title: Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.
abstract: Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Chutima
authors.initials: C
authors.lastname: Talchai
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.forename: Hua V
authors.initials: HV
authors.lastname: Lin
authors.forename: Lori
authors.initials: L
authors.lastname: Sussel
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D010179:Pancreas / Q000473:pathology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin