Impact of sarcosine on diabetic retinopathy: Findings based on weighted gene co-expression network analysis and machine learning techniques.

AIM: To quantify the association between serum sarcosine and diabetic retinopathy (DR) using weighted gene co-expression network analysis (WGCNA). METHODS: We measured serum metabolites in 69 pairs of type 2 diabetes (T2D) patients with and without DR matched by age, gender, body mass index（BMI and HbA1c, using a propensity score matching-based approach. To identify modules and metabolites linked to DR, pathway analysis was performed using WGCNA, the Kyoto Encyclopedia of Genes and Genomes and Small-Molecule Pathway Database. The association of sarcosine with DR was estimated by restricted cubic spline and conditional logistic regression models. Its joint effects with covariates on DR were also extensively examined. RESULTS: With per interquartile range elevation of sarcosine, the adjusted odds ratio (AOR) of DR significantly decreased by 67% (AOR: 0.33, 95% confidence interval [CI]: 0.19-0.58). Similar results were also found in the tertile analysis. Compared with those in the first tertile of sarcosine, the AOR significantly decreased by 54% (AOR: 0.46, 95% CI: 0.18-1.17) and 78% (AOR: 0.22, 95% CI: 0.08-0.59) for subjects in the second and third tertiles, respectively. Compared with subjects with lower sarcosine and lower HDL-C levels, those with higher sarcosine and lower HDL-C levels had the lowest odds of DR (OR: 0.13, 95% CI: 0.04, 0.43). CONCLUSIONS: Serum sarcosine was inversely related to DR, especially in T2D patients with insufficient HDL-C. This study provides insights on a possible novel target for DR precision prevention and control, as well as a better understanding of the DR mechanism.

Comparison of the Early Warning Effects of Novel Inflammatory Markers SIRI, NLR, and LMR in the Inhibition of Carotid Atherosclerosis by Testosterone in Middle-Aged and Elderly Han Chinese Men in the Real World: A Small Sample Clinical Observational Study.

The purpose of this study was to explore and compare the relationship among serum testosterone, systemic inflammatory response index (SIRI), lymphocyte-to-monocyte ratio (LMR) neutrophil-lymphocyte ratio (NLR), and carotid atherosclerosis in middle-aged and elderly men of Han nationality in the real world. With reference to the inclusion criteria, 89 middle-aged and elderly Han male patients were finally selected. Local weighted regression (LOESS) and multivariate logistic regression models were used to explore the independent correlation between serum testosterone, new inflammatory markers, and atherosclerosis. The diagnostic value of related indexes was evaluated by the receiver working curve characteristic curve (ROC), and the best critical value of testosterone and related inflammatory indexes was discussed. In the LOESS model, bioavailable testosterone (BT), free testosterone (FT), total testosterone (TT) and SIRI, NLR, LMR, and atherosclerosis were significantly correlated. After adjusting for confounding factors, BT, FT, TT, and LMR were negatively correlated with atherosclerosis (odds ratio [OR] < 1, p < .05), and SIRI and NLR were positively associated with atherosclerosis (OR > 1, p < .05). According to the ROC curve results, the area under the curve (AUG) of BT is 0.870, and the optimal threshold point is 4.875. The AUG of SIRI is 0.864, and the best threshold point is 0.769. Low testosterone and high inflammatory levels are closely related to atherosclerosis. Testosterone (TT, FT, and BT) and new inflammatory markers, SIRI, NLR, and LMR, are associated with carotid atherosclerosis in middle-aged and elderly men.

Plasma acylcarnitine and diabetic retinopathy: A study from Eastern China.

