Adipose Tissue-specific Angiogenesis and Insulin Sensitivity

脂肪组织特异性血管生成和胰岛素敏感性

• 批准号: 7689309
• 负责人: Silvia Corvera
• 金额: $ 20.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689309
• 关键词: 2,4-thiazolidinedione; Abdomen; Accounting; Address; Adipocytes; Adipose tissue; Angiogenic Factor; Area; Bariatrics; Biochemical; Biogenesis; Biopsy; Body Weight; Calories; Carbohydrates; Cell physiology; Characteristics; Coculture Techniques; Complement; Conditioned Culture Media; Deposition; Development; Diabetes Mellitus; Differentiation and Growth; Disease; Drug Prescriptions; Drug usage; Endothelial Cells; Fatty acid glycerol esters; Goals; Heart Diseases; Hip region structure; Homeostasis; Human; Incidence; Individual; Insulin; Insulin Resistance; Leg; Legal patent; Leptin; Link; Lipids; Liver; Malignant Neoplasms; Measurement; Measures; Medical; Metabolic; Methodology; Methods; Mus; Muscle; Needle biopsy procedure; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Population Study; Predisposition; Process; Research; Risk; Sampling; Serum; Shapes; Stem cells; Technology; Testing; Therapeutic Effect; Thiazolidinediones; Tissues; Triglycerides; Vascular blood supply; Weight Gain; Western World; Work; adiponectin; angiogenesis; bariatric surgery; base; diabetic patient; insulin sensitivity; lipid biosynthesis; nutrition; prevent; public health relevance; rosiglitazone; subcutaneous; volunteer; waist circumference

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.

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。当脂肪细胞储存和保留甘油三酯形式的脂质的能力通过细胞功能或数量的变化而增强时，胰岛素抵抗就会得到改善。足够的脂肪细胞容量对于脂质保留的重要性解释了明显矛盾的发现，即噻唑烷二酮类（例如罗格列酮）通过刺激新脂肪细胞的生物发生而导致净体重增加，从而改善胰岛素抵抗。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会导致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，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有效的促血管生成作用，这增加了这种作用可能对于胰岛素敏感脂肪组织的生物发生以及该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其在肥胖糖尿病患者中的使用产生重要影响。因此，确定罗格列酮是否对人体脂肪组织发挥促血管生成作用非常重要。使用来自接受减肥手术的患者的组织，我们开发了技术，使我们能够在体外研究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并测量正常志愿者皮下脂肪组织的血管生成潜力。在本提案中，我们的主要目标是检验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与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。糖尿病通常但并非总是与体重增加有关。具有某种体形的人，身体中部周围体重增加的人，比腿部或腹部以外身体部位体重增加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。我们的结果表明，不同区域的血液供应可能会影响这些区域的脂肪积累量。然而，我们没有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，或者是否可以开发出作用于这种血液供应的疗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发挥作用的问题。此外，这项工作将帮助我们确定这些药物在治疗癌症患者中是否有用（或相反）。