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

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

Author information

1
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.
2
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.
3
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
4
Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst NSW, Australia.
5
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.
6
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.

Abstract

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.

PMID:
26046931
PMCID:
PMC4457418
DOI:
10.1371/journal.pone.0128012
[Indexed for MEDLINE]
Free PMC Article

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