Conclusions
Basal low-level proliferation of β-cells during adulthood is important for maintaining sufficient β-cell mass and good glucose tolerance and β-cell FoxM1 underlies this mechanism. Preserving β-cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.
Methods
FoxM1 deficiency was induced specifically in β-cells of 8-week-old mice, followed by analyzing its short- (2 weeks) and long- (10 months) term effects on β-cell proliferation, β-cell mass, and glucose tolerance.
Results
FoxM1 deficiency suppressed β-cell proliferation at both ages, indicating critical roles of FoxM1 in basal β-cell proliferation throughout adulthood. While short-term FoxM1 deficiency affected neither β-cell mass nor glucose tolerance, long-term FoxM1 deficiency suppressed β-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 β-cell FoxM1 deficiency. Therefore, β-cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long-term β-cell FoxM1 deficiency. Conclusions: Basal low-level proliferation of β-cells during adulthood is important for maintaining sufficient β-cell mass and good glucose tolerance and β-cell FoxM1 underlies this mechanism. Preserving β-cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.