What are the thiazolidinediones and how do they act

A new category of antidiabetic medicines consists of thiazolidine-diones (TZDs) or glitazones. the main action of which is the reduction of insulin resistance in the peripheral tissues (mainly the adipose tissue, but also the muscles and less so the liver). The first medicine of this category (troglitazone) came out in the USA in 1997, but was withdrawn in 2000 because of serious hepatotoxicity. Today two substances of this category are available, pioglitazone and rosiglita-zone.

TZDs bind to special nuclear cell receptors, called PPAR-g (Peroxisome Proliferator Activated Receptor-g), which are found all over the body, but with higher concentration in the adipose tissue, the muscles and the liver. After binding to the receptor, the complex interacts with the Retinoid X Receptor (RXR) so that an activated heterodimer complex is produced, that then causes transcription of genes of various proteins. The manifestation of the action of TZDs is expressed via these proteins. The presence of insulin is essential for the hypoglycaemic action of TZDs, which actually potentiate its action. This fact renders these medicines useful in Type 2 DM, since it is characterized by insulin resistance. Concisely, TZDs have the following effects:

• they cause an increase of glucose transporters GLUT1 (in the adipose tissue) and of GLUT4 (in muscles), resulting in an increase of the intracellular transport of glucose;

• they increase the phosphorylation of the insulin receptor after the binding of insulin, so that the message of binding is transmitted more rapidly into the cell;

• they decrease the hepatic gluconeogenesis;

• they inhibit lipolysis and thus decrease the free fatty acids, which are incriminated in the development of insulin resistance, and they potentiate the action of lipoprotein lipase, via which the chylomicrons and endogenous triglycerides are removed from the circulation;

• they cause redistribution of adipocytes, so that more small adipocytes -sensitive to insulin - are distributed in the periphery, and less intraabdominal;

• they promote the expression of the adiponectin gene and inhibit the resi stin gene, thus increasing the sensitivity of the adipose tissue to insulin.

However, several aspects of the mechanism of action of TZDs, both in muscles and in the adipose tissue, still remain elusive.

TZDs manifest other actions as well. These include an improvement in endothelial function, reduction of the carotid intima-media thickness and inhibition of the proliferation of smooth muscle cell fibres, as well as the decrease of fibrinogen, CRP (C-reactive protein), PAI-1 (plasminogen activator inhibitor-1), tumour necrosis factor-a (TNF-a) and small-dense atherogenic LDL. They also cause a reduction in the urine albumin excretion rate and the arterial pressure. These effects most likely exert an antiatheromatous effect and are the subject of continuing research. If these preliminary, very encouraging effects of TZDs on the atherosclerotic risk factors are to be translated to a reduction of cardiovascular events, this will become clear in the near future, from the results of ongoing large studies. The multiple effects of TZDs in the various tissues and multiple genes (> 100) that these influence, currently renders precise determination of their mechanism of action impossible with regard to their hypoglycaemic effect.

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