In both the US and the UK the incidence of obesity is increasing by about 1% per year, a tendency related to the rise in other serious co-morbidities. As a general guide, obesity increases the likelihood of death from coronary heart disease by 25%. In addition obese individuals are at twice the risk of developing diabetes. Many people are obese, suffer cardiovascular problems and are also diabetic, leading to the hypothesis that the coexistence of these diseases is not a coincidence, but that a common underlying abnormality allows them to develop. In 1988 it was suggested that co-morbid obesity and diabetes was related to insulin resistance, and hence the insulin resistance syndrome was first described. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance (see our recent report "Targeting links between obesity and diabetes). Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. MAP kinase cascades represent major signaling pathways that couple transcription factors to extracellular stimuli. German researchers have recently suggested that SREBPs are substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly insulin resistance. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression. Targeting insulin resistance with PPAR agonists has already received considerable pharmaceutical attention. The activation of SREBP has however lags behind. The therapeutic potential of such molecules has recently been exploited by GSK researchers who have developed a new class of compounds that directly binds to the SREBP cleavage-activating protein (SCAP). This series is currently being developed as new class of hypolipidemic drugs however the potential of this and similar classes of molecule is expected to eventually cover the treatment of insulin resistance in general.

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