Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and Is Overexpressed in Type 2 Diabetes
Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and Is Overexpressed in Type 2 Diabetes
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分泌型Frizzled相关蛋白4可减少胰岛素分泌并在2型糖尿病患者中过度表达
DOI：
10.1016/j.cmet.2012.10.009
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发表时间：
2012-11-07
期刊：
影响因子：
29
通讯作者：
Rosengren, Anders H.
中科院分区：
文献类型：
--
作者：
Mahdi, Taman;Hanzelmann, Sonja;Rosengren, Anders H.
已经鉴定出复杂多基因疾病的大量候选基因，但潜在的疾病机制在很大程度上仍然未知。我们通过分析人类胰岛中的整体基因表达来探索2型糖尿病（T2 D）的病理生理学。一组富含白细胞介素-1相关基因的共表达基因（模块）与2型糖尿病和胰岛素分泌减少相关。在来自T2 D患者的胰岛中高度过表达的模块基因之一是SFRP 4，其编码分泌型卷曲相关蛋白4。SFRP 4的表达与炎症标志物相关，并且其从胰岛的释放受到白细胞介素-1 β的刺激。升高的系统性SFRP 4通过降低胰岛Ca 2+通道表达和抑制胰岛素胞吐作用引起葡萄糖耐量降低。因此，SFRP 4提供了胰岛炎症和胰岛素分泌受损之间的联系。此外，该蛋白在诊断前几年在T2 D患者的血清中增加，表明SFRP 4可能是T2 D中胰岛功能障碍的潜在生物标志物。
A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly over-expressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1 beta. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca2+ channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.