WNT/β-catenin increases the production of incretins by entero-endocrine cells
WNT/β-catenin increases the production of incretins by entero-endocrine cells
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DOI：
10.1007/s00125-009-1429-1
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发表时间：
2009-09-01
期刊：
影响因子：
8.2
通讯作者：
Garcia-Jimenez, C.
中科院分区：
文献类型：
--
作者：
Garcia-Martinez, J. M.;Chocarro-Calvo, A.;Garcia-Jimenez, C.
葡萄糖依赖的促胰岛素多肽(GIP)在调节血糖稳态中起着关键作用。当GIP信号在小鼠体内受到干扰时，饮食诱导的肥胖、胰岛素抵抗和2型糖尿病的发生率会降低，这表明GIP在2型糖尿病的发病中发挥了作用。WNT信号与2型糖尿病有关，并诱导合成另一种胰岛素，即胰高血糖素样肽1(GLP-1)。GLP-1类似物改善了2型糖尿病患者的治疗，在这些患者中，GLP-1信号完整，并引起了临床关注。GIP水平在2型糖尿病发作时及以后发生改变，而GIP信号转导受损。因此，从预防的角度来看，GIP不是治疗的候选对象，但可能是一个重要的靶点。假设GIP连接的高分泌改变了WNT信号对2型糖尿病发病的影响，我们试图确定WNT信号是否诱导肠内分泌细胞产生GIP。确定了介导WNT/Li诱导的GIP启动子元件(凝胶迁移率改变分析，缺失突变体共转染，CHIP)。锂或WNT/β-catenin通过GIP启动子近端的保守位置信号增强肠内分泌细胞产生GIP。锂通过T细胞因子-4和组蛋白去乙酰基酶1促进淋巴增强因子-1/β-连环素与GIP启动子结合，减少CHIP。锂和WNT通常是INS诱导剂。这项工作提供了WNT信号、肥胖和糖尿病之间的新联系。
Glucose-dependent insulinotropic peptide (GIP) plays a pivotal role in the regulation of glucose homeostasis. Rates of diet-induced obesity, insulin resistance and type 2 diabetes are decreased when GIP signalling is disturbed in mice, suggesting that GIP plays a role in the onset of type 2 diabetes. WNT signalling is linked to type 2 diabetes and induces synthesis of the other incretin, glucagon-like peptide 1 (GLP-1). GLP-1 analogues improve treatment of type 2 diabetes patients in whom GLP-1 signalling is intact and have captured clinical attention. GIP levels are altered at the onset of type 2 diabetes and later on, while GIP signalling is impaired. Thus, GIP is not a candidate for treatment but might be an important target from a prevention perspective. Hypothesising that hypersecretion of GIP links altered WNT signalling to the onset of type 2 diabetes, we sought to determine whether WNT signalling induces GIP production by entero-endocrine cells.RT-PCR and chromatin immunoprecipitation (ChIP) were used to study Gip gene induction. Gip promoter elements mediating WNT/lithium induction were identified (electrophoretic mobility shift assay, co-transfection of deletion mutants, ChIP).Lithium or WNT/beta-catenin signalling enhanced GIP production by entero-endocrine cells through a conserved site in the proximal Gip promoter. Lithium favours lymphoid enhancer factor-1/beta-catenin binding to Gip promoter and diminishes ChIP through T cell factor-4 and histone deacetylase 1.Lithium and WNT are incretin inducers in general. This work provides a novel link between WNT signalling, obesity and diabetes.