Untargeted serum metabolomics and tryptophan metabolism profiling in type 2 diabetic patients with diabetic glomerulopathy

Abstract

Diabetic glomerulopathy (DG) remains the prevalent microvascular complication and leading cause of shortened lifespan in type-2 diabetes mellitus (T2DM) despite improvement in hyperglycemia control. Considering the pivotal role of kidney in metabolism, using untargeted metabolomic techniques to globally delineate the serum metabolite profiles will help advance understanding pathogenetic underpinnings of renal biopsy-confirmed DG from the perspective of metabolism specifically. Fourteen pathologically diagnosed DG patients secondary to T2DM and 14 age-and gender-matched healthy controls (HCs) were recruited for study. We employed mass spectrometry-based untargeted metabolomic methods to reveal the metabolite profiles of serum samples collected from all included subjects. We identified a total of 334 and 397 metabolites in positive and negative ion mode respectively. One hundred and eighty-two important differential metabolites whose variable importance in projection (VIP) > 1 and p value <0.05 were selected and annotated to metabolic pathways. KEGG pathway enrichment analysis revealed tryptophan metabolism enriched most significantly. Among the tryptophan derivatives, L-tryptophan (L-Trp) and serotonin were relatively accumulated in DGs compared with HCs, while 5-hydroxyindoleacetic acid (5-HIAA) and indole-3-acetamide were depleted. Correlation analysis showed serotonin and L-Trp are negatively correlated with 24 h urine protein and glycosylated hemoglobin (Ghb). To exclude the interference of preexisting T2DM on DG exacerbation, we selected 5-HIAA and 3-(3-hydroxyphenyl) propionic acid (3-OHPPA) which are not correlated with Ghb and analyzed their correlation relationship with crucial renal indices. We found 3-OHPPA is positively correlated with urine total protein and creatinine ratio (T/Cr) and 24 h urine protein, 5-HIAA is positively correlated with serum creatinine and urea.

Sacubitril/Valsartan contributes to improving the diabetic kidney disease and regulating the gut microbiota in mice

“…Finally, we explored the underlying mechanism of Sac/Val ameliorating renal damage from the aspect of plasma metabolomics. Tryptophan metabolism was more active in DKD and En groups, which further validates previous reports (23,49). Disturbed tryptophan metabolism was related to the decrease in eGFR (49).…”

“…The plasma samples preparation and LC-MS analysis were performed according to the previous description (23). As a metabolomics processing software, Progenesis QI (WatersCorporation, Milford, USA) was used to analyze the LC-MS raw data, by which a data matrix of retention time, mass charge ratio, and peak intensity was reaped.…”

Metabolomic Signature of Diabetic Kidney Disease in Cerebrospinal Fluid and Plasma of Patients with Type 2 Diabetes Using Liquid Chromatography-Mass Spectrometry

“…Tryptophan, an essential amino acid, is metabolized mainly by the indole (<5%) and kynureine (95%) pathway [ 8 ]. Downstream metabolites of tryptophan, such as kynurenic acid and NAD, contribute to the enhanced oxidative stress and inflammation in endothelial cells, leading to the development and progression of DKD [ 10 , 26 ]. In the previous serum metabolomic analyses, tryptophan was regarded as a potential prognostic marker for DKD, and the increased serum levels of tryptophan (or tryptophan/kynurenine ratio) were inversely associated with renal function deterioration in patients with DKD [ 8 , 27 ].…”