Argininosuccinic acid was the only metabolite whose association with diabetes status survived false-discovery-rate correction in patients with coronary artery disease, though all estimates were extrapolated below the lowest calibrator and should be interpreted as semiquantitative.
Key Findings
Results
Argininosuccinic acid concentrations were significantly higher in diabetic patients with coronary artery disease compared to non-diabetic patients with coronary artery disease.
Estimated concentrations were 0.28 [0.21–0.34] µmol/L in diabetes versus 0.15 [0.13–0.19] µmol/L in non-diabetes.
Cliff's delta = 0.765, indicating a large effect size.
Exact Wilcoxon test p < 0.001; Benjamini-Hochberg corrected q = 0.035.
Argininosuccinic acid was available for 26 of the 33 patients in the cohort.
This was the only association among 45 screened amino acids and related metabolites to survive false-discovery-rate correction.
Methods
All argininosuccinic acid concentration estimates were extrapolated below the lowest calibrator and must be interpreted as semiquantitative.
The study used targeted LC-MS/MS methodology to screen 45 amino acids and related metabolites.
Because all values fell below the lowest calibration standard, they represent extrapolated rather than directly measured concentrations.
The authors explicitly state these should be interpreted as semiquantitative.
This limitation means the absolute concentration values carry substantial analytical uncertainty.
Results
The positive association between diabetes status and argininosuccinic acid persisted in crude and adjusted regression models, but renal and influence analyses were imprecise.
The diabetes coefficient remained positive in both crude and age- and sex-adjusted HC3-robust regression models.
HC3-robust standard errors were used to account for heteroscedasticity.
The diabetes-by-CAD interaction term was not statistically significant (p = 0.183).
Results
Argininosuccinic acid levels were inversely correlated with estimated glomerular filtration rate (eGFR) and positively correlated with creatinine.
Inverse correlation with eGFR: Spearman's rho = -0.445, p = 0.023.
Positive correlation with creatinine: Spearman's rho = 0.486, p = 0.012.
These correlations indicate a relationship between argininosuccinic acid accumulation and renal function.
The authors note that careful renal phenotyping will be necessary in future validation studies.
Methods
The study was an exploratory, retrospective, disease-restricted cohort design screening 45 amino acids and related metabolites by diabetes status in CAD patients.
Total cohort size was n = 33, with argininosuccinic acid data available for n = 26.
Inclusion required a recorded diseased-vessel count ≥ 1.
Comparisons used exact Wilcoxon tests, Cliff's delta effect size, and Benjamini-Hochberg false-discovery-rate correction.
The authors describe findings as 'hypothesis-generating' requiring validation with an appropriate calibration range.
What This Means
This research suggests that a molecule called argininosuccinic acid — an intermediate in the body's urea cycle, which processes nitrogen — is present at higher levels in the blood of people who have both diabetes and coronary artery disease (blocked heart arteries) compared to those with coronary artery disease alone. Out of 45 different amino acids and related compounds tested, argininosuccinic acid was the only one whose link to diabetes held up after accounting for the possibility of false positives from testing so many substances at once. The study was small, involving 33 patients with heart disease, and the measurements themselves were below the reliable detection limit of the equipment, meaning the numbers are approximate rather than precise.
The study also found that argininosuccinic acid levels were related to kidney function — higher levels corresponded with worse kidney filtration and higher creatinine, a waste product the kidneys normally clear. This is important because both diabetes and coronary artery disease can affect the kidneys, and kidney problems could independently raise argininosuccinic acid levels, making it harder to know exactly what is driving the association.
Because of the small sample size, the measurement limitations, and the inability to fully account for kidney disease, the authors are careful to frame this as a hypothesis-generating finding rather than a definitive result. This research suggests that argininosuccinic acid deserves further investigation as a potential metabolic marker in people with diabetes and heart disease, but larger studies with better-calibrated laboratory methods and thorough assessment of kidney health will be needed before any firm conclusions can be drawn.
Krasińska B, Kang M, Baek S, Pietkiewicz D, Plewa S, Kowalewski M, et al.. (2026). Serum Argininosuccinic Acid Is Associated with Diabetes in Patients with Coronary Artery Disease: An Exploratory Targeted LC-MS/MS Study.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198766