Activation of FoxM1 revitalizes the replicative potential of aged β -cells in male mice and enhances insulin secretion.
AUTHORS
- PMID: 26251404[PubMed].
ABSTRACT
Type 2 diabetes incidence increases with age, while β-cell replication declines. The transcription factor FoxM1 is required for β-cell replication in various situations, and its expression declines with age. We hypothesized that increased FoxM1 activity in aged β-cells would rejuvenate proliferation. Induction of an activated form of FoxM1 was sufficient to increase β-cell mass and proliferation in twelve-month-old male mice after just two weeks. Unexpectedly, at two months of age, induction of activated FoxM1 in male mice improved glucose homeostasis with unchanged β-cell mass; cells expressing activated FoxM1 demonstrated enhanced glucose- stimulated Ca(2+) influx, which resulted in improved glucose tolerance through enhanced β-cell function. Conversely, our lab has previously demonstrated that mice lacking FoxM1 in the pancreas display glucose intolerance or diabetes with only a 60% reduction in β-cell mass, suggesting that the loss of FoxM1 is detrimental to β-cell function. Ex vivo insulin secretion was therefore examined in size-matched islets from young mice lacking FoxM1 in β-cells. Foxm1- deficient islets indeed displayed reduced insulin secretion. Our studies reveal that activated FoxM1 increases β-cell replication while simultaneously enhancing insulin secretion and improving glucose homeostasis, making FoxM1 an attractive therapeutic target for diabetes.
Type 2 diabetes incidence increases with age, while β-cell replication declines. The transcription factor FoxM1 is required for β-cell replication in various situations, and its expression declines with age. We hypothesized that increased FoxM1 activity in aged β-cells would rejuvenate proliferation. Induction of an activated form of FoxM1 was sufficient to increase β-cell mass and proliferation in twelve-month-old male mice after just two weeks. Unexpectedly, at two months of age, induction of activated FoxM1 in male mice improved glucose homeostasis with unchanged β-cell mass; cells expressing activated FoxM1 demonstrated enhanced glucose- stimulated Ca(2+) influx, which resulted in improved glucose tolerance through enhanced β-cell function. Conversely, our lab has previously demonstrated that mice lacking FoxM1 in the pancreas display glucose intolerance or diabetes with only a 60% reduction in β-cell mass, suggesting that the loss of FoxM1 is detrimental to β-cell function. Ex vivo insulin secretion was therefore examined in size-matched islets from young mice lacking FoxM1 in β-cells. Foxm1- deficient islets indeed displayed reduced insulin secretion. Our studies reveal that activated FoxM1 increases β-cell replication while simultaneously enhancing insulin secretion and improving glucose homeostasis, making FoxM1 an attractive therapeutic target for diabetes.