da Silva Xavier Gabriela, Mondragon Angeles, Mourougavelou Vishnou, Cruciani-Guglielmacci Céline, Denom Jessica, Herrera Pedro Luis, Magnan Christophe, Rutter Guy A
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Université Paris Diderot Paris 7 - CNRS UMR 8251, Paris, France.
Diabetologia. 2017 Jun;60(6):1043-1050. doi: 10.1007/s00125-017-4242-2. Epub 2017 Mar 25.
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.
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.
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.
目的/假设：转录因子7样2（TCF7L2）是一种含高迁移率族（HMG）盒的转录因子，也是Wnt信号通路的下游效应分子。在全基因组关联研究中，TCF7L2基因中的单核苷酸多态性（SNP）先前已被证明与2型糖尿病风险增加有关。在动物研究中，Tcf7l2功能丧失与胰岛β细胞功能和存活缺陷有关。在此，我们通过构建在胰腺α细胞中选择性缺失Tcf7l2基因的小鼠，来探究TCF7L2在低血糖反调节反应控制中的作用。
通过将携带floxed Tcf7l2等位基因的小鼠与携带由胰高血糖素原启动子驱动的Cre重组酶转基因（PPGCre）的小鼠杂交，实现Tcf7l2在α细胞中的选择性缺失，从而获得Tcf7l2AKO小鼠。使用标准技术测量体内和体外的葡萄糖稳态、激素分泌以及胰岛细胞质量。
虽然Tcf7l2AKO小鼠的葡萄糖耐量未受影响，但葡萄糖输注速率增加（在高胰岛素-低血糖钳夹试验的前60分钟期间，Tcf7l2AKO小鼠的葡萄糖曲线下面积比野生型小鼠增加了1.98±0.26倍[p<0.05；n = 6]），胰高血糖素分泌也趋于降低（血浆胰高血糖素：相对于野生型同窝对照为0.40±0.03倍[p<0.01；n = 6]）。Tcf7l2AKO小鼠的空腹血糖浓度降低。从Tcf7l2AKO小鼠分离的胰岛在低血糖时的胰高血糖素释放受损（相对于野生型同窝对照小鼠的胰岛为0.37±0.02倍[p<0.01；n = 6]）。与野生型小鼠相比，Tcf7l2AKO小鼠的α细胞质量也减少（72.3±20.3%[p<0.05；n = 7]）。
结论/解读：目前的研究结果表明，Tcf7l2在控制胰腺胰高血糖素分泌以及维持α细胞质量和功能方面具有α细胞自主性作用。
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