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

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 Pdx1-Cre;Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 in the pancreas. Results We confirm an impaired glucose-stimulated insulin secretion in islets from Pdx1-Cre;Sirt1ex4F/F mice. We reveal that this defect was associated with reduced expression of the glucose transporter Slc2A2/Glut2 and of Glucagon like peptide-1 receptor (Glp1r). In addition, we find marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, Sirt1 deficient mice do not develop hyperglycaemia and have reduced fasting blood glucose levels. Besides the beta-cell defect, the expression of pancreatic polypeptide (PP) is significantly reduced due to a lower number of PP cells. 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. Moreover, we uncover a context in which impaired beta-cell function is accompanied by lower glycaemia. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.

Type Journal
Authors Pinho, A.V.; Bensellam, M.; Wauters, E.; Rees, M.; Giry-LaterriA"re, M.; Mawson, A.; Ly, L.Q.; Biankin, A.V.; Wu, J.; Laybutt, D.R.; Rooman, I.
Garvan Authors Dr Andreia Pinho , Dr Jianmin Wu , A/Prof Ross Laybutt
Publisher Name PLoS ONE
Published Date 2015-06-05 00:00:00
Published Volume 10
Published Pages e0128012
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12475_12981/journal.pone.0128012.pdf