Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice.
Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice.
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DOI：
10.1007/s00125-017-4242-2
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发表时间：
2017-06
期刊：
影响因子：
8.2
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
da Silva Xavier G;Mondragon A;Mourougavelou V;Cruciani-Guglielmacci C;Denom J;Herrera PL;Magnan C;Rutter GA
转录因子7-like 2 （Transcription factor 7-like 2, TCF7L2）是一种含有高迁移率基团（HMG）盒的转录因子，是Wnt信号通路的下游效应因子。在之前的全基因组关联研究中，TCF7L2基因的snp与2型糖尿病风险增加有关。在动物研究中，Tcf7l2功能的丧失与胰岛β细胞功能和存活缺陷有关。在这里，我们通过在胰腺α细胞中产生选择性缺失TCF7L2基因的小鼠，探索TCF7L2在控制低血糖的反调节反应中的作用。通过将携带Tcf7l2固定等位基因的小鼠与携带由胰高血糖素前原启动子（PPGCre）驱动的Cre重组酶转基因小鼠杂交，实现了Tcf7l2的α细胞选择性缺失，从而产生Tcf7l2AKO小鼠。采用标准技术测定体内、体外葡萄糖稳态、激素分泌及胰岛细胞质量。Tcf7l2AKO小鼠葡萄糖耐量不受影响，但葡萄糖输注率升高（与野生型小鼠相比，Tcf7l2AKO小鼠高胰岛素-低血糖钳夹试验前60 min葡萄糖AUC升高1.98±0.26倍[p < 0.05; n = 6]），胰高血糖素分泌有降低的趋势（与野生型小鼠相比，血浆胰高血糖素升高0.40±0.03倍[p < 0.01; n = 6]）。Tcf7l2AKO小鼠显示空腹血糖浓度降低。Tcf7l2AKO小鼠胰岛低糖时胰高血糖素释放受损（0.37±0.02倍）（p < 0.01; n = 6）。与野生型小鼠相比，Tcf7l2AKO小鼠α细胞质量减少（72.3±20.3%）[p < 0.05; n = 7]。目前的研究结果表明，Tcf7l2在控制胰高血糖素分泌和维持α细胞质量和功能方面具有α细胞自主作用。
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.