How does glucagon‐like peptide 1 stimulate human β‐cell proliferation? A lesson from islet graft experiments

The incidence of type 2 diabetes increases with age. The age‐dependent decline in functional β‐cell mass contributes to the increased risk of onset of diabetes, reflecting the central role of pancreatic β‐cells in glucose homeostasis. Indeed, the replication rate of human and rodent β‐cells is known to decline sharply with age, and such a characteristic of β‐cells might explain the increased onset of type 2 diabetes in the older population. The molecular mechanism involved in the age‐dependent decline of β‐cell proliferation has been extensively studied, mainly using rodents and in vitro culture systems, but its molecular basis is still largely unknown. A mechanism by which glucagon‐like peptide‐1 receptor activation induces human β‐cell proliferation only within a restricted time window was recently suggested in a study in which human islets were grafted into immunodeficient mice. The authors found that the mitogenic effects of exendin‐4 require calcineurin/nuclear factor of activated T‐cells signaling, and that only in juvenile islets, exendin‐4 induced the expression of nuclear factor of activated T‐cells signaling components, as well as downstream target genes that facilitate β‐cell proliferation. These findings provide a mechanistic explanation as to why glucagon‐like peptide 1 exerts mitogenic effects only in juvenile human β‐cells.