Figure 3. Select signaling pathways known to regulate β cell proliferation.

Growth factors (PDGF), nutrients (glucose), and hormones (GLP-1 and insulin) have been shown to induce β cell proliferation by activating both canonical and noncanonical mitogenic pathways. Activation of their respective receptors induces signaling via the ERK (also called MAPK) signaling pathway either directly (in the case of PDGF) or via crosstalk mechanisms. Glucose, GLP-1, and insulin have been shown to activate mitogenic signaling via the PI3K/AKT/mTOR pathway. Glucose signals through the calcineurin/NFAT and ERK pathways, while signaling via GLP-1 induces cAMP synthesis to induce proliferation. Small molecules/compounds have been identified that target proteins in these signaling pathways, inhibiting either DYRK1a or GSK3β, both of which phosphorylate NFAT, sequestering it in the cytoplasm. Black and gray arrows indicate canonical and noncanonical signaling, respectively. The depicted pathways regulating β cell proliferation are mainly based on evidence in rodents and do not represent a comprehensive overview of all published work. Compounds shown to induce human β cell replication are indicated in red. AP, aminopyrazine; 5-IT, 5-iodotubercidin; Ca²⁺, calcium; CN, calcineurin.