EFFECTS OF GROWTH HORMONE ON INTRAMYOCELLULAR LIPIDS

描述（由申请人提供）：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，并研究细胞内脂质（IMCL）积累是内脏性肥胖受试者胰岛素抵抗的机制。肥胖是心血管疾病和2型糖尿病的独立危险因素。与瘦人相比，内脏肥胖已被证明与生长激素分泌减少有关，肥胖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机制尚不清楚。鉴于胰岛素抵抗与心血管疾病之间的密切联系，了解生长激素诱导的葡萄糖代谢、胰岛素抵抗以及身体成分变化的病理生理学，将对未来在不影响胰岛素敏感性的情况下提高生长激素疗效的策略的发展至关重要。我们假设肥胖受试者的IMCL与瘦对照相比增加，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

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.