Epigenomic and transcriptional control of insulin resistance

Insulin resistance is one of the defining features of type 2 diabetes and the metabolic syndrome and accompanies many other clinical conditions, ranging from obesity to lipodystrophy to glucocorticoid excess. Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signalling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional cofactors, and chromatin-modifying enzymes will be considered. Well-studied examples of the first include PPAR- in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin-sensitive tissues. These proteins work in concert with cofactors such as PGC-1 and CRTC2, and chromatin-modifying enzymes including DNA methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin-stimulated glucose uptake, gluconeogenesis or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a noncoding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small-molecule inhibitors and activators of these factors and their related pathways.