Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Vital-IT Group, SIB Swiss Institute for Bioinformatics, 1015 Lausanne, Switzerland.
Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France.
Mol Metab. 2021 Dec;54:101355. doi: 10.1016/j.molmet.2021.101355. Epub 2021 Oct 9.
To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic β-cell deregulations or defects in the function of insulin target tissues.
We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions, as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules.
We identified strong correlation between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for negative and positive correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In the liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the β-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification of PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion.
TAGs emerge as biomarkers of a liver-to-β-cell axis that links hepatic β-oxidation to β-cell functional mass and insulin secretion.
寻找预测 2 型糖尿病的血浆生物标志物，这些标志物还可以提示胰腺β细胞失调或胰岛素靶组织功能缺陷。
我们采用系统生物学方法来描述 C57Bl/6J、DBA/2J 和 BALB/cJ 小鼠在不同营养条件下的血浆脂质组，以及它们的胰岛和肝脏转录组。我们搜索了血浆脂质与组织基因表达模块之间的相关性。
我们发现血浆三酰甘油(TAGs)与胰岛基因模块之间存在强烈相关性，这些模块包含葡萄糖和脂质调节胰岛素分泌以及胰岛素信号通路的关键调节剂，两个最显著的是 Gck 和 Abhd6，分别为负相关和正相关。鞘磷脂与胰岛基因模块之间也存在相关性，部分与与 TAGs 相关的基因模块重叠。在肝脏中，与血浆 TAGs 相关性最强的基因模块富含编码脂肪酸和肉碱转运体以及β-氧化途径的多种酶的 mRNA。在人类中，血浆 TAGs 也与在小鼠中鉴定的胰岛素分泌和胰岛素信号通路的几个相同关键调节剂的表达相关。这种跨物种比较分析进一步导致鉴定出 PITPNC1 是葡萄糖刺激胰岛素分泌的候选调节剂。
TAGs 作为连接肝内β氧化与β细胞功能质量和胰岛素分泌的肝-β细胞轴的生物标志物出现。
