title: TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.
abstract: Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor-deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.
authors.affiliation: Division of Pediatric Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. gittesgk@upmc.edu
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.forename: John
authors.initials: J
authors.lastname: Wiersch
authors.forename: Yousef
authors.initials: Y
authors.lastname: El-Gohary
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasadan
authors.forename: Jose
authors.initials: J
authors.lastname: Paredes
authors.forename: Carey
authors.initials: C
authors.lastname: Welsh
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.forename: George K
authors.initials: GK
authors.lastname: Gittes
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010180:Pancreatectomy / Q000379:methods; D012194:RNA-Directed DNA Polymerase; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D012194:RNA-Directed DNA Polymerase; D005947:Glucose