Thiazolidinediones and biguanides improve insulin resistance and are used in the management of type 2 diabetes. Use of biguanides is associated with a reduction in vascular complications in patients with diabetes. Pre-clinical studies with thiazolidinediones suggest improvements in vascular function and long-term clinical trials in type 2 diabetes are in progress. These effects are proposed to be mediated through inhibition of complex 1 in the mitochondrial respiratory chain and activation of the fuel sensing enzyme AMP-activated protein kinase (AMPK) although the precise mode of action remains uncertain.
We studied the effects of rosiglitazone, metformin and it's closely related analogue phenformin, in cultured human aortic endothelial cells (HAEC). AMPK activity was assessed using a peptide kinase assay and the phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC) in HAECs incubated in rosiglitazone, phenformin or metformin. Nitric oxide (NO) release was evaluated with a Sievers NO meter.
Both rosiglitazone and phenformin stimulated AMPK activity with a parallel increase in ACC phosphorylation in a time dependent-manner. In addition, rosiglitazone and phenformin stimulated NO synthesis. Incubation of HAECs with metformin had no effect on AMPK activity or basal NO release.
To our knowledge our results provide the first evidence that rosiglitazone and phenformin activate AMPK in human endothelial cells. Metformin is less lipophilic than phenformin and this may explain the neutral results. We propose that the beneficial effects of thiazolidinediones and biguanides in patients with type 2 diabetes are in part mediated by activation of AMPK. The observed increase in NO production may be important in the vascular effects of both drugs. Further investigation of the way in which thiazolidinediones and biguanides affect intracellular signalling in vascular endothelial cells may identify novel therapeutic targets in patients with diabetes and vascular disease.
04 - 06 Apr 2005
British Endocrine Societies