title: Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult β-Cell Mass and Function.
abstract: β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded β-cell mass. In contrast, ablation of Foxo1 in terminally differentiated β-cells did not increase β-cell mass nor did it affect Neurogenin3 expression. Despite the increased β-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult β-cell mass and function. Our results illustrate how developmental programming predisposes to β-cell dysfunction in adults and raise questions on the desirability of increasing β-cell mass for therapeutic purposes in type 2 diabetes.
authors.affiliation: Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY Faculty of Science, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
authors.forename: Shivatra Chutima
authors.initials: SC
authors.lastname: Talchai
authors.affiliation: Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY da230@columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D048429:Cell Size; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin