Figure 2.

Mechanisms of β-cell dedifferentiation. (A) Reduced expression of raptor-induced suppression of the mTORC1 signaling pathway increased the expressions of β-cell-specific disallowed genes (e.g. Hk1, Dlk1, Pdgfra, Oat, and Mylk). (B) Stress is a major contributor to β-cell dedifferentiation via activating Nf-κB signaling, which compromises β-cell identity and thus decreases insulin secretion. (C) The JNK pathway is activated under diabetic conditions such as stress and cytokine release, accompanied by Pdx1 nuclear translocation and suppression of insulin and GLUT2 gene expression. (D) The p38 MAPK pathway mediates the degradation of endogenous MafA during hyperglycemia. The dotted and solid boxes represent signaling pathway inhibition and activation, respectively. 4E-BP1, 4E binding protein 1; eIF4F, eukaryotic initiation factor 4F; Hk1, hexokinase 1; Oat:,ornithine aminotransferase; Pdgfrα, platelet-derived growth factor receptor α; Mylk, myosin light chain kinase; IKK, IκB kinase; IκB, nuclear factor-kappaB inhibitor alpha; NIK, Nf-κB inducing kinase; RTK, receptor tyrosine kinases; TNF, tumor necrosis factor; TRAF2, TNF receptor-associated factor 2; RIP1, receptor-interacting protein1; MEK, MAPK kinase; MEKK, MEK kinase; TRADD, TNFR1-associated death domain-containing protein; FADD, Fas-associated death domain-containing protein; TAK-1, TGF-beta-activating kinase 1.