PPAR agonists in the treatment of insulin resistance and associated arterial disease

Augmented release of non-esterified fatty acids (NEFA) from insulin-resistant adipocytes appears to be the main cause of the 'atherogenic lipoprotein profile' associated with insulin resistance and type 2 diabetes. This atherogenic profile is characterised by large very-low-density lipoproteins (VLDL), small, dense low-density lipoproteins (LDL) and low levels of high-density lipoproteins (HDL), resulting in deposition of apo B lipoproteins in the vascular intima and subsequent inhibition of reverse cholesterol transport. This lipoprotein retention also results in a proinflammatory response from the vascular endothelium, which is increased in insulin resistance. Thus the ideal therapy for insulin resistance, and its complications, should both improve its associated dyslipidaemia and ameliorate the vascular atherogenic reaction. Some peroxisome proliferator-activated receptor (PPAR)-gamma and dual PPARalpha/gamma agonists improve insulin resistance and its dyslipidaemia, both in rodents and man, while in animal models they can show clear antiatherosclerotic effects. Nonetheless, it is difficult to evaluate how much of these antiatherosclerotic actions are caused by effects on the dyslipidaemia or by direct effects on vascular cells. Upregulation of PPARgamma and PPARalpha/gamma activity in macrophages can reduce secretion of proinflammatory cytokines and matrix metalloproteases, as well as increase HDL-mediated cholesterol efflux transport--all potentially antiatherosclerotic results. In addition, treatment of smooth muscle cells with PPARgamma agonists can partially revert possible atherogenic changes in the production of matrix proteoglycans induced by exposure to NEFA. Although these findings are still preliminary, and their relevance to human atherosclerosis has not been fully elaborated, these results suggest that improved PPARalpha/gamma agonism may positively modulate several of the metabolic steps connecting insulin resistance with dyslipidaemia and with the atherogenic response.