Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease

Abstract

IntroductionPathophysiology of diabetic kidney disease (DKD) is incompletely understood. We aim to elucidate metabolic abnormalities associated with DKD in type 2 diabetes mellitus (T2DM) by targeted plasma metabolomics.MethodsA total of 126 T2DM participants with early DKD (urinary albumin-to-creatinine ratio [ACR] 30−299 mg/g and eGFR ≥ 60 ml/min/1.73 m2), 154 overt DKD (ACR ≥ 300 mg/g or eGFR < 60 ml/min/1.73 m2), and 129 non-DKD T2DM controls (ACR < 30 mg/g and eGFR ≥ 60 ml/min/1.73 m2) were included in discovery study. Findings were subsequently validated in 149 T2DM with macroalbuminuria (ACR ≥ 300 mg/g) and 149 matched non-DKD T2DM controls. Plasma amino acid, acylcarnitine, Krebs cycle organic acid, and sphingolipids/ceramide levels were quantified by liquid chromatography−mass spectrometry and gas chromatography−mass spectrometry.ResultsOf 123 metabolites included in the data analysis, 24 differed significantly between DKD and controls in the same direction in both discovery and validation subpopulations. A number of short acylcarnitines including their dicarboxylic derivatives (C2−C6) were elevated in DKD, suggesting abnormalities in fatty acids and amino acids metabolic pathways. Five phosphatidylcholines were lower whereas 4 metabolites in the sphingomyelin−ceramide subfamily were higher in DKD. Principal component regression revealed that long-chain ceramides were independently associated with ACR but not eGFR. Conversely, essential amino acids catabolism and short dicarboxylacylcarnitine accumulation were associated with eGFR but not ACR.DiscussionDKD is associated with altered fuel substrate use and remodeling of sphingolipid metabolism in T2DM with DKD. Associations of albuminuria and impaired filtration function with distinct metabolomic signatures suggest different pathophysiology underlying these 2 manifestations of DKD.

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population

“…This would lead to accumulation of fatty acid fuels in the mitochondria and contribute to insulin resistance via the mismatching of fuel and ATP demand. 45 While we did not observe significant associations between medium-chain species and diabetes risk following multiple testing correction, it has been suggested that the accumulation of medium-chain species results in activation of the proinflammatory NFκB pathway, which in turn promotes insulin resistance. 44 The accumulation of long-chain species, such as C16-OH, is similarly thought to be reflective of impaired tricarboxylic acid cycle activity, as they are the initial products of βoxidation.…”

The role of mass spectrometry in studies of glycation processes and diabetes management

“…Liu et al . () performed a targeted plasma metabolomic study, whose findings were somehow in agreement with the findings by Niewczas et al . () that amino acids or their derivatives are associated with the risk of progression to ESRD.…”

“…The amino acid derivative most positively associated with progression to ESRD was C-glycosyltryptophan, odd ratio of 6.6 (95% CI: 2.8, 15). Liu et al (2017) performed a targeted plasma metabolomic study, whose findings were somehow in agreement with the findings by Niewczas et al (2014) that amino acids or their derivatives are associated with the risk of progression to ESRD. Metabolic pathways related to DKD in an Asian T2DM population were studied by analyzing 123 plasma metabolites using LC-MS and GC-MS.…”

Machine Learning Approaches Reveal Metabolic Signatures of Incident Chronic Kidney Disease in Individuals With Prediabetes and Type 2 Diabetes

“…2A). Increased SM levels in relation with CKD were also reported in individuals with Type 1 Diabetes (T1D) (33) and T2D (34), except for the non-targeted lipidomic study of T1D (35). Isomer annotation of the top significant metabolite SM C18:1 in our study revealed that it may consist of several sphingoid backbones (d16:1, d18:0, d18:1, d18:2, d19:1) bound to mainly saturated or monounsaturated fatty acyls with 16-18 carbons (36).…”