Background and purpose: Acylcarnitines (ACars) are important for insulin resistance and type 2 diabetes (T2D). However, their roles in diabetic retinopathy (DR) remain controversial. In this study, we aimed to investigate the association of ACars with DR and their values in DR detection. Methods: This was a two-center case-control study based on the propensity score matching approach between August 2017 to June 2018 in Eastern China. Multivariable logistic regression models were applied to estimate the association of plasma ACars with DR. Differential ACars were screened by models of least absolute shrinkage and selection operator, elastic net, and weighted quantile sum regression, and their roles in DR identification were further evaluated by the area under the receiver operating curve (AUC). Results: Eight of twenty plasma ACars (8:0, 12:0, 12:1, 14:1, 16:2, 18:0, 18:2 and 18:3) were associated with DR, while only ACar 8:0 was selected by three variable selection methods. As compared to those with the 1st tertile of ACar 8:0, the adjusted odds ratio (OR) and 95% confidence interval (CI) of DR were 0.22 (0.08, 0.59) and 0.12 (0.04, 0.36) for subjects in the 2nd and 3rd tertiles, respectively (P for trend < 0.001). Consistent associations were also observed in both restricted cubic spline regression models and subgroup analyses. AUC (95% CI) were 0.74 (0.66, 0.82) for ACar 8:0 alone and 0.77 (0.70, 0.85) for ACar 8:0 combined with covariates. Conclusions: Our findings suggest higher ACar 8:0 is significantly associated with a decreased risk of DR, which provides a unique window for early identification of DR.

Interpretable machine learning-derived nomogram model for early detection of diabetic retinopathy in type 2 diabetes mellitus: a widely targeted metabolomics study.

OBJECTIVE: Early identification of diabetic retinopathy (DR) is key to prioritizing therapy and preventing permanent blindness. This study aims to propose a machine learning model for DR early diagnosis using metabolomics and clinical indicators. METHODS: From 2017 to 2018, 950 participants were enrolled from two affiliated hospitals of Wenzhou Medical University and Anhui Medical University. A total of 69 matched blocks including healthy volunteers, type 2 diabetes, and DR patients were obtained from a propensity score matching-based metabolomics study. UPLC-ESI-MS/MS system was utilized for serum metabolic fingerprint data. CART decision trees (DT) were used to identify the potential biomarkers. Finally, the nomogram model was developed using the multivariable conditional logistic regression models. The calibration curve, Hosmer-Lemeshow test, receiver operating characteristic curve, and decision curve analysis were applied to evaluate the performance of this predictive model. RESULTS: The mean age of enrolled subjects was 56.7 years with a standard deviation of 9.2, and 61.4% were males. Based on the DT model, 2-pyrrolidone completely separated healthy controls from diabetic patients, and thiamine triphosphate (ThTP) might be a principal metabolite for DR detection. The developed nomogram model (including diabetes duration, systolic blood pressure and ThTP) shows an excellent quality of classification, with AUCs (95% CI) of 0.99 (0.97-1.00) and 0.99 (0.95-1.00) in training and testing sets, respectively. Furthermore, the predictive model also has a reasonable degree of calibration. CONCLUSIONS: The nomogram presents an accurate and favorable prediction for DR detection. Further research with larger study populations is needed to confirm our findings.

High-Coverage Serum Metabolomics Reveals Metabolic Pathway Dysregulation in Diabetic Retinopathy: A Propensity Score-Matched Study.

Background: Diabetic retinopathy (DR) is a major diabetes-related disease linked to metabolism. However, the cognition of metabolic pathway alterations in DR remains scarce. We aimed to corroborate alterations of metabolic pathways identified in prior studies and investigate novel metabolic dysregulations that may lead to new prevention and treatment strategies for DR. Methods: In this case-control study, we tested 613 serum metabolites in 69 pairs of type 2 diabetic patients (T2DM) with DR and propensity score-matched T2DM without DR via ultra-performance liquid chromatography-tandem mass spectrometry system. Metabolic pathway dysregulation in DR was thoroughly investigated by metabolic pathway analysis, chemical similarity enrichment analysis (ChemRICH), and integrated pathway analysis. The associations of ChemRICH-screened key metabolites with DR were further estimated with restricted cubic spline analyses. Results: A total of 89 differentially expressed metabolites were identified by paired univariate analysis and partial least squares discriminant analysis. We corroborated biosynthesis of unsaturated fatty acids, glycine, serine and threonine metabolism, glutamate and cysteine-related pathways, and nucleotide-related pathways were significantly perturbed in DR, which were identified in prior studies. We also found some novel metabolic alterations associated with DR, including the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives in DR. Conclusions: The results suggest that the metabolism disorder in DR can be better understood through integrating multiple biological knowledge databases. The progression of DR is associated with the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives.

