MAPK8 and obesity due to melanocortin 4 receptor deficiency: Of note, the obesity-induced transition from insulin resistance to T2DM involves dysfunction of both pancreatic α- and β-cells resulting in upregulation of hepatic gluconeogenic gene transcription with the cytokines and adipocytokines released in systemic inflammation suppressing insulin action (will be discussed later), which in turn, increases hepatic gluconeogenic enzymes transcription through the activation of nuclear factor κB (NF-κB), Jun N-terminal kinase (JNK), and ceramide biosynthetic pathways (39) (Figure 3).