Aims/hypothesis

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes.

Methods

We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function.

Results

Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions.

Conclusions/interpretation

Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes.

Graphical Abstract

中文翻译：

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新加坡 2 型糖尿病患者的多祖先个体的代谢组学分析确定了与肾功能下降相关的代谢物

 目标/假设

本研究旨在探讨 2 型糖尿病患者血浆代谢物与慢性肾病进展之间的关联。

 方法

我们在一项对新加坡 5144 名多祖先 2 型糖尿病患者的前瞻性队列研究中进行了全面的代谢组学分析，使用 eGFR 斜率作为肾功能下降的主要结局。此外，我们对代谢物进行了全基因组关联研究，以评估这些代谢物如何受到代谢物数量性状位点的遗传影响，并进行了共定位分析以鉴定影响代谢物和肾功能的基因。

 结果

61 种具有长不饱和脂肪酸链的脂质（如磷脂酰乙醇胺、三酰基甘油、甘油二酯、神经酰胺和脱氧鞘脂）水平升高与肾功能更快下降前瞻性相关。此外，血浆中 7 个氨基酸和 3 种脂质水平升高与 eGFR 下降缓慢有关。我们还确定了 15 个与这些代谢物相关的代谢物数量性状位点，其中 TM6SF2 、 APOE 和 CPS1 附近的变异会影响代谢物水平和肾功能。

结论/解释

我们的研究确定了与预期肾功能下降相关的血浆代谢物，为脂肪酸供应过剩引起的代谢物异常可能反映β氧化受损并与糖尿病患者未来慢性肾病进展相关的潜在机制提供了见解。

 图形摘要