title: Generation of functional insulin-producing cells in the gut by Foxo1 ablation.
abstract: Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells that express markers of mature β cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins(+) cells. Following ablation by the β-cell toxin streptozotocin, gut Ins(+) cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3(+) enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins(+) cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York, USA.
authors.forename: Chutima
authors.initials: C
authors.lastname: Talchai
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002096:C-Peptide / Q000096:biosynthesis / Q000378:metabolism; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000628:therapy; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D055099:Neuroendocrine Cells / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D013311:Streptozocin / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D060449:Wnt Signaling Pathway
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002096:C-Peptide; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose; D007328:Insulin; D009419:Nerve Tissue Proteins; D013311:Streptozocin; D013453:Sulfonylurea Compounds; C467200:Foxo1 protein, mouse; C407737:Neurog3 protein, mouse