The majority of insulin resistant individuals (predominantly individuals with type 2 diabetes - T2DM) develop a disproportionate incidence of cardiovascular disease burden including hypertension, coronary artery disease, peripheral vascular disease and heart failure. The underlying pathophysiology is multifactorial but is primarily driven by insulin-resistance mediated regulatory events. These include augmented oxidative stress, upregulation of pro-inflammatory and anti-thrombotic signaling pathways, detrimental effects of advanced glycosylation end-products and perturbations in lipid and fatty acid metabolism. Evidence is emerging to support a role of perturbed mitochondrial respiratory regulation and subsequent endothelial dysfunction as early events in the insulin-resistance syndrome. These in turn, are proposed to result in the subsequent development of the cardiovascular clinical sequelae.

In the last few years, pharmacologic compounds have been developed that directly modulate insulin resistance/sensitivity. Activation of the peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been shown to augment insulin sensitivity. Agents that activate numerous PPAR family members, i.e. pan-PPAR agonists and PPAR gamma (PPAR gamma) specific agonists, promote improved insulin sensitivity. Whether these compounds modify the underlying mitochondrial and endothelial pathophysiology, with the potential of preventing progression of cardiovascular disease in insulin-resistant subjects has not been systematically investigated.

The hypothesis intrinsic to this proposal is that PPAR activation will improve mitochondrial respiratory and endothelial cell function in parallel with improved insulin sensitization in insulin-resistant and T2DM subjects. The primary objective of this study is to establish the effects of the PPAR gamma agonist (rosiglitazone) on exercise-modulated cardiopulmonary-metabolic function (functional measures of mitochrondrial respiratory function) in insulin resistant and T2DM subjects that are either naive to hypoglycemic therapy or are on current therapy with other established classes on anti-diabetic agents with or without associated cardiovascular disease. As secondary end points we will evaluate numerous biological assays of skeletal muscle mitochondrial function, endothelial function and changes in parameters of insulin sensitivity. These include: 1) skeletal muscle mitochondrial respiration, 2) skeletal muscle expression profiles of genes encoding mitochondrial biogenesis program and mitochondrial respiratory control, 3) brachial artery reactivity, 4) endothelial progenitor cell number and colony-forming capacity, 5) monocyte gene expression profiling to evaluate insulin and inflammatory-mediator regulatory events and 6) serological evaluation in change in insulin sensitivity and inflammation. The study is designed as a phase II clinical trial where subjects will receive rosiglitazone for three months duration. Baseline and 3 month laboratory studies will include: 1) rest and exercise cardiopulmonary metabolic testing; 2) skeletal muscle biopsy for mitochondrial function and gene expression profiling analysis, 3) brachial artery reactivity testing and 4) serological and blood cell sampling to determine biochemical, cellular and genomic perturbations in response to insulin-sensitization therapy in this cohort.