Diagnostic yield of the plasma free amino acid index for pancreatic cancer in patients with diabetes mellitus.

OBJECTIVES: A multivariate index calculated using plasma free amino acids (PFAA index) was reported as a diagnostic biomarker for pancreatic cancer (PaC). Although diabetes mellitus (DM) is expected to be an early diagnostic indicator of PaC, identifying the high-risk individuals among patients with DM is warranted. We evaluated the diagnostic yield of the PFAA index for PaC in patients with DM. METHODS: We compared the diagnostic yield of the PFAA index between individuals with and those without DM. Cases and controls were recruited prospectively, and controls were matched to cases at a 1:1 ratio for age, sex, and DM status. RESULTS: A total of 180 case-control pairs were included in the analysis. The prevalence of DM was 53.3%. The sensitivity of the PFAA index was 66.7% in cases with DM and 56.0% in those without DM (P = 0.14), and the specificity was 92.7% in controls with DM and 94.0% in those without DM (P = 0.95). CONCLUSIONS: This matched case-control study revealed a comparable diagnostic yield of the PFAA index for PaC in individuals with and those without DM. The PFAA index can be used as a biomarker for further diagnostic imaging in selected patients with DM.

Normalization of abnormal plasma amino acid profile-based indexes in patients with gynecological malignant tumors after curative treatment.

BACKGROUND: We developed a novel plasma amino acid profile-based index (API) to detect ovarian, uterine, cervical, and endometrial cancers. In this study, we aimed to evaluate whether abnormal API values could be normalized after curative treatment in patients with gynecological malignant tumors. METHODS: Patients with gynecological cancer with abnormal API values were included in this study. Pre-operative absolute API values were compared with those after curative treatment. The normalization rates of API values in patients negative for the expression of three well-known tumor markers (SCC, CA125, and CA19-9) were also evaluated. In addition, related amino acid profiles in healthy controls and patients under pre- and post-treatment conditions were analyzed. RESULTS: Among 94 patients with abnormal pre-operative API values, the median API value was decreased from 9.52 to 2.17 after treatment (normalization rate: 88.3%). The decreased ranges were similar in patients with adenocarcinoma (6.28; 95% confidence interval [CI]: 5.43-6.95) and squamous carcinoma (7.44; 95% CI: 3.04-8.46). In 93.5% (43/46) of patients negative for tumor markers prior to operation, API values were normalized after the successful treatment. In addition, some pre-operative abnormal amino acid profiles, including Ile, Trp, and His, were reversibly normalized after treatment. CONCLUSION: The API is a promising tumor marker in gynecological malignancies for the diagnosis of remission, particularly in patients negative for general tumor markers. Further studies are needed to explore the mechanisms related to the normalization of abnormal amino acid profiles.

Early nocturnal meal skipping alters the peripheral clock and increases lipogenesis in mice.

BACKGROUND: In humans, skipping meals, especially breakfast, has been associated with obesity and other related syndromes. Recent studies in rodents suggest that fasting and feeding times are potential factors that affect the peripheral circadian clocks and metabolism. However, the link between fasting and obesity in rodents has yet to be fully demonstrated. METHOD: We conducted early nocturnal fasting (ENF) from zeitgeber time (ZT) 12 to 18 for 4 consecutive days in C57B6 mice. The first set of experiments was performed under ad libitum conditions, where ENF and free-feeding (FF) control groups were compared. The second set was performed under isocaloric adjustment by restricting the diet to 90% of the basal intake of ENF mice. Calorie-restricted ENF (ENF-CR) mice were then compared with isocaloric controls (IC-control). Body weight, food intake, core body temperature, activity, adiposity, and clock-related gene expression levels in the liver and adipose tissues were investigated. A stable isotopic analysis was also conducted to estimate de novo lipogenesis fluxes. RESULTS: In the ad libitum condition, the ENF mice ate more during the day, increased their overall daily food intake and gained more weight than FF-control mice. The amplitude of the body core temperature rhythm in ENF mice was also lower than in the FF-controls. Under isocaloric conditions, ENF-CR attenuated the CR-induced body weight loss, compared with the IC-control. ENF-CR also altered the acrophase time of the expression of the clock genes, which is associated with time-shift of genes involved in lipid metabolism and increased lipogenesis, compared with the IC-control. CONCLUSIONS: ENF in nocturnal mice disturbs the peripheral clock and increases de novo lipid synthesis and results in a predisposition to obesity.

