EFFECTS OF GROWTH HORMONE ON INTRAMYOCELLULAR LIPIDS

描述（由申请人提供）：本提案的目标是研究生长激素（GH）对身体成分的短期和长期影响，并研究肌细胞内脂质（IMCL）积累是内脏肥胖受试者胰岛素抵抗机制的假设。肥胖是心血管疾病和2型糖尿病的重要独立危险因素。与瘦对照相比，内脏肥胖已被证明与 GH 分泌减少有关，肥胖患者施用 GH 可以减少内脏脂肪并增加肌肉质量。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尚不清楚。鉴于胰岛素抵抗与心血管疾病之间的密切关联，了解 GH 引起的葡萄糖代谢和胰岛素抵抗以及身体成分变化的病理生理学对于制定未来增强 GH 功效而不损害胰岛素敏感性的策略至关重要。我们假设与瘦对照相比，肥胖受试者的 IMCL 增加，并且 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 磁共振波谱 (1H MRS) 作为一种非侵入性技术，可量化内脏肥胖和瘦对照受试者骨骼肌中的 IMCL，并检查其与胰岛素抵抗和身体成分详细测量值的关系。我们的第二个假设是短期 GH 给药会增加 IMCL 和胰岛素抵抗。我们将评估短期（6 周）GH 给药后与安慰剂对照相比 GH 引起的 IMCL 和身体成分的变化。我们假设长期施用 GH 会降低胰岛素抵抗，并随着内脏脂肪组织的减少而增加瘦体重。我们的第三个目标是评估长期（6 个月）GH 给药后 GH 引起的 IMCL 和身体成分的变化，并研究胰岛素抵抗和身体成分变化的关系。这项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方面的作用和用途，以及 2) 了解胰岛素抵抗的病理生理学以及内脏肥胖短期和长期 GH 给药期间身体成分变化的变化。最终，这些数据可能揭示提高 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.