scholarly journals Metabolomic analysis of obesity, metabolic syndrome, and type 2 diabetes: amino acid and acylcarnitine levels change along a spectrum of metabolic wellness

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5410 ◽  
Author(s):  
Diane M. Libert ◽  
Amy S. Nowacki ◽  
Marvin R. Natowicz
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Amino Acids ◽  
Cluster Analysis ◽  
Amino Acid ◽  
Statistical Significance ◽  
Aromatic Amino Acids ◽  
Large Neutral Amino Acid ◽  
Metabolomic Analysis

Background Metabolic syndrome (MS) is a construct used to separate “healthy” from “unhealthy” obese patients, and is a major risk factor for type 2 diabetes (T2D) and cardiovascular disease. There is controversy over whether obese “metabolically well” persons have a higher morbidity and mortality than lean counterparts, suggesting that MS criteria do not completely describe physiologic risk factors or consequences of obesity. We hypothesized that metabolomic analysis of plasma would distinguish obese individuals with and without MS and T2D along a spectrum of obesity-associated metabolic derangements, supporting metabolomic analysis as a tool for a more detailed assessment of metabolic wellness than currently used MS criteria. Methods Fasting plasma samples from 90 adults were assigned to groups based on BMI and ATP III criteria for MS: (1) lean metabolically well (LMW; n = 24); (2) obese metabolically well (OBMW; n = 26); (3) obese metabolically unwell (OBMUW; n = 20); and (4) obese metabolically unwell with T2D (OBDM; n = 20). Forty-one amino acids/dipeptides, 33 acylcarnitines and 21 ratios were measured. Obesity and T2D effects were analyzed by Wilcoxon rank-sum tests comparing obese nondiabetics vs LMW, and OBDM vs nondiabetics, respectively. Metabolic unwellness was analyzed by Jonckheere-Terpstra trend tests, assuming worsening health from LMW → OBMW → OBMUW. To adjust for multiple comparisons, statistical significance was set at p < 0.005. K-means cluster analysis of aggregated amino acid and acylcarnitine data was also performed. Results Analytes and ratios significantly increasing in obesity, T2D, and with worsening health include: branched-chain amino acids (BCAAs), cystine, alpha-aminoadipic acid, phenylalanine, leucine + lysine, and short-chain acylcarnitines/total carnitines. Tyrosine, alanine and propionylcarnitine increase with obesity and metabolic unwellness. Asparagine and the tryptophan/large neutral amino acid ratio decrease with T2D and metabolic unwellness. Malonylcarnitine decreases in obesity and 3-OHbutyrylcarnitine increases in T2D; neither correlates with unwellness. Cluster analysis did not separate subjects into discreet groups based on metabolic wellness. Discussion Levels of 15 species and metabolite ratios trend significantly with worsening metabolic health; some are newly recognized. BCAAs, aromatic amino acids, lysine, and its metabolite, alpha-aminoadipate, increase with worsening health. The lysine pathway is distinct from BCAA metabolism, indicating that biochemical derangements associated with MS involve pathways besides those affected by BCAAs. Even those considered “obese, metabolically well” had metabolite levels which significantly trended towards those found in obese diabetics. Overall, this analysis yields a more granular view of metabolic wellness than the sole use of cardiometabolic MS parameters. This, in turn, suggests the possible utility of plasma metabolomic analysis for research and public health applications.

scholarly journals A High Level of Circulating Valine Is a Biomarker for Type 2 Diabetes and Associated with the Hypoglycemic Effect of Sitagliptin

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaoyu Liao ◽  
Bingyao Liu ◽  
Hua Qu ◽  
LinLin Zhang ◽  
Yongling Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Aromatic Amino Acids ◽  
Gas Chromatography Mass Spectrometry ◽  
Glucose Levels ◽  
Increased Risk ◽  
Normal Glucose ◽  
Potential Strategy ◽  
High Level

