD)，它经常伴有其他垂体缺陷，因此很难确定哪些变化是由GH丢失引起的。此外，在人类中，很难将遗传、环境和生活方式的混杂影响与特别是内分泌病理造成的混杂影响区分开来。为了绕过这些问题并更准确地定义内源性GH在成人(病理)生理学中的重要性，目前的提议将利用一种独特的成人型孤立性GHD(AOiGHD)基因工程小鼠模型。初步研究表明，当AOiGHD小鼠喂食低脂饮食时，脂肪质量增加，但全身胰岛素敏感性改善。然而，饮食诱导的肥胖AOiGHD小鼠出现了葡萄糖耐量异常，这与低饮食和空腹胰岛素水平有关，这表明GH/IGF-I在维持b细胞功能方面也可能是重要的。鉴于多个器官系统参与维持血糖稳态，拟议的一系列研究将采用综合方法来确定1)AOiGHD对b细胞功能(胰岛素表达、增殖、新生和/或凋亡)的影响程度，2)AOiGHD诱导的胰岛素敏感性增加是由于胰岛素作用的全面改善还是由于特定组织的变化(肝脏、脂肪、骨骼肌)3)确定AOiGHD是否会影响全身的新陈代谢和体重变化，以应对急性禁食/再喂养或长期饮食诱导的减肥。从这些研究中获得的知识将提供有关生长激素替代疗法的益处或风险的重要信息。

DESCRIPTION (provided by applicant): Growth hormone (GH) is produced by somatotropes of the anterior pituitary gland and is released into the general circulation where it stimulates the production of insulin-like growth factor I (IGF-I) from multiple target tissues. GH and IGF-I work in concert to mediate various aspect of cellular function. In normal individuals, circulating GH/IGF-I levels steadily rise after to birth, plateau around the peripubertal period, then decline thereafter at a rate of ~14% for every decade of life. Circulating GH levels also decline with weight gain, independent of age. Based on human and animal studies examining the metabolic impact of GH deficiency (GHD), with and without GH or IGF-I replacement, it is clear that GH can inhibit fat accumulation and promote protein accretion, while the metabolic actions of IGF-I resemble those of insulin. GH and IGF-I are also reported to have positive effects on pancreatic b-cell function, cardiovascular performance and bone remodeling. The metabolic benefits of GH replacement in GHD patients has fueled the off-label use and abuse of GH in normal healthy adults to enhance body image and athletic performance, as well as providing a rationale for GH replacement in elderly and/or obese individuals to help combat metabolic disease. Despite the potential positive effects of GH in adults, there is also ongoing debate whether GH, at physiologic levels, can reduce insulin sensitivity, exacerbate cancer, and shorten lifespan. The true importance of endogenous GH in maintaining health OR promoting disease in adults, remains to be clarified since the bulk of our knowledge is based on studies of 1 ) acute or long-term GH administration in normal subjects, 1) developmental GHD, that might not reflect the consequences of GH decline after sexual maturation and 2) adult onset GHD (AOGHD) which is frequently accompanied by other pituitary defects, making it difficult to determine what changes are due specifically to GH loss. In addition, in humans it is difficult to separate out the confounding effects of genetics, environment and lifestyle from those due specifically to endocrine pathologies. To circumvent these problems and more accurately define the importance of endogenous GH in adult (patho)physiology the current proposal will utilize a unique genetically engineered mouse model of adult-onset, isolated GHD (AOiGHD). Preliminary studies demonstrated when AOiGHD mice were fed a low-fat diet, adipose mass increased, but whole body insulin sensitivity improved. However, diet-induced obese AOiGHD mice developed glucose intolerance which was associated with low fed and fasted insulin levels, suggesting GH/IGF-I may also be important in maintaining b-cell function. Given multiple organs systems are involved in maintaining glucose homeostasis, the proposed series of studies will take an integrative approach to determine 1) at what level AOiGHD impacts b-cell function (insulin expression, proliferation, neogenesis and/or apoptosis), 2) if the AOiGHD-induced increase in insulin sensitivity is due to global improvement in insulin actions or due to tissue-specific changes (liver, fat, skeletal muscle) 3) determine if AOiGHD will influence whole body metabolism and weight changes in response to acute fasting/refeeding or longterm diet-induced weight loss. Knowledge gained from these studies will provide important information regarding the benefits or risks of GH replacement therapy.