Correction of insulin resistance and the metabolic syndrome.
Insulin resistance is a common phenomenon of the metabolic syndrome, which is clinically characterized by a clustering of various cardiovascular risk factors in a single individual and a higher prevalence of respective complications, such as coronary heart disease and stroke. At the cellular level, insulin resistance is defined as a reduced insulin action, which can affect not only glucose uptake, but also gene regulation. Elucidation of novel signaling networks within the cell which are mediating and affecting insulin action will reveal many new genes and drug targets that are potentially of clinical relevance in the future. In this chapter, we propose that the metabolic syndrome might be a clinical consequence of altered gene regulation. This is illuminated in the context of transcription factors, e.g., sterol regulatory element binding proteins (SREBPs), coupling signals from nutrients, metabolites, and hormones at the gene regulatory level with pathobiochemical features of increased lipid accumulation in lean nonadipose tissues. The phenomenon of ectopic lipid accumulation (lipotoxicity) appears to be a novel link between insulin resistance, obesity, and possibly other features of the metabolic syndrome. Therefore, the investigation of specific gene regulatory networks and their alterations might be a clue to understanding the development and clustering of different cardiovascular risk factors in different individuals. As cellular sensors transcription factors--as common denominators of gene regulatory networks--might thereby also determine the susceptibility of individuals to cardiovascular risk factors and their complications.
Müller-Wieland
D
D
Deutsches Diabetes-Zentrum, Institut für Klinische Biochemie und Pathobiochemie, Düsseldorf, Germany. mueller-wieland@ddfi.uni-duesseldorf.de
Kotzka
J
J
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000209:etiology; D010766:Phosphorylation; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors
D007328:Insulin; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1