Background. High levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) were associated with an increased risk of hyperglycemia and the onset of diabetes. This study is aimed at assessing circulating valine concentrations in subjects with type 2 diabetes (T2D) and in T2D patients and high-fat diet- (HFD-) fed mice treated with the hypoglycemic agent sitagliptin (Sit) and analyzing the association of valine concentrations with metabolic parameters. Methods. Metabolomics in HFD-fed mice were analyzed by gas chromatography-mass spectrometry (GC-MS) systems. Plasma valine concentrations were detected with a commercial kit in 53 subjects with normal glucose levels (n=19), newly diagnosed T2D (n=20), placebo-treated T2D (n=7), or Sit-treated T2D (n=7). Biochemical parameters were also assessed in all participants. Results. Sit treatment markedly changed the pattern of amino acid in HFD-fed mice, especially by reducing the level of the BCAA valine. Compared with the healthy controls, the plasma valine concentrations were significantly higher in the T2D patients (p<0.05). Correlation analysis showed that the plasma valine concentration was positively correlated with the level of fasting plasma glucose (p<0.05). Moreover, the plasma valine concentrations were notably reduced after Sit treatment in T2D patients (p<0.05). Conclusions. Our findings demonstrate an important effect of Sit on the BCAA valine in T2D patients and HFD-fed mice, revealing a new hypoglycemic mechanism of it. Furthermore, the results suggest that the circulating valine level might be a novel biomarker for T2D and restoring the level of valine might be a potential strategy for diabetes therapy.

scholarly journals Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Abdelrahim Alqudah ◽  
Mohammed Wedyan ◽  
Esam Qnais ◽  
Hassan Jawarneh ◽  
Lana McClements
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Amino Acids ◽  
Amino Acid ◽  
Fasting Blood Glucose ◽  
Plasma Concentrations ◽  
Essential Amino Acids ◽  
Amino Acid Profile ◽  
Healthy Controls

The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p &lt; 0.01, Lysine, p &lt; 0.001, Phenylalanine, p &lt; 0.01, Tryptophan, p &lt; 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D (p &lt; 0.01, p &lt; 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls (p &lt; 0.001, p &lt; 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p &lt; 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls (p &lt; 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c (p &lt; 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment (p &lt; 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.

scholarly journals Gut-Microbial Metabolites, Probiotics and Their Roles in Type 2 Diabetes

2021 ◽  
Vol 22 (23) ◽  
pp. 12846
Author(s):  
Lixiang Zhai ◽  
Jiayan Wu ◽  
Yan Y. Lam ◽  
Hiu Yee Kwan ◽  
Zhao-xiang Bian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Gut Microbiota ◽  
Aromatic Amino Acids ◽  
Microbial Metabolites ◽  
High Blood Glucose ◽  
Gaseous Products ◽  
Glucose Levels ◽  
Novel Therapeutic Strategies

Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.

scholarly journals Rate of appearance of amino acids after a meal regulates insulin and glucagon secretion in patients with type 2 diabetes: a randomized clinical trial

2018 ◽  
Vol 108 (2) ◽  
pp. 279-291 ◽  
Author(s):  
Mariya Markova ◽  
Silke Hornemann ◽  
Stephanie Sucher ◽  
Katrin Wegner ◽  
Olga Pivovarova ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Amino Acid ◽  
Total Protein ◽  
Protein Quality ◽  
Gastrointestinal Hormones ◽  
Glucagon Secretion ◽  
Casein Protein ◽  
Gip Release

