Adipose Tissue-specific Angiogenesis and Insulin Sensitivity

描述（由申请人提供）：2型糖尿病发病率的增加与西方世界营养过剩的增加密切相关。多余的热量以脂质的形式异位沉积在组织中，如肝脏和肌肉，导致胰岛素抵抗，碳水化合物稳态紊乱，最终导致糖尿病。当脂肪细胞以甘油三酯形式储存和保留脂质的能力增强时，胰岛素抵抗得到改善，无论是通过细胞功能还是数量的变化。足够的脂肪细胞能力对脂质潴留的重要性解释了明显矛盾的发现，即噻唑烷二酮类药物如罗格列酮通过刺激新脂肪细胞的生物合成而引起净体重增加，改善胰岛素抵抗。在这种情况下，很明显，决定脂肪组织库的能力，以扩大可能有助于个人对糖尿病的易感性的因素。在发育过程中，脂肪组织的扩张需要血管生成，并且脂肪细胞分泌有效的促血管生成因子。我们最近发现，罗格列酮在小鼠脂肪组织中发挥了强效的促血管生成作用，这增加了这种作用可能对胰岛素敏感性脂肪组织的生物发生以及这种药物的治疗作用至关重要的可能性。此外，罗格列酮促进脂肪组织血管生成的作用可能在其用于肥胖糖尿病患者的背景下具有重要的影响。因此，确定罗格列酮是否对人体脂肪组织产生促血管生成作用是非常重要的。使用接受减肥手术的患者的组织，我们开发了一种技术，使我们能够研究离体网膜和皮下脂肪组织的血管生成。为了克服手术患者样本固有的局限性，我们还开发了一种方法来研究血管生成和测量正常志愿者皮下脂肪组织的血管生成潜力。本研究的主要目的是验证罗格列酮对正常人皮下脂肪组织具有促血管生成作用的假设。次要终点包括确定正常人皮下脂肪组织血管生成潜力和胰岛素敏感性之间的相关性。公共卫生相关性：美国和世界上最大的医疗问题之一是糖尿病患者人数的增加。糖尿病通常但不总是与体重增加有关。有一定形状的人，谁在他们的身体中间增加体重，有一个更大的风险发展糖尿病和心脏病的人比谁在他们的腿或他们的身体不是腹部的部分增加体重。我们不知道为什么人们有不同的脂肪分布。我们的研究结果表明，不同区域的血液供应可能会影响这些区域积累的脂肪量。然而，我们没有很好的方法来研究脂肪的血液供应是如何控制的，它是否与疾病有关，或者是否可以开发并在糖尿病或心脏病患者中使用这种血液供应的治疗方法。我们的研究将帮助我们开发这些方法，并回答有关某些用于治疗糖尿病的药物如何起作用的问题。此外，这项工作将帮助我们确定这些药物是否可能在治疗癌症患者中有用（或相反）。

DESCRIPTION (provided by applicant): The growing incidence of type 2 diabetes is correlated closely with an increase in over nutrition in the Western world. Excess calories, in the form of lipids, are ectopically deposited in tissues such as liver and muscle, causing insulin resistance, disordered carbohydrate homeostasis, and ultimately diabetes. Insulin resistance is ameliorated when the capacity of adipose cells to store and retain lipids in the form of triglycerides is enhanced, either by changes in cell function or number. The importance of adequate adipose cell capacity for lipid retention accounts for the apparently paradoxical finding that thiazolidinediones such as rosiglitazone, that cause net weight gain by stimulating the biogenesis of new adipose cells, ameliorate insulin resistance. In this context, it becomes clear that factors that determine the capacity of adipose tissue depots to expand may contribute to individual susceptibility to diabetes. During development, the expansion of adipose tissue requires angiogenesis, and adipocytes secrete potent pro- angiogenic factors. We have recently discovered that rosiglitazone exerts a potent pro- angiogenic effect in adipose tissue in mice, raising the possibility that this effect may be essential for the biogenesis of insulin-sensitive adipose tissue, and for the therapeutic effect of this drug. Moreover, the effect of rosiglitazone to promote angiogenesis in adipose tissue may have important repercussions in the context of its use in obese diabetic patients. Thus, it is highly important to determine whether rosiglitazone exerts a pro-angiogenic effect on adipose tissue in humans. Using tissue from patients undergoing bariatric surgery, we have developed technology that allows us to study angiogenesis from omental and subcutaneous adipose tissues ex-vivo. To overcome the limitations inherent to samples from surgical patients, we have also developed a method to study angiogenesis and measure the angiogenic potential of subcutaneous adipose tissue from normal volunteers. In this proposal our primary goal is to test the hypothesis that rosiglitazone has a pro-angiogenic effect on normal human subcutaneous adipose tissue. Secondary end-points include determining the correlation between subcutaneous adipose tissue angiogenic potential and insulin sensitivity in normal humans. PUBLIC HEALTH RELEVANCE: One of the greatest medical problems in the USA and the world is the increase in the number of people with Diabetes. Diabetes is often, but not always, linked to weight gain. People with a certain shape, who gain weight around the middle of their bodies, have a much greater risk of developing Diabetes and heart disease than people who gain weight in their legs or parts of their bodies that are not the abdomen. We don't know why people have a different fat distribution. Our results suggest that the blood supply to different areas may influence how much fat accumulates in those areas. However, we don't have good methods to study how the blood supply to fat is controlled, whether it has anything to do with diseases, or whether therapies that act on this blood supply can be developed and used in patients with diabetes or heart disease. Our study will help us develop these methods, and answer questions about how certain drugs used to treat diabetes work. Also, this work will help us determine whether these drugs may be useful (or counter- indicated) in treating patents with cancer.