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Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses in mice

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Title: Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses in mice
Authors: Da Silva Xavier, G
Mondragon, A
Mourougavelou, V
Cruciani-Guglielmacci, C
Denom, J
Herrera, PL
Magnan, C
Rutter, GA
Item Type: Journal Article
Abstract: Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the Tcf7l2 gene in pancreatic alpha cells. Methods Alpha cell-selective deletion of Tcf7l2 was achieved by crossing mice with floxed Tcf7l2 alleles to mice bearing a Cre recombinase transgene driven by the preproglucagon promoter (PPGCre), resulting in Tcf7l2AKO mice. Glucose homeostasis and hormone secretion in vivo and in vitro, and islet cell mass were measured using standard techniques. Results While glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased (AUC for glucose during the first 60 min period of hyperinsulinaemic–hypoglycaemic clamp test was increased by 1.98 ± 0.26-fold [p < 0.05; n = 6] in Tcf7l2AKO mice vs wild-type mice) and glucagon secretion tended to be lower (plasma glucagon: 0.40 ± 0.03-fold vs wild-type littermate controls [p < 0.01; n = 6]). Tcf7l2AKO mice displayed reduced fasted plasma glucose concentration. Glucagon release at low glucose was impaired in islets isolated from Tcf7l2AKO mice (0.37 ± 0.02-fold vs islets from wild-type littermate control mice [p < 0.01; n = 6). Alpha cell mass was also reduced (72.3 ± 20.3% [p < 0.05; n = 7) in Tcf7l2AKO mice compared with wild-type mice. Conclusions/interpretation The present findings demonstrate an alpha cell-autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function.
Issue Date: 25-Mar-2017
Date of Acceptance: 9-Feb-2017
URI: http://hdl.handle.net/10044/1/44491
DOI: https://dx.doi.org/10.1007/s00125-017-4242-2
ISSN: 0012-186X
Publisher: Springer Verlag (Germany)
Start Page: 1043
End Page: 1050
Journal / Book Title: Diabetologia
Volume: 60
Issue: 6
Copyright Statement: © The Author(s) 2017. This article is published with open access at Springerlink.com
Sponsor/Funder: The Royal Society
Medical Research Council (MRC)
Diabetes UK
Diabetes UK
Wellcome Trust
European Foundation for the Study of Diabetes
European Foundation for the Study of Diabetes
Rosetrees Trust
Funder's Grant Number: WM100078
MR/K001981/1
BDA number 13/0004672
13/0004672
098424/Z/12/ZR
n/a
A987
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Alphacell
Diabetes
Gene
Glucagon
GWAS
Islet
GENOME-WIDE ASSOCIATION
GLUCOSE-HOMEOSTASIS
DIABETES-MELLITUS
BETA-CELLS
RISK LOCI
GENE
INSULIN
VARIANTS
MOUSE
ISLETS
Alpha cell
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
1117 Public Health And Health Services
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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