EFFECTS OF GROWTH HORMONE ON INTRAMYOCELLULAR LIPIDS

描述（由申请方提供）：本提案的目的是研究生长激素（GH）对身体成分的短期和长期影响，并研究肌细胞内脂质（IMCL）蓄积是内脏型肥胖受试者胰岛素抵抗的一种机制的假设。肥胖是心血管疾病和2型糖尿病的一个强有力的独立危险因素。内脏肥胖已被证明与减少GH分泌相比，瘦对照，和GH管理肥胖患者减少内脏脂肪和增加肌肉质量。然而，GH给药对葡萄糖代谢和胰岛素敏感性的短期和长期影响的生理学基础尚不清楚。鉴于胰岛素抵抗和心血管疾病之间的密切联系，了解GH诱导的葡萄糖代谢和胰岛素抵抗以及身体组成变化的病理生理学将是未来发展的关键策略，以提高GH的疗效，而不损害胰岛素敏感性。我们假设，IMCL增加肥胖受试者相比，瘦控制，IMCL与胰岛素抵抗密切相关。在我们的第一个目标中，我们将使用1H磁共振光谱 (1H MRS）作为一种非侵入性技术来量化内脏型肥胖受试者和瘦对照者骨骼肌中的IMCL，并检查与胰岛素抵抗和身体组成的详细测量的关系。我们的第二个假设是，短期GH管理增加IMCL和胰岛素抵抗。我们将评价与安慰剂对照相比，短期（6周）GH给药后GH诱导的IMCL和身体组成变化。我们推测，长期生长激素管理降低胰岛素抵抗和增加瘦体重减少内脏脂肪组织。我们的第三个目标是评估长期（6个月）GH给药后GH诱导的IMCL和身体组成的变化，并研究胰岛素抵抗和身体组成变化的关系。本研究将提供以下方面的新数据：1）IMCL在确定葡萄糖耐受不良中的作用和用途; 2）了解内脏型肥胖患者短期和长期GH给药期间胰岛素抵抗和身体组成改变的病理生理学。最终，这些数据可能揭示增加GH治疗安全性和有效性的策略。

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the short and long-term effects of growth hormone (GH) on body composition and to investigate the hypothesis that intramyocellular lipid (IMCL) accumulation is a mechanism of insulin resistance in subjects with visceral obesity. Obesity is a strong independent risk factor for cardiovascular disease and type 2 diabetes. Visceral obesity has been shown to be associated with decreased secretion of GH compared to lean controls, and GH administration in obese patients reduces visceral fat and increases muscle mass. However, the physiology underlying the short and long-term effects of GH administration on glucose metabolism and insulin sensitivity are not well understood. Given the strong association between insulin resistance and cardiovascular disease, an understanding of the pathophysiology of GH induced changes on glucose metabolism and insulin resistance as well as body composition will be critical in the development of future strategies for enhancing GH efficacy without compromising insulin sensitivity. We hypothesize that IMCL are increased in obese subjects compared to lean controls, and IMCL correlate strongly with insulin resistance. In our first aim we will use 1H magnetic resonance spectroscopy (1H MRS) as a non-invasive technique to quantify IMCL in skeletal muscle in subjects with visceral obesity and lean controls and examine the relationship with detailed measures of insulin resistance and body composition. Our 2nd hypothesis is that short-term GH administration increases IMCL and insulin resistance. We will evaluate GH induced changes on IMCL and body composition after short-term (6 week) GH administration compared to placebo controls. We hypothesize that long-term GH administration decreases insulin resistance and increases lean mass with a decrease in visceral adipose tissue. In our third aim will evaluate GH induced changes on IMCL and body composition after long-term (6 month) GH administration and study the relationship of insulin resistance and change in body composition. This study will provide novel data on 1) the role and use of IMCL in determining glucose intolerance and 2) understanding of the pathophysiology of insulin resistance and altered body composition changes during short and long-term GH administration in visceral obesity. Ultimately, these data may reveal strategies to increase safety and efficacy of GH therapy.