Plasma Amino Acids and Residual Hypertriglyceridemia in Diabetic Patients Under Statins: Two Independent Cross-Sectional Hospital-Based Cohorts.

Objective: The objective of the study was to investigate the relationship of amino acid metabolism with hypertriglyceridemia in diabetic patients under statins free of prior cardiovascular diseases. Methods: Two independent cross-sectional hospital based cohorts, i.e., Liaoning Medical University First Affiliated Hospital (LMUFAH, n = 146) and the Second Affiliated Hospital of Dalian Medical University (SAHDMU, n = 294) were included in the current analysis. Hypertriglyceridemia was defined as triglyceride ≥1.7 mmol/L, and well-controlled LDL-C was defined as <2.6 mmol/L. The adjusted ORs (95% CI) of circulating metabolic measures for hypertriglyceridemia were assessed using logistic regression. Pooled results of metabolites with the same direction of association in both cohorts were combined using inverse variance-weighted fixed-effect meta-analysis. Difference of identified metabolites in patients with and without hypertriglyceridemia were also obtained in the context of LDL-C. Results: Patients, 86 and 106, were with hypertriglyceridemia in LMUFAH and SAHDMU, respectively. We observed that elevated alanine, asparagine, leucine, and valine were consistently associated with increased hypertriglyceridemia in both cohorts. In fixed-effect pooled analysis, the OR (95% CI) per SD increase was 1.71 (1.32-2.20) for alanine, 1.62 (1.20-2.19) for asparagine, 1.64 (1.22-2.20) for leucine, and 1.62 (1.22-2.13) for valine (all P values ranged from 0.0018 to <0.0001); adjusting for C-peptide attenuated effect sizes of Ala, Leu, and Val for hypertriglyceridemia. The difference were robust in groups with well- or bad-controlled LDL-C. Conclusion: Among 23 amino acids, alanine, asparagine, leucine, and valine were positively associated with increased residual risk of hypertriglyceridemia in diabetic patients with statin treatment.

Decreased plasma n6 : n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type 2 diabetes patients.

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Interactive effects of asparagine and aspartate homeostasis with sex and age for the risk of type 2 diabetes risk.

BACKGROUND: Asparagine and aspartate homeostasis are linked with type 2 diabetes (T2D). This study aimed to explore whether asparagine and aspartate metabolism interacted with sex and age to increase the risk of T2D. METHODS: From 27 May 2015 to 3 August 2016, we consecutively retrieved 1032 T2D patients and 1522 subjects without T2D from a tertiary care hospital in Liaoning, China. Restricted cubic spline nested in the logistic regression was used to draw odds ratio curves of plasma asparagine to aspartate ratio for T2D by sex and age. Cut-off point was selected where curves went apart, indicating possible interaction. Addictive interactions of asparagine to aspartate ratio with sex or age and secondary interaction with copresence of unfavorable sex and age were further estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RESULTS: Ratio of asparagine to aspartate > 1.5 was associated with elevated risk of T2D (OR 7.99, 95%CI 5.50 to 11.6), which was enhanced by female gender to 13.6, (95%CI 8.10-22.9) and by > 50 years of age to 28.7 (14.6-56.3), with significant additive interactions. There was a significant secondary-interaction of copresence of female sex and > 50 years of age with high asparagine to aspartate ratio for increased T2D risk with the OR being further increased to 34.4 (20.5-57.5). CONCLUSIONS: High asparagine to aspartate ratio was associated with markedly increased risk of T2D, which was further amplified by either female gender or > 50 years of age, and especially both.

Plasma phenylalanine and tyrosine and their interactions with diabetic nephropathy for risk of diabetic retinopathy in type 2 diabetes.

OBJECTIVE: Tight control of hyperglycemia reduces risk of diabetic retinopathy (DR), but the residual risk remains high. This study aimed to explore relationships between plasma phenylalanine and tyrosine with DR in type 2 diabetes (T2D) and interactions between the two amino acids, and their secondary interaction with renal dysfunction. RESEARCH DESIGN AND METHODS: We extracted data of 1032 patients with T2D from tertiary hospital consecutively from May 2015 to August 2016. Binary logistic regression models with restricted cubic spline were used to check potential non-linear associations and to obtain ORs and 95% CIs of variables under study. Addictive interaction was estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Area under the receiver operating characteristic curve was used to check increased predictive values. RESULTS: Of 1032 patients, 162 suffered from DR. Copresence of low phenylalanine and low tyrosine increased DR risk (OR 6.01, 95% CI 1.35 to 26.8), while either of them alone did not have a significant effect with significant additive interaction. Presence of diabetic nephropathy further increased the OR of copresence of low phenylalanine and low tyrosine for DR to 25.9 (95% CI 8.71 to 76.9) with a significant additive interaction. Inclusion of phenylalanine and tyrosine in a traditional risk factor model significantly increased area under the curve from 0.81 to 0.83 (95% CI 0.80 to 0.86). CONCLUSION: Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.

