Effect of rosiglitazone on capillary density and angiogenesis in adipose tissue of normoglycaemic humans in a randomised controlled trial

Recent reports of decreased capillary density in the adipose tissue of obese individuals suggest that an imbalance of angiogenesis and adipogenesis may, in part, underlie insulin resistance. This study aimed to determine whether the insulin-sensitising peroxisome proliferator-activated receptor gamma (PPAR gamma) activator rosiglitazone affects adipose tissue vascularisation in normal humans. A randomised, parallel-group, investigator-blinded placebo-controlled trial was conducted with normoglycaemic volunteers with BMI 27-43, recruited from the community at the University of Massachusetts Medical School, Worcester, MA, USA. Peri-umbilical adipose tissue biopsies were obtained before and after treatment for 6 weeks with rosiglitazone (8 mg once daily) or placebo, which were randomly allocated from a sequentially numbered list. The primary outcomes were adipocyte size and capillary density measured by immunohistochemistry, and angiogenic potential assessed by capillary sprout formation in Matrigel. Secondary outcomes were serum adiponectin, glycaemic, lipid and liver function variables. A total of 35 individuals fulfilling the inclusion criteria were randomised, and complete before-vs-after analyses were achieved in 30 participants (13 and 17, placebo and rosiglitazone, respectively). Significant differences, assessed by paired two-tailed Student t tests, were seen in response to rosiglitazone for adipocyte size (3,458 +/- 202 vs 2,693 +/- 223 mu m(2), p = 0.0049), capillary density (5.6 +/- 0.5 vs 7.5 +/- 0.5 lumens/field, p = 0.0098), serum adiponectin (14.3 +/- 1.5 vs 28.6 +/- 3.0 ng/ml, p < 0.0001) and alkaline phosphatase (1.04 +/- 0.07 vs 0.87 +/- 0.05 mu kat/l, p = 0.001). A difference in angiogenic potential before and after treatment between the placebo and rosiglitazone groups was also seen (-23.88 +/- 14 vs 13.42 +/- 13, p = 0.029, two-tailed Mann-Whitney test). Significant effects on adipose tissue vascular architecture occur after a short period of treatment with rosiglitazone in individuals with normal glucose tolerance. Improved adipose tissue vascularisation may, in part, mediate the therapeutic actions of this class of drugs. ClinicalTrials.gov NCT01150981 The study was funded by National Institutes of Health grant DK089101 to S. Corvera, and by pilot funding from the University of Massachusetts (UMASS) Center for Clinical Translational Sciences (M. Thompson, S. Malkani and S. Corvera). Morphology core services were supported by UMASS Diabetes Endocrine Research Center (DERC) grant DK32520.