title: Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice.
abstract: The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated β cell dysfunction and loss of proliferation capacity, two features of β cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in β cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in β cells prevented β cell dysfunction and loss in this model. Thus, we present a model of accelerated β cell aging that may be useful for studying the mechanisms underlying β cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining β cell identity in the context of SMAD7 failure.
authors.affiliation: Divisions of Pediatric Surgery. Electronic address: xiangwei.xiao@chp.edu.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Divisions of Pediatric Surgery; Department of Pediatric Surgery, Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325000, China.
authors.forename: Congde
authors.initials: C
authors.lastname: Chen
authors.affiliation: Divisions of Pediatric Surgery; Department of Orthopedic Surgery, University of Texas Health Sciences Center, Houston, Texas 77054.
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.affiliation: Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Divisions of Pediatric Surgery.
authors.forename: Shane
authors.initials: S
authors.lastname: Fischbach
authors.affiliation: Divisions of Pediatric Surgery.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fusco
authors.affiliation: Divisions of Pediatric Surgery.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.affiliation: Divisions of Pediatric Surgery.
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasadan
authors.affiliation: Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Henry
authors.initials: H
authors.lastname: Dong
authors.affiliation: Divisions of Pediatric Surgery. Electronic address: gittesgk@upmc.edu.
authors.forename: George K
authors.initials: GK
authors.lastname: Gittes
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse
keywords: Aging; FoxO1; SMAD7; TGFβ; cell proliferation; diabetes; type 2 diabetes; β cell