title: Postnatal β-cell proliferation and mass expansion is dependent on the transcription factor Nkx6.1.
abstract: All forms of diabetes are characterized by a loss of functional β-cell mass, and strategies for expanding β-cell mass could have significant therapeutic benefit. We have recently identified the transcription factor Nkx6.1 as an essential maintenance factor of the functional β-cell state. In addition, Nkx6.1 has been proposed to control β-cell proliferation, but a role for Nkx6.1 in regulating β-cell mass has not been demonstrated. Here, we show that Nkx6.1 is required for postnatal β-cell mass expansion. Genetic inactivation of Nkx6.1 in newly formed β-cells caused a drastic decrease in early postnatal β-cell proliferation, leading to reduced β-cell mass and glucose intolerance. Interestingly, Nkx6.1 was dispensable for prenatal β-cell proliferation. We found that Nkx6.1 regulates the expression of several β-cell maturation markers as well as expression of the nutrient sensors Glut2 and Glp1r. Manifestation of the β-cell mass defect at the transition to postnatal feeding suggests that Nkx6.1 could regulate β-cell growth by enabling β-cells to respond to nutrient-dependent proliferation signals, such as glucose and Glp1. Identification of β-cell-intrinsic regulators that connect nutrient-sensing and proliferation suggests new therapeutic targets for expanding functional β-cell mass.
authors.affiliation: Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Taylor
authors.affiliation: Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Benthuysen
authors.affiliation: Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA masander@ucsd.edu.
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D018398:Homeodomain Proteins; C491328:Nkx6-1 protein, mouse