title: Activation of FoxM1 Revitalizes the Replicative Potential of Aged β-Cells in Male Mice and Enhances Insulin Secretion.
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 12-month-old male mice after just 2 weeks. Unexpectedly, at 2 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 Ca2+ influx, which resulted in improved glucose tolerance through enhanced β-cell function. Conversely, our laboratory 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.
authors.affiliation: VA Tennessee Valley Healthcare System, Nashville, TN Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Golson
authors.affiliation: VA Tennessee Valley Healthcare System, Nashville, TN Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dunn
authors.affiliation: VA Tennessee Valley Healthcare System, Nashville, TN Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Maulis
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Dadi
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN Vanderbilt Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Osipovich
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN Vanderbilt Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.affiliation: VA Tennessee Valley Healthcare System, Nashville, TN Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN maureen.gannon@vanderbilt.edu.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D007328:Insulin