Ketogenic essential amino acids modulate lipid synthetic pathways and prevent hepatic steatosis in mice.

BACKGROUND: Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high-fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high-sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogenesis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL-derived fatty acids into hepatic ceramides. CONCLUSION: Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways.

Determining important regulatory relations of amino acids from dynamic network analysis of plasma amino acids.

The changes in the concentrations of plasma amino acids do not always follow the flow-based metabolic pathway network. We have previously shown that there is a control-based network structure among plasma amino acids besides the metabolic pathway map. Based on this network structure, in this study, we performed dynamic analysis using time-course data of the plasma samples of rats fed single essential amino acid deficient diet. Using S-system model (conceptual mathematical model represented by power-law formalism), we inferred the dynamic network structure which reproduces the actual time-courses within the error allowance of 13.17%. By performing sensitivity analysis, three of the most dominant relations in this network were selected; the control paths from leucine to valine, from methionine to threonine, and from leucine to isoleucine. This result is in good agreement with the biological knowledge regarding branched-chain amino acids, and suggests the biological importance of the effect from methionine to threonine.

Plasma amino acid analysis for diagnosis and amino acid-based metabolic networks.

PURPOSE OF REVIEW: To highlight the usefulness of amino acid profiling in clinical diagnosis and current developments in analysis revealing underlying metabolic relationships. RECENT FINDINGS: Recent innovations in metabolomics and systems biology enable high throughput measurement of diverse amino acids and the subsequent data mining for various uses. Recent studies show new possibilities of using plasma amino acid analysis as biomarker discovery tools by generating diagnostic indices through systematic computation. Such studies show that amino acid-based clinical diagnostic indices for hepatic fibrosis in type C hepatitis patients can be generated. In addition, several studies show the potential of treating amino acid profile data as a metabolomic subset, which can be integrated through the analysis of correlation with different types of 'omics' data for describing metabolite-to-metabolite or metabolite-to-gene interaction networks. CONCLUSION: Amino acid profiling of biological samples could be used to generate indices that could be used for clinical diagnosis and is a useful tool for understanding metabolic implications under various physiological conditions. Although further improvements in analytical methods are needed, amino acids could be useful indicators for facilitating nutritional management of specific physiological and pathological states.

Characterization of dietary protein-dependent amino acid metabolism by linking free amino acids with transcriptional profiles through analysis of correlation.

This study aims to characterize diet-dependent amino acid metabolism by linking profiles of amino acids concentrations ("aminograms") with transcript datasets through the analysis of correlation. We used a dietary model of protein restriction-to-excess, where rats were fed diets with different levels of casein (5, 10, 15, 20, 30, 50, and 70%) for 2 wk. Twenty-five different amino acids in the plasma, liver, kidney, small intestine, and muscle and 71 gene transcripts in these compartments were measured together with general physiological variables. Under low-protein diet (LPD) conditions, the plasma aminogram for EAA was similar to that of the liver and the small intestine, respectively. Under the high-protein diet (HPD), however, the plasma aminogram for EAA became like that of muscle, while that of NEAA was similar with that of both liver and muscle. To assess the impact of gene expressions in each tissue on the plasma aminograms, correlations were obtained between aminograms and transcripts in each tissue under a diet with different protein levels. Based on the correlations obtained, amino acids and transcripts were systematically connected and then a metabolite-to-gene network was constructed for either LPD or HPD condition. The networks obtained and some other metabolically meaningful relationships such as ureagenesis and serine metabolism clearly illustrated activation of either body protein breakdown with LPD or amino acid catabolism with HPD.