Impaired Amino Acid Metabolism and Its Correlation with Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Abstract

Background: Metabolomics is useful in elucidating the progression of diabetes; however, the follow-up changes in metabolomics among health, diabetes mellitus, and diabetic kidney disease (DKD) have not been reported. This study was aimed to reveal metabolomic signatures in diabetes development and progression. Methods: In this cross-sectional study, we compared healthy (n = 30), type 2 diabetes mellitus (T2DM) (n = 30), and DKD (n = 30) subjects with the goal of identifying gradual altering metabolites. Then, a prospective study was performed in T2DM patients to evaluate these altered metabolites in the onset of DKD. Logistic regression was conducted to predict rapid eGFR decline in T2DM subjects using altered metabolites. The prospective association of metabolites with the risk of developing DKD was examined using logistic regression and restricted cubic spline regression models. Results: In this cross-sectional study, impaired amino acid metabolism was the main metabolic signature in the onset and development of diabetes, which was characterized by increased N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine levels in both the T2DM and DKD groups. These candidate metabolites could distinguish the DKD group from the T2DM group. In the follow-up study, higher baseline levels of L-valine and isoleucine were significantly associated with an increased risk of rapid eGFR decline in T2DM patients. Of these, L-valine and isoleucine were independent risk factors for the development of DKD. Notably, nonlinear associations were also observed for higher baseline levels of L-valine and isoleucine, with an increased risk of DKD among patients with T2DM. Conclusion: Amino acid metabolism was disturbed in diabetes, and N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine could be biomarkers for the onset and progression of diabetes. Furthermore, high levels of L-valine and isoleucine may be risk factors for DKD development.

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

“…The imbalance in plasma concentration or AA proportion in the body can also be used for disease prediction and diagnosis. For example, valine, Cys, N -acetylaspartate, isoleucine, asparagine, betaine, and L-methionine may be the main factors of type 2 diabetes patient progression to DKD, while decreased plasma histidine and valine levels may be used to distinguish DKD patients from type 2 diabetes patients and healthy controls [ 8 , 87 ]. Particularly, it has been clarified that BCAAs and related metabolites are recognized as potential biomarkers of obesity, insulin resistance, type 2 diabetes, and cardiovascular disease in human cohorts [ 88 , 89 ].…”

“…Disruption of AA homeostasis conversely affects kidney-dominated AA metabolism. In response to this disruption, disorder of the relative cellular signaling pathway network directly or indirectly drives development of DKD [ 8 ]. On one hand, disorder of functional AA levels in plasma reflects renal dysfunction in diabetes patients; on the other hand, disturbance in AA metabolic homeostasis causes abnormal accumulation of harmful metabolites or activation of metabolism enzymes, which may trigger cellular signaling in DKD progressions such as oxidative stress, inflammation, fibrosis, and apoptosis.…”

Metabolome panels as potential noninvasive biomarkers for Primary Glomerulonephritis Sub-types: Meta-analysis of Profiling Metabolomics Studies

“…The pathway enrichment analysis results for the dysregulated urinary metabolites in PGDs also revealed the association of the metabolism of the amino acids, including glycine, serine, and threonine (Gly-Ser-Thr), as well as alanine, aspartate, and glutamate (Ala-Asp-Glu) metabolism with PGDs. The association of abnormal amino acid metabolism with kidney diseases has long been discussed by various studies (24,32,(34)(35)(36). For instance, the results of a recent proteomics and metabolomics experiment on IgAN samples revealed a distortion in the energy and amino acid metabolism in IgAN patients (37).…”

On the limits of 16S rRNA gene-based metagenome prediction and functional profiling

“…These KO terms are reported to be enriched in CRC patients [69][70][71][72][73]. For the KORA cohort, we focused on KO terms classified under pathways in carbohydrate [74] and amino acid metabolism [75,76]. In diabetes, particularly in type two diabetes, impaired carbohydrate metabolism is a hallmark feature.…”