PPARγ is a regulator of lipid and glucose metabolism and therefore its synthetic ligands such as glitazones - the derivatives of thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone) - improve insulin and glucose parameters and increase whole body insulin sensitivity. Therefore, they are called insulin-sensitizing medications used in the treatment of diabetes [
61]. They indirectly increase insulin-stimulated glucose uptake in adipocytes, hepatocytes and skeletal muscle cells [
62,
63]. The effects of pharmacological PPARγ activation by thiazolidinediones have been attributed, at least in part, to decreased free fatty acid (FFA) levels and increased lipid storage in adipose tissue, in which it is most highly expressed. In consequence, lipotoxicity in the muscles and liver is reduced. PPARγ agonists also have the ability to redistribute fat from visceral to subcutaneous depots and increase adiponectin and reduce tissue necrosis factors [
63,
64]. Moreover, rosiglitazone and pioglitazone are used in the treatment of patients with type 2 diabetes because they decrease hepatic glucose production and prolong pancreatic β-cell function by preventing apoptosis of β-cells [
62,
63]. They reduce fasting plasma glucose and glycated hemoglobin A1c (pioglitazone 15-45 mg/day, rosiglitazone 2-6 mg/twice a day) [
65-
67]. However, the influence of both thiazolidinediones on cardiovascular outcomes in patients with diabetes mellitus is different. The positive effect of pioglitazone was demonstrated in a PROactive study revealing 16% reduced cardiovascular complications in the main secondary endpoint (a composite of all-cause-mortality, non-fatal myocardial infarction and stroke) compared with placebo treatment [
68]. Conversely, rosiglitazone was associated with significant increases in myocardial infarction and death from cardiovascular causes after only relatively short-term exposure [
69] and the European Medicines Agency withdrew approval of this medication in 2010 due to these cardiovascular safety concerns [
64]. The differences between thiazolidinediones are probably caused by their diverse effects on lipid sub-fractions [
63]. Pioglitazone increases HDL cholesterol and decreases triglycerides and fasting plasma free fatty acids (without any influence on total cholesterol and LDL cholesterol) [
64,
70,
71]. Rosiglitazone significantly augments HDL levels [
64,
70,
71], total cholesterol and the LDL fraction [
71].
In diabetes mellitus, long-term activation of PPARγ by thiazolidinediones not only reduces glycaemia and insulinemia but also attenuates vascular dysfunction [
72]. PPARγ is expressed in vessels, specifically in vascular smooth muscle cells and endothelium. Recent studies suggest that activators of PPARγ not only modify metabolic disturbances but also protect vascular function in diabetes [
72]. Using an animal model, Bagi et al. proved that short-term treatment of type 2 diabetic mice with rosiglitazone augmented NO-mediated flow-dependent dilations of coronary arterioles by reducing vascular superoxide production via a favorable alteration of oxidant/antioxidant enzyme activities [
73]. PPARγ agonists also lower blood pressure and decrease circulating PAI-1 and CRP levels in patients with diabetes [
27,
28].
Apart from these positive effects, activation of PPARγ by glitazones attenuates systemic inflammation [
3,
4] and reduces tumor growth and angiogenesis. PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth [
74]. Only troglitazone revealed tumor-promoting and pro-angiogenic properties - it promoted hepatic carcinogenesis and liposarcomas, and thus this agonist was rejected from the treatment [
72,
75].
Despite many beneficial features of glitazones (metabolic and anti-arteriosclerotic activity), they also exhibit side effects, such as weight gain, edema, bone fractures, heart failure and increased risk of myocardial infarctions, which have limited the use of these drugs in diabetic patients with high lipid levels [
76]. Fortunately, new selective PPAR
γ modulators are currently in development (such as S26948 [
77] and INT131 [
78]) and these should stimulate glucose metabolic pathways and minimize the side effects of full PPAR-
γ agonists.