Metabolic and Additional Vascular Effects of Thiazolidinediones
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Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome.
Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-γ improves insulin sensitivity. Expression of PPAR-γ is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-γ activity is an interesting therapeutic approach to reduce cardiovascular events.
Thiazolidinediones are PPAR-γ agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature.
Several questions remain to be answered about PPAR-γ agonists, particularly with respect to the role of PPAR-γ in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress.
In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.
- Metabolic and Additional Vascular Effects of Thiazolidinediones
Volume 62, Issue 10 , pp 1463-1480
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- 1. Department of Internal Medicine, Section of Vascular Medicine and Diabetology, University Medical Center Utrecht, Room F.02.126 Heidelberglaan 100, PO Box 85500, Utrecht, 3508 GA, The Netherlands
- 2. Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Canada