Individual and joint effects of trehalose and glutamate on diabetic retinopathy: a propensity score-matched case-control study.

Although previous studies demonstrate that trehalose can help maintain glucose homeostasis in healthy humans, its role and joint effect with glutamate on diabetic retinopathy (DR) remain unclear. We aimed to comprehensively quantify the associations of trehalose and glutamate with DR. This study included 69 pairs of DR and matched type 2 diabetic (T2D) patients. Serum trehalose and glutamate were determined via ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system. Covariates were collected by a standardized questionnaire, clinical examinations and laboratory assessments. Individual and joint association of trehalose and glutamate with DR were quantified by multiple conditional logistic regression models. The adjusted odds of DR averagely decreased by 86% (odds ratio (OR): 0.14; 95% CI: 0.06, 0.33) with per interquartile range increase of trehalose. Comparing with the lowest quartile, adjusted OR (95% CI) were 0.20 (0.05, 0.83), 0.14 (0.03, 0.63) and 0.01 (<0.01, 0.05) for participants in the second, third and fourth quartiles of trehalose, respectively. In addition, as compared to their counterparts, T2D patients with lower trehalose (

Serum ω-6/ω-3 polyunsaturated fatty acids ratio and diabetic retinopathy: A propensity score matching based case-control study in China.

BACKGROUND: Optimal ω-6/ω-3 polyunsaturated fatty acids ratio (PUFAR) is reported to exert protective effects against chronic diseases. However, data on PUFAR and diabetic retinopathy (DR) remains scarce. We aimed to thoroughly quantify whether and how PUFAR was related to DR as well as its role in DR detection. METHODS: This two-centre case-control study was conducted from August 2017 to June 2018 in China, participants were matched using a propensity score matching algorithm. We adopted multivariable logistic regression models and restricted cubic spline analyses to estimate the independent association of PUFAR with DR, adjusting for confounders identified using a directed acyclic graph. The value of PUFAR as a biomarker for DR identification was further evaluated by receiver operating characteristic analyses and Hosmer-Lemeshow tests. FINDINGS: An apparent negative relationship between PUFAR and DR was observed. Adjusted odds of DR decreased by 79% (OR: 0·21, 95% CI: 0·10-0·40) with an interquartile range increase in PUFAR. Similar results were also obtained in tertile analysis. As compared to those in the 1st tertile of PUFAR, the adjusted odds of DR decreased by 76% (OR: 0·24, 95% CI: 0·08-0·66) and 93% (OR: 0·07, 95% CI: 0·03-0·22) for subjects in the 2nd and 3rd tertiles, respectively. Good calibration and discrimination of the PUFAR associated predictive model were detected and PUFAR = 35 would be an ideal cut-off value for DR identification. INTERPRETATION: Our results suggest that serum PUAFR is inversely associated with DR. Although PUFAR-alteration is not observed amongst different stages of DR, it can serve as an ideal biomarker in distinguishing patients with DR from those without DR. FUNDING: This study was funded by Natural Science Foundation of Zhejiang Province, Zhejiang Basic Public Welfare Research Project, the Major Project of the Eye Hospital of Wenzhou Medical University, and the Academician's Science and Technology Innovation Program in Zhejiang province. Part of this work was also funded by the National Nature Science Foundation of China, and Research Project for College Students in Wenzhou Medical University.