The Association Between Acylcarnitine Metabolites and Cardiovascular Disease in Chinese Patients With Type 2 Diabetes Mellitus.

Objective: The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM. Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD. Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50). Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.

Plasma Free Amino Acids and Risk of Cardiovascular Disease in Chinese Patients With Type 2 Diabetes.

Objectives: This study aimed to explore associations between plasma free amino acids (PFAA) and risk of cardiovascular disease (CVD) in Chinese with Type 2 diabetes (T2D). Methods: We retrieved 741 inpatients with T2D consecutively from tertiary hospital. Twenty-three PFAA were measured. CVD was defined as having coronary heart disease (CHD) or stroke. Principal component analysis was used to extract factors of PFAA. Factors and their components were introduced into binary logistic regressions as continuous and tertiles to obtain OR (odds ratio) and 95% confidence interval (CI) for CVD (or its components) risk. Results: Of 741 inpatients, 282 (38.1%) had CVD (CHD alone: 122, stroke alone: 109, both: 51). Five factors were extracted, accounting for 65% of the total variance. Factor 3 composed of glutamate and tryptophan was associated with increased CVD risk (ORs, 95%CI of top vs. bottom tertiles: 1.60, 1.02-2.50 for CVD; 2.19, 1.17-4.07 for stroke, 1.51, 0.83-2.73 for CHD); the ORs (top vs. bottom tertiles) of glutamate were 2.62 (95%CI, 1.18-5.84) for stroke and 1.44 (0.80-2.61) for CHD; the ORs (top vs. bottom tertiles) of tryptophan were 1.50 (0.81-2.75) for stroke and 1.07 (0.58-1.97) for CHD. Comparable results were observed according to important confounders (all P for interaction >0.05). Conclusions: Elevated factor 3 composed of glutamate and tryptophan was associated with increased CVD, especially stroke in T2D in China.

The Association Between Leucine and Diabetic Nephropathy in Different Gender: A Cross-Sectional Study in Chinese Patients With Type 2 Diabetes.

Objective: This study aimed to evaluate how leucine are associated with diabetic nephropathy (DN) in type 2 diabetes (T2D) patients and the gender difference of this association. Methods: We retrieved 1,031 consecutive patients with T2D who meet the inclusion and exclusion criteria from the same tertiary care center and extracted clinical information from electronic medical record. Plasma leucine was measured by liquid chromatography-mass spectrometer. Restricted cubic spline (RCS) was conducted to examine potential non-linear relationship between leucine and the risk of DN. Logistic regression was used to obtain odds ratio (OR) and confidence interval (CI). Additive interaction was used to estimate the interaction effect between leucine and gender for DN. Results: We found there was a negative correlation between leucine and the risk of DN. After stratifying all patients by gender, this relationship only remained significant in women (OR:0.57, CI:0.41-0.79). Conclusions: In conclusion, T2D patients with high levels of leucine have a lower risk of developing DN in female.

Plasma Levels of Amino Acids Related to Urea Cycle and Risk of Type 2 Diabetes Mellitus in Chinese Adults.

Objective: This study aimed to test associations between type 2 diabetes mellitus (T2DM) and metabolites in urea cycle including arginine, citrulline and ornithine. Methods:This study used a hospital-based cross-sectional study design. We retrieved medical notes of 401 in-patients with onset of T2DM within 2 years and 1,522 healthy subjects who attended annual physical examination. All cases were admitted to a tertiary care center in Jinzhou, China from May 2015 to August 2016. Binary logistic regression analyses were performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Results:Patients with T2DM had higher arginine, and lower ornithine than control subjects. Levels of citrulline were similar in two groups. Arginine was positively associated with T2DM (ORs: 1.20, 1.17-1.23) while ornithine was negatively associated with T2DM (OR: 0.89, 0.88-0.91). After adjustment for other amino acids and traditional risk factors, these associations were still significant and persistent for arginine and ornithine. The association between citrulline and T2DM was not significant. Their ratios of pairs of two amino acids were associated with increased risk of T2DM. After adjustment for other ratios of amino acids, effect size for T2DM remained significant. Further adjustment for traditional risk factors did not lead to large changes (ORs: 1.78, 1.20-2.65 for the ratio of arginine to ornithine; ORs: 1.59, 1.37-1.86 for the ratio of citrulline to ornithine, respectively) except the ratio of arginine to citrulline. Conclusions: Plasma levels of amino acids related to urea cycle and their ratios of these amino-acids were associated with T2DM in Chinese adults.