Insulin-regulated transcription factors: molecular link between insulin resistance and cardiovascular risk factors

Patients with insulin resistance and/or type 2 diabetes have a 5-fold incre ase in cardiovascular mortality rate. Therefore, it is a current issue of d iscussion that arterial hypertension, lipid disorders as well as visceral o besity are coronary risk factors, which might belong to a syndrome that is caused by decreased insulin sensitivity. Concerning a possible molecular li nk between insulin resistance, atherosclerosis and obesity, we focus in our research on questions looking for a molecular link between lipid metabolis m, insulin action, and obesity at a gene regulatory level. Alterations in the structure, function and regulation of transcription fact ors appear to be such signalling steps which might play an essential role i n the pathogenesis and therapy of cardiovascular risk factors associated wi th insulin resistance, eg the so called metabolic syndrome. Recent examples are members of the nuclear hormone receptor superfamily, eg peroxisome pro liferator-activated receptor (PPAR) isoforms and sterol regulatory element- binding proteins (SREBPs). Beside their regulation by different metabolites , these transcription factors are also targets of hormones, like insulin an d leptin, growth factors, and inflammatory signals. Therefore, they appear to be a point of signalling convergence at a gene regulatory level. Major signalling pathways coupling receptors at the cell surface for hormon es, growth factors as well as cytokines to gene regulatory events in the nu cleus are the MAP-kinase cascades. We have recently defined different postr eceptor defects in these pathways in patients with clinical phenotypes corr esponding to congenital lipoatrophy. Therefore, these studies may identify novel pathways which play a role in the control of body weight, insulin sen sitivity and cardiovascular risk.