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



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.



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.



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.
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK. g.dasilva-xavier@imperial.ac.uk.
Gabriela
G
da Silva Xavier
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Angeles
A
Mondragon
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Vishnou
V
Mourougavelou
Université Paris Diderot Paris 7 - CNRS UMR 8251, Paris, France.
Céline
C
Cruciani-Guglielmacci
Université Paris Diderot Paris 7 - CNRS UMR 8251, Paris, France.
Jessica
J
Denom
Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Pedro Luis
PL
Herrera
Université Paris Diderot Paris 7 - CNRS UMR 8251, Paris, France.
Christophe
C
Magnan
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Guy A
GA
Rutter
D000818:Animals; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052336:Proglucagon / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*
C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D052336:Proglucagon; D005934:Glucagon; D005947:Glucose
Alpha cell; Diabetes; GWAS; Gene; Glucagon; Islet