title: Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia: evidence for a circulating α-cell growth factor.
abstract: Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. Gcgr(Hep)(-/-) mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr(-/-) mice. Despite preservation of islet Gcgr signaling, Gcgr(Hep)(-/-) mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr(-/-) or Gcgr(Hep)(-/-) mice. Wild-type islets beneath the renal capsule of Gcgr(-/-) or Gcgr(Hep)(-/-) mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.
authors.affiliation: Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, The University of Toronto, Toronto, Ontario, Canada. al.powers@vanderbilt.edu
authors.forename: Christine
authors.initials: C
authors.lastname: Longuet
authors.forename: Ana M
authors.initials: AM
authors.lastname: Robledo
authors.forename: E Danielle
authors.initials: ED
authors.lastname: Dean
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.forename: Safina
authors.initials: S
authors.lastname: Ali
authors.forename: Ian
authors.initials: I
authors.lastname: McGuinness
authors.forename: Vincent
authors.initials: V
authors.lastname: de Chavez
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Vuguin
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D001786:Blood Glucose; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006965:Hyperplasia; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D036341:Intercellular Signaling Peptides and Proteins; D018027:Receptors, Glucagon; D005934:Glucagon; D005947:Glucose