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

Tijdschriftbijdrage - Tijdschriftartikel

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.

Tijdschrift: PLOS ONE
ISSN: 1932-6203
Issue: 6
Volume: 10
Pagina's: e0128012
Jaar van publicatie:2015
Trefwoorden:Animals, Blood Glucose, Down-Regulation, Endoplasmic Reticulum, Glucagon-Like Peptide-1 Receptor, Glucose Transporter Type 2, Homeodomain Proteins, Hyperglycemia, Insulin-Secreting Cells, Islets of Langerhans, Mice, Mice, Knockout, Microscopy, Fluorescence, Molecular Chaperones, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Sirtuin 1, Trans-Activators, Unfolded Protein Response
CSS-citation score:1