Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring
Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring
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DOI：
10.1172/jci74237
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发表时间：
2014-10-01
影响因子：
15.9
通讯作者：
Bernal-Mizrachi, Ernesto
中科院分区：
文献类型：
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作者：
Alejandro, Emilyn U.;Gregg, Brigid;Bernal-Mizrachi, Ernesto
低蛋白质的母亲饮食通过诱导p细胞质量和功能的长期改变，增加了后代患2型糖尿病的易感性。营养物质和生长因子信号通过mTOR汇聚，表明该途径参与胎儿发育过程中的p细胞编程。在本研究中，我们发现在整个妊娠期间暴露于低蛋白饮食（LP0.5）的新生儿表现出胰岛素水平降低、β细胞分数降低和mTOR信号传导减少。暴露于lp0.5的母亲的成年后代由于胰岛素分泌缺陷而不是β细胞质量减少而表现出葡萄糖耐受不良。β细胞胰岛素分泌缺陷远超葡萄糖依赖性Ca2+内流，由胰岛素原生物合成和胰岛素含量减少引起。lp0.5喂养的母鼠后代的胰岛表现出mTOR减少和一组microrna表达增加，阻断这些胰岛中的microRNA-199a-3p和-342可恢复mTOR和胰岛素分泌正常。最后，在妊娠最后一周，喂食LP0.5的母鼠的后代中mTORC1信号的短暂β细胞激活挽救了新生儿β细胞部分的缺陷和成年鼠的代谢异常。总之，这些发现表明，母亲的低蛋白饮食改变了后代的microRNA和mTOR表达，影响了胰岛素分泌和葡萄糖稳态。
A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in p cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in p cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower beta cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not beta cell mass reduction. The beta cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient beta cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal beta cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis.