Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia

PLoS One. 2015 Jun 5;10(6):e0128012. doi: 10.1371/journal.pone.0128012. eCollection 2015.


Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Down-Regulation
  • Endoplasmic Reticulum / metabolism
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucose Transporter Type 2 / genetics
  • Glucose Transporter Type 2 / metabolism
  • Homeodomain Proteins / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Real-Time Polymerase Chain Reaction
  • Sirtuin 1 / deficiency
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Trans-Activators / genetics
  • Unfolded Protein Response


  • Blood Glucose
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Transporter Type 2
  • Homeodomain Proteins
  • Molecular Chaperones
  • Slc2a2 protein, mouse
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Sirtuin 1