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.