Roles of FoxM1-driven basal beta-cell proliferation in maintenance of beta-cell mass and glucose tolerance during adulthood

Aims/Introduction: Whether basal beta-cell proliferation during adulthood is involved in maintaining sufficient beta-cell mass, and if so, the molecular mechanism(s) underlying basal beta-cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' beta-cell proliferation, which facilitates rapid increases in beta-cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of beta-cell FoxM1 in 'basal' beta-cell proliferation under normal conditions and in the maintenance of sufficient beta-cell mass as well as glucose homeostasis during adulthood. Materials and Methods: FoxM1 deficiency was induced specifically in beta-cells of 8-week-old mice, followed by analyzing its short- (2 weeks) and long- (10 months) term effects on beta-cell proliferation, beta-cell mass, and glucose tolerance. Results: FoxM1 deficiency suppressed beta-cell proliferation at both ages, indicating critical roles of FoxM1 in basal beta-cell proliferation throughout adulthood. While short-term FoxM1 deficiency affected neither beta-cell mass nor glucose tolerance, long-term FoxM1 deficiency suppressed beta-cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long-term beta-cell FoxM1 deficiency. Therefore, beta-cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long-term beta-cell FoxM1 deficiency. Conclusions: Basal low-level proliferation of beta-cells during adulthood is important for maintaining sufficient beta-cell mass and good glucose tolerance and beta-cell FoxM1 underlies this mechanism. Preserving beta-cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.