title: Nupr1 deletion protects against glucose intolerance by increasing beta cell mass.
abstract: OBJECTIVE
  The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1(-/-) mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD).
  
  
  METHODS
  Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity.
  
  
  RESULTS
  Nupr1(-/-) mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1(-/-) mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance.
  
  
  CONCLUSIONS
  Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes.
authors.affiliation: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, King's College London, 2.9N Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Barbosa-Sampaio
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Drynda
authors.forename: Ana M
authors.initials: AM
authors.lastname: Rodriguez de Ledesma
authors.forename: Aileen J
authors.initials: AJ
authors.lastname: King
authors.forename: James E
authors.initials: JE
authors.lastname: Bowe
authors.forename: Cédric
authors.initials: C
authors.lastname: Malicet
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.forename: Shanta J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: Dany S
authors.initials: DS
authors.lastname: Muller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse
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