FIGURE 8.

Model depicting the regulation of FoxO by the PGC-1α-OGT complex in response to glucose. In the diabetic liver, GlcNAcylation of FoxO (12) and CRTC2 (TORC2) (13) mediates inappropriate gluconeogenesis in response to glucose by activating these key transcription factors. In a second step of activation of gluconeogenesis, elevated expression of PGC-1α, possibly through CRTC2 (35) and CREB (36), can bind and target OGT to FoxOs. Thus, glucose activates inappropriate gluconeogenesis in a two-step process. First, an O-GlcNAc-dependent activation of CRTC2/CREB drives PGC-1α expression. Second, higher levels of PGC-1α increase targeting of OGT to FoxOs. MnSOD, manganese superoxide dismutase.