TCF7L2 splice variants have distinct effects on β-cell turnover and function
TCF7L2 splice variants have distinct effects on β-cell turnover and function
复制标题
DOI：
10.1093/hmg/ddr072
复制
发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Maedler, Kathrin
中科院分区：
文献类型：
--
作者：
Le Bacquer, Olivier;Shu, Luan;Maedler, Kathrin
2型糖尿病表现为β细胞不能分泌足够量的胰岛素来维持正常血糖，并发生细胞凋亡。疾病的进展是环境因素和遗传易感性相互作用的结果。t细胞因子7-样2 （TCF7L2）多态性与2型糖尿病（T2DM）密切相关。糖尿病患者胰岛TCF7L2 mRNA表达上调，而TCF7L2蛋白水平下调。TCF7L2的缺失导致功能受损和细胞凋亡。通过对人类离体胰岛细胞的分析，我们对这种相反的调控以及TCF7L2对β细胞功能和存活的机制提供了三种解释。(i)我们在人β细胞中发现了TCF7L2转录本，它对β细胞存活、功能和Wnt信号激活有相反的影响。TCF7L2克隆B1缺乏外显子13,14,15和16，诱导β细胞凋亡，功能受损，抑制胰高血糖素样肽1反应和Wnt信号的下游靶点，克隆B3和B7都含有外显子13，改善β细胞存活和功能，激活Wnt信号。（ii） TCF7L2 mRNA非常不稳定，在糖尿病前期会迅速降解；（iii）胰岛中TCF7L2的消耗会诱导糖原合成酶激酶3- β的激活，但这与内质网应激无关。我们证明了TCF7L2的功能特异性转录本，它对β细胞具有不同的生理和病理生理作用。有害的TCF7L2剪接变体的存在可能是T2DM中β细胞衰竭的一种机制。
Type 2 diabetes manifests when the beta-cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis. The disease progression results from an interplay of environmental factors and genetic predisposition. Polymorphisms in T-cell factor 7-like 2 (TCF7L2) strongly correlate with type 2 diabetes mellitus (T2DM). While TCF7L2 mRNA is upregulated in islets in diabetes, protein levels are down-regulated. The loss of TCF7L2 induces impaired function and apoptosis. By analyzing human isolated islets, we provide three explanations for this opposite regulation and the mechanisms of TCF7L2 on beta-cell function and survival. (i) We found TCF7L2 transcripts in the human beta-cell, which had opposite effects on beta-cell survival, function and Wnt signaling activation. While TCF7L2 clone B1, which lacks exons 13, 14, 15 and 16 induced beta-cell apoptosis, impaired function and inhibited glucagon-like peptide 1 response and downstream targets of Wnt signaling, clones B3 and B7 which both contain exon 13, improved beta-cell survival and function and activated Wnt signaling. (ii) TCF7L2 mRNA is extremely unstable and is rapidly degraded under pro-diabetic conditions and (iii) TCF7L2 depletion in islets induced activation of glycogen synthase kinase 3-beta, but this was independent of endoplasmic reticulum stress. We demonstrated function-specific transcripts of TCF7L2, which possessed distinct physiological and pathophysiological effects on the beta-cell. The presence of deleterious TCF7L2 splice variants may be a mechanism of beta-cell failure in T2DM.