Nuclear Mechanisms of Insulin Resistance

Abstract

Insulin resistance is a sine qua non of type 2 diabetes and is associated with many other clinical conditions. Decades of research into mechanisms underlying insulin resistance have mostly focused on problems in insulin signal transduction and other mitochondrial and cytosolic pathways. By contrast, relatively little attention has been focused on transcriptional and epigenetic contributors to insulin resistance, despite strong evidence that such nuclear mechanisms play a major role in the etiopathogenesis of this condition. In this review, we summarize the evidence for nuclear mechanisms of insulin resistance, focusing on three transcription factors with a major impact on insulin action in liver, muscle, and fat.

Figure 1

Multi-organ effects of PPARγ, GR, and FoxO1 and their impact on insulin sensitivity. Multiple sites of action for these transcription factors contribute to their effects on metabolism and glycemic control. See text for details.

Figure 2

Different modes of transcriptional regulation by PPARγ and GR in insulin sensitivity. In fat, muscle, and liver, ligand activation of PPARγ induces heterodimerization with RXR, allowing DNA binding to specific response elements and subsequent transcriptional activation. Negative regulation by PPARγ, as occurs with pro-inflammatory genes in immune cells, is incompletely understood but likely involves ‘tethering’ via direct interactions with other transcription factors. Ligand binding of GR induces homodimerization of GR, allowing DNA binding to activate and repress GR target genes in multiple tissues. Similar to PPARγ, GR can exert trans-repression via tethering to other transcription factors to repress genes in inflammation.

Figure 3

Transcriptional activity of FOXO1 and PGC-1α in hepatic glucose production. FOXO1 is a key driver of gluconeogenic gene expression (e.g. Pck1 and G6pc) in the liver. Its activity is regulated by a variety of factors, including phosphorylation by Akt, which reduces FOXO1 levels in the nucleus, and by phosphorylation via AMPK, which promotes its activity. Other post-translational modifications, such as O-linked GlcNAcylation and acetylation, also affect the activity of FOXO1, as does interaction with the co-factor PGC-1α. See text for more details.