Figure 5. Model of GLP-1 mitogenic effect mediated by calcineurin/NFAT signaling in juvenile human cells.

GLP-1 (or Ex-4) binds and activates GLP-1R, which increases intracellular calcium concentration (56), Ca²⁺-sensitive phosphatase, and calcineurin (Cn). Calcineurin dephosphorylates NFATc factors to expose their nuclear localization sequences, which triggers rapid entry into the nucleus. In the nucleus, NFATc proteins assemble on DNA with partner proteins (termed NFATn) to activate transcription of target genes, including cell cycle activators (e.g., cyclins, CDKs) and proliferation-promoting transcription factors (TFs) such as FOXM1, which are all produced at a low level in adult islets. GLP-1/calcineurin/NFAT signaling does not appear to regulate the expression of age-associated cell cycle inhibitors such as CDKN2A (normally very low level in juvenile islets or its repressor EZH2 in juvenile human β cells, which may explain the absence of proliferative response to GLP-1 or Ex-4 in adult islets.