title: R-spondin1 deficiency enhances β-Cell neogenesis in a murine model of diabetes.
abstract: OBJECTIVE
  The cWnt activator, R-spondin1 (Rspo1), regulates β-cell growth, function, and neogenesis, although its role in conditions such as streptozotocin (STZ)-induced diabetes is unknown. We hypothesized that Rspo1 deficiency enhances β-cell neogenesis in STZ-induced diabetes.
  
  
  METHODS
  Wild-type (Rspo1) and knockout (Rspo1) mice were injected with STZ (40 mg/kg) for 5 days, followed by analysis of oral glucose and insulin tolerance, and were killed on day 6 (acute; 9-11 mice) or 32 (chronic; 11-16 mice). Immunohistochemistry was performed for β-cell apoptosis, proliferation, neogenesis, and markers of β-cell maturity.
  
  
  RESULTS
  There was no difference in oral glucose handling between STZ-induced Rspo1 and Rspo1 mice, although Rspo1 mice demonstrated increased insulin sensitivity. β-cell mass, islet number, and islet size distribution did not differ between STZ-induced Rspo1 and Rspo1 mice, but Rspo1 animals had reduced β-cell apoptosis and increased numbers of insulin-positive ductal cells, indicating β-cell neogenesis. Furthermore, the increased β-cell regeneration observed in the Rspo1 animals was associated with a more differentiated/mature β-cell phenotype as assessed by increased immunopositivity for Nkx6.1, MafA, and GLUT2.
  
  
  CONCLUSIONS
  These findings indicate that Rspo1 is a negative regulator of β-cell neogenesis, development, and survival in the face of STZ-induced diabetes, providing a therapeutic target for the enhancement of β-cell mass.
authors.affiliation: From the *Department of Physiology, University of Toronto, Toronto, Ontario, Canada; †Centre for Neuroscience, UC Davis, Davis, CA; ‡iBV, INSERM U1091, CNRS UMR7277, University of Nice Sophia-Antipolis, UFR Sciences, F-06108 Nice, France; and §Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jasleen K
authors.initials: JK
authors.lastname: Chahal
authors.forename: Victor S C
authors.initials: VS
authors.lastname: Wong
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Chaboissier
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019699:Thrombospondins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; C561967:Ins2 protein, mouse; D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; C491328:Nkx6-1 protein, mouse; C518903:RSPO1 protein, mouse; C495682:Slc2a2 protein, mouse; D019699:Thrombospondins