CRTC2 and obesity due to melanocortin 4 receptor deficiency: Because of insulin resistance and impaired insulin signaling [68], patients with obesity and T2DM have low AKT activity and impaired phosphorylation of FOXO1and Crtc2 by AKT, leading to increased FOXO1 and Crtc2 protein levels that drive further gluconeogenic gene expressions (Figure 4).