Adipose Tissue-specific Angiogenesis and Insulin Sensitivity

描述（由申请人提供）：在西方世界，2型糖尿病发病率的增长与营养过剩的增加密切相关。以脂质形式存在的过量热量会异常地沉积在肝脏和肌肉等组织中，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的形式储存和保留脂质的能力增强时，通过改变细胞功能或数量，胰岛素抵抗得到改善。脂肪细胞保持脂质能力的重要性解释了一个明显矛盾的发现，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生成导致净体重增加，改善胰岛素抵抗。在这种情况下，很明显，决定脂肪组织库扩张能力的因素可能有助于个体对糖尿病的易感性。在发育过程中，脂肪组织的扩张需要血管生成，脂肪细胞分泌强大的促血管生成因子。我们最近发现，罗格列酮在小鼠脂肪组织中发挥了强大的促血管生成作用，提高了这种作用可能对胰岛素敏感脂肪组织的生物发生和这种药物的治疗效果至关重要的可能性。此外，罗格列酮促进脂肪组织血管生成的作用可能对肥胖糖尿病患者的使用产生重要影响。因此，确定罗格列酮是否对人类脂肪组织产生促血管生成作用是非常重要的。利用接受减肥手术的患者的组织，我们开发了一种技术，使我们能够研究大网膜和皮下脂肪组织的体外血管生成。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并测量正常志愿者皮下脂肪组织的血管生成潜力。在这个提议中，我们的主要目标是验证罗格列酮对正常人类皮下脂肪组织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能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数量的增加。糖尿病通常与体重增加有关，但并非总是如此。与腿部或腹部以外的身体部位增重的人相比，体型特定、在身体中部增重的人患糖尿病和心脏病的风险要大得多。我们不知道为什么人们的脂肪分布不同。我们的研究结果表明，不同部位的血液供应可能会影响这些部位的脂肪积累量。然而，我们没有很好的方法来研究脂肪的血液供应是如何被控制的，它是否与疾病有关，或者是否可以开发出针对这种血液供应的治疗方法，并用于糖尿病或心脏病患者。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在治疗癌症患者方面是否有用（或反指）。

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.