Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia

Andreia V. Pinho, Mohammed Bensellam, Elke Wauters, Maxine Rees, Marc Giry-Laterriere, Amanda Mawson, Le Quan Ly, Andrew V. Biankin, Jianmin Wu, D. Ross Laybutt, Ilse Rooman

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Article numbere0128012
Pages1-13
Number of pages13
JournalPLoS ONE
Volume10
Issue number6
DOIs
Publication statusPublished - 5 Jun 2015
Externally publishedYes

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Sirtuin 1
islets of Langerhans
hyperglycemia
pancreas
Hyperglycemia
Pancreas
blood glucose
mice
unfolded protein response
Islets of Langerhans
glucose
Insulin
insulin secretion
Blood Glucose
Unfolded Protein Response
Pancreatic Polypeptide
Glucose
cells
insulin
pancreatic polypeptide

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Pinho, A. V., Bensellam, M., Wauters, E., Rees, M., Giry-Laterriere, M., Mawson, A., ... Rooman, I. (2015). Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia. PLoS ONE, 10(6), 1-13. [e0128012]. https://doi.org/10.1371/journal.pone.0128012
Pinho, Andreia V. ; Bensellam, Mohammed ; Wauters, Elke ; Rees, Maxine ; Giry-Laterriere, Marc ; Mawson, Amanda ; Ly, Le Quan ; Biankin, Andrew V. ; Wu, Jianmin ; Laybutt, D. Ross ; Rooman, Ilse. / Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia. In: PLoS ONE. 2015 ; Vol. 10, No. 6. pp. 1-13.
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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.",
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Pinho, AV, Bensellam, M, Wauters, E, Rees, M, Giry-Laterriere, M, Mawson, A, Ly, LQ, Biankin, AV, Wu, J, Laybutt, DR & Rooman, I 2015, 'Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia', PLoS ONE, vol. 10, no. 6, e0128012, pp. 1-13. https://doi.org/10.1371/journal.pone.0128012

Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia. / Pinho, Andreia V.; Bensellam, Mohammed; Wauters, Elke; Rees, Maxine; Giry-Laterriere, Marc; Mawson, Amanda; Ly, Le Quan; Biankin, Andrew V.; Wu, Jianmin; Laybutt, D. Ross; Rooman, Ilse.

In: PLoS ONE, Vol. 10, No. 6, e0128012, 05.06.2015, p. 1-13.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia

AU - Pinho, Andreia V.

AU - Bensellam, Mohammed

AU - Wauters, Elke

AU - Rees, Maxine

AU - Giry-Laterriere, Marc

AU - Mawson, Amanda

AU - Ly, Le Quan

AU - Biankin, Andrew V.

AU - Wu, Jianmin

AU - Laybutt, D. Ross

AU - Rooman, Ilse

N1 - Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2015/6/5

Y1 - 2015/6/5

N2 - 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.

AB - 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.

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