title: Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia.
abstract: OBJECTIVE
  Sirtuin 1 (Sirt1) has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear.
  
  
  METHODS
  This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas.
  
  
  RESULTS
  We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r) as well as a marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP) cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas.
  
  
  CONCLUSIONS
  This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia.
authors.forename: Andreia V
authors.initials: AV
authors.lastname: Pinho
authors.affiliation: St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW, Australia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bensellam
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: Wauters
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia.
authors.forename: Maxine
authors.initials: M
authors.lastname: Rees
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Giry-Laterriere
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mawson
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia.
authors.forename: Le Quan
authors.initials: le Q
authors.lastname: Ly
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia; Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW, Australia.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Randwick NSW, Australia; Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics; D056811:Unfolded Protein Response
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D056564:Sirtuin 1