Adipose Tissue-specific Angiogenesis and Insulin Sensitivity

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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.