Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction.
Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction.
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鞘磷脂代谢减弱是未来2型糖尿病发病机制的一个标志，与胰腺β细胞功能障碍有关。
DOI：
10.1016/j.isci.2020.101566
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发表时间：
2020-10-23
期刊：
影响因子：
5.8
通讯作者：
Wheeler MB
中科院分区：
文献类型：
--
作者：
Khan SR;Manialawy Y;Obersterescu A;Cox BJ;Gunderson EP;Wheeler MB
妊娠糖尿病（GDM）是未来2型糖尿病（T2 D）发展的首要危险因素。种族深刻影响谁将从GDM过渡到T2 D，在西班牙裔妇女中观察到高风险。为了更好地了解这种风险，采用嵌套1：1配对、西班牙裔特异性病例对照设计，对有GDM病史的前瞻性队列进行研究。监测产后6-9周（基线）非糖尿病妇女的T2 D发展。对基线血浆进行代谢组学分析，以确定与T2 D风险相关的代谢途径。值得注意的是，鞘脂代谢减少与未来的T2 D高度相关。通过整合代谢组学和全基因组关联数据，发现了两个显著富集的T2 D连锁基因CERS 2和CERS 4，进一步暗示了鞘脂代谢的缺陷。在小鼠和细胞中的后续实验表明，抑制鞘脂代谢会损害胰腺β细胞功能。这些数据表明，产后早期鞘脂生物合成的改变有助于β细胞功能障碍和T2 D风险。鞘脂代谢降低与GDM向T2 D的转变相关合并代谢组学和GWAS数据识别出与T2 D相关的鞘脂代谢基因抑制鞘脂代谢损害胰腺β细胞功能使用OGTT测量鞘脂SM C16：10可改善T2 D预测病理生理学;人类生理学;基因组学;生物信息学;系统生物学
Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6–9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics were performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic β cell function. These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to β cell dysfunction and T2D risk. Diminished sphingolipid metabolism is associated with a transition from GDM to T2D Merging metabolomics and GWAS data identifies sphingolipid metabolism genes associated with T2D Inhibiting sphingolipid metabolism impairs pancreatic β cell function Incorporating sphingolipid SM C16:10 measurements with an OGTT improves T2D prediction Pathophysiology; Human Physiology; Genomics; Bioinformatics; Systems Biology
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影响因子：
120.7
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通讯作者：
Wheeler MB