LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans.
LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans.
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DOI：
10.1016/j.cmet.2013.01.009
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发表时间：
2013-02-05
期刊：
影响因子：
29
通讯作者：
Mani A
中科院分区：
文献类型：
--
作者：
Singh R;De Aguiar RB;Naik S;Mani S;Ostadsharif K;Wencker D;Sotoudeh M;Malekzadeh R;Sherwin RS;Mani A
Wnt信号基因的常见遗传变异与代谢综合征和糖尿病有关，其机制尚不清楚。wnt辅助受体LRP6 （LRP6R611C）的一种罕见的非保守突变已被证明是常染色体显性早发性冠状动脉疾病、2型糖尿病和代谢综合征的基础。我们研究了健康非糖尿病LRP6R611C突变携带者骨骼肌和皮肤成纤维细胞中Wnt和胰岛素信号通路之间的相互作用。与非携带LRP6突变的亲属相比，携带LRP6突变的亲属在口服葡萄糖摄入时表现出高胰岛素血症和胰岛素敏感性降低，这与胰岛素受体（IR）和胰岛素信号活性的组织表达显著下降有关。进一步的研究表明，LRP6R611C突变减少了tcf7l2依赖性IR的转录，同时增加了IGFR的稳定性，增强了mTORC1的活性。这些发现表明Wnt/LRP6/TCF7L2轴是葡萄糖代谢的调节因子和胰岛素抵抗的潜在治疗靶点。
Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are not well understood. A rare nonconservative mutation in Wnt-coreceptor LRP6 (LRP6R611C) has shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscles and skin fibroblasts of healthy non-diabetic LRP6R611C mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to the non-carrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor (IR) and insulin signaling activity. Further investigations showed that LRP6R611C mutation diminishes TCF7L2-dependent transcription of IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.
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影响因子：
82.9
作者：
Foti, D;Chiefari, E;Brunetti, A
通讯作者：
Brunetti, A
影响因子：
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作者：
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DOI：
10.1073/pnas.1019443108
发表时间：
2011-02-01
影响因子：
11.1
作者：
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通讯作者：
Mani, Arya
影响因子：
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作者：
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通讯作者：
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