PPAR-γ agonists, insulin resistance and dyslipidemia: not a simple relationship

Insulin-mediated glucose uptake varies more than sixfold in apparently healthy individuals, and a third of the population that is most insulin resistant is at greatly increased risk of developing a number of clinical syndromes, including Type 2 diabetes mellitus and cardiovascular disease. Insulin-resistant individuals have a characteristic dyslipidemia, including high plasma triglyceride and low HDL-C concentrations, smaller and denser LDL particles, and an enhanced degree of postprandial lipemia. PPAR-gamma agonists have been clearly demonstrated to improve insulin sensitivity, and ameliorate hyperglycemia in insulin-resistant patients, with and without Type 2 diabetes. However, the ability of the two PPAR-gamma agonists currently available for clinical use to correct the dyslipidemia associated with insulin resistance is less clear. This article attempts to provide insight into these complex relationships. First, the association of insulin resistance and dyslipidemia will be discussed. Following this, preclinical data on the effects of PPAR-gamma agonists in experimental animals will be reviewed. Finally, data from human studies will be examined, with particular attention paid to the divergent effects of pioglitazone and rosiglitazone on lipoprotein profiles and the discussion of some potential mechanistic explanations.