Effect of Rosiglitazone on the Vascular Biology of Human Fat Tissue (RAPA)

Insulin resistance is a common condition that can lead to type 2 diabetes. One of the commonly prescribed diabetes medications, called rosiglitazone, works by decreasing insulin resistance. Rosiglitazone appears to work on fat cells. Animal studies suggest that rosiglitazone may work by increasing blood vessel growth in fat cells. The purpose of this research is to see if rosiglitazone also increases blood vessel growth in human fat cells. The investigators will compare results from before and after being on rosiglitazone for 6 weeks.

Adipocytes play a crucial role in the control of metabolic homeostasis, by sequestering excess calories in the form of triglycerides, and secreting cytokines that control systemic fuel utilization. Sustained excess calorie consumption results in adipocyte hypertrophy and hyperplasia, and like any expanding tissue, requires increased capillary expansion to nourish the enlarged adipose tissue mass. Recent reports indicate that decreased capillary density in adipose tissue of obese individuals correlates with insulin resistance, suggesting that an imbalance of angiogenesis and adipogenesis may underlie this condition. To determine whether improvement in insulin sensitivity is related to changes in adipose tissue capillary development, we conducted a randomized, double-blind, placebo-controlled trial to determine capillary density, angiogenic growth potential, and metabolic parameters in healthy human volunteers before and after treatment with rosiglitazone, a potent insulin sensitizer.

Adipose tissue collected at 8 weeks was cut into ~1mm pieces which were embedded in individual wells of a 96 well plate containing growth factor depleted Matrigel. Wells were filled with media supplemented with endothelial growth factors, replaced every second day. Values for each patient are expressed as the difference in the average number of capillary branches (sprouts) formed by each of approximately 50 explants between day 14 and day 7. The number of branches forming on the periphery (defined as at least three cells in a branch structure) was counted by two investigators at day 7 and 14.

Adiponectin concentrations in serum were measured in ng/ml, in both arms at baseline and at 8 weeks, i.e. 2 weeks after stopping drug or placebo treatment

Inclusion Criteria: Overweight but otherwise in good general health. Age 18 - 55 years. Normal glucose tolerance. Stable weight with BMI (27-44). Stable medication use for the preceding month. BP < 150/90. Negative pregnancy test (*HCG), if female and of childbearing potential. Practicing, and willing to continue to practice appropriate contraception throughout the study if a female of childbearing potential. Exclusion Criteria: Serious medical illness. Pregnancy. Tobacco use within the past 6 months. Prior or current treatment with a thiazolidinedione. Patients who have received an investigational drug in the past 30 days. Use of systemic corticosteroids. Known or suspected allergy to Rosiglitazone or any component of the preparation

Gealekman O, Guseva N, Gurav K, Gusev A, Hartigan C, Thompson M, Malkani S, Corvera S. Effect of rosiglitazone on capillary density and angiogenesis in adipose tissue of normoglycaemic humans in a randomised controlled trial. Diabetologia. 2012 Oct;55(10):2794-2799. doi: 10.1007/s00125-012-2658-2. Epub 2012 Jul 31.