EFFECTS OF GROWTH HORMONE ON INTRAMYOCELLULAR LIPIDS

描述(申请人提供)：这项建议的目标是调查生长激素(GH)对体成分的短期和长期影响，并调查心肌细胞内脂质(IMCL)积累是内脏肥胖者胰岛素抵抗的机制的假说。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。与瘦身对照组相比，内脏肥胖与生长激素分泌减少有关，肥胖症患者服用生长激素可减少内脏脂肪并增加肌肉质量。然而，生长激素对葡萄糖代谢和胰岛素敏感性的短期和长期影响的生理机制还不是很清楚。鉴于胰岛素抵抗与心血管疾病之间的密切联系，了解生长激素引起的糖代谢、胰岛素抵抗和身体成分变化的病理生理学机制，对于未来在不损害胰岛素敏感性的情况下提高生长激素疗效的策略的制定至关重要。我们假设肥胖受试者的IMCL较瘦对照组增加，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 (1HMRS)作为一种非侵入性技术，可以量化内脏肥胖者和瘦身对照组患者骨骼肌中的IMCL，并检查与胰岛素抵抗和身体成分的详细测量之间的关系。我们的第二个假设是短期服用生长激素会增加IMCL和胰岛素抵抗。我们将评估短期(6周)GH给药后对IMCL和身体成分的影响，并与安慰剂对照组进行比较。我们假设长期服用生长激素可降低胰岛素抵抗，增加瘦体重，同时减少内脏脂肪组织。第三个目的是评价长期(6个月)应用GH后对IMCL和体成分的影响，并研究胰岛素抵抗与体成分改变的关系。这项研究将在以下方面提供新的数据：1)IMCL在确定糖耐量异常中的作用和使用；2)了解胰岛素抵抗的病理生理学以及在短期和长期服用GH治疗内脏肥胖期间身体成分的变化。最终，这些数据可能揭示提高生长激素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.