ABSTRACT Background Meal composition regulates the postprandial response of pancreatic and gastrointestinal hormones and plays an important role in patients with type 2 diabetes (T2D). Proteins have glucagon and insulinotropic effects, which may differ depending on amino acid composition, form of intake, and rate of digestibility and absorption. Objective The aim of this study was to test effects of isolated pea protein–based (PP) compared with casein protein–based (CP) meals differing in amino acid compositions on endocrine responses to meal tolerance tests (MTTs) in patients with T2D. Design Thirty-seven individuals with T2D [mean ± SD age: 64 ± 6 y; mean ± SD body mass index (kg/m2): 30.2 ± 3.6; mean ± SD glycated hemoglobin: 7.0% ± 0.6%] were randomly assigned to receive either high-animal-protein (∼80% of total protein) or high-plant-protein (∼72% of total protein) diets (30% of energy from protein, 40% of energy from carbohydrate, 30% of energy from fat) for 6 wk. MTTs were performed at study onset and after 6 wk. Participants received standardized high-protein (30% of energy) meals 2 times/d containing either CP-rich (∼85% wt:wt) or PP-rich (∼95% wt:wt) foods. Results The CP and PP meals produced differences in insulin, C-peptide, glucagon, and glucose-dependent insulinotropic peptide (GIP) release. Total areas under the curve after CP were significantly lower than after the PP lunch by 40% for insulin and 23% for glucagon. Indexes of insulin sensitivity and secretion were significantly improved for the second CP MTT. This was accompanied by differential rates of appearance of amino acids. The ingestion of PP resulted in significant increases in amino acids after both meals, with a decline between meals. By contrast, CP intake resulted in increases in most amino acids after breakfast, which remained elevated but did not increase further after lunch. Conclusions PP elicits greater postprandial increases in glucagon than does CP and consequently requires higher insulin to control glucose metabolism, which appears to be related to the rate of amino acid appearance. The metabolic impact of protein quality could be used as a strategy to lower insulin needs in patients with T2D. This trial was registered at www.clinicaltrials.gov as NCT02402985.

scholarly journals Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED Trial

Diabetologia ◽  
2018 ◽  
Vol 61 (7) ◽  
pp. 1560-1571 ◽  
Author(s):  
Miguel Ruiz-Canela ◽  
Marta Guasch-Ferré ◽  
Estefanía Toledo ◽  
Clary B. Clish ◽  
Cristina Razquin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Cohort Study ◽  
Mediterranean Diet ◽  
Aromatic Amino Acids ◽  
Diabetes Case ◽  
Branched Chain

PM20D1 Is a Circulating Biomarker Closely Associated with Obesity, Insulin resistance and Metabolic Syndrome

2021 ◽  
Author(s):  
Ranyao Yang ◽  
Yue Hu ◽  
Chi Ho Lee ◽  
Yan Liu ◽  
Candela Diaz-Canestro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Amino Acids ◽  
Metabolic Complications ◽  
The Metabolic Syndrome ◽  
Clinical Biomarkers ◽  
The Impact ◽  
Circulating Levels

Objective: Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans. Design and Methods: Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography-mass spectrometry respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes. Results: Serum PM20D1 level was significantly elevated in overweight/obese individuals, and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2-h postprandial glucose, HbA1c, fasting insulin, and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes. Conclusions: Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS, and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

2021 ◽  
Vol 46 (1) ◽  
pp. 1-9
Author(s):  
Oana Ancu ◽  
Monika Mickute ◽  
Nicola D. Guess ◽  
Nicholas M. Hurren ◽  
Nicholas A. Burd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Amino Acid ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Protein Intake ◽  
High Protein Diets ◽  
Protein Diets

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

Effect of hypothyroidism on pathways for iodothyronine and tryptophan uptake into rat adipocytes

2001 ◽  
Vol 280 (2) ◽  
pp. E254-E259 ◽  
Author(s):  
James W. A. Ritchie ◽  
Charmian J. F. Collingwood ◽  
Peter M. Taylor
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Thyroid Hormone ◽  
Aromatic Amino Acids ◽  
Target Tissue ◽  
Large Neutral Amino Acid ◽  
Major Pathway ◽  
Transport Component ◽  
System L ◽  
Adipocyte Cell

Adipocytes are an important target tissue for thyroid hormone action, but little is known of the mechanisms of thyroid hormone entry into the cells. The present results show a strong interaction between transport of iodothyronines [l-thyroxine (T4),l-triiodothyronine (T3), reverset3 (rT3)], aromatic amino acids, and the System L amino acid transport inhibitor 2-amino[2,2,1]heptane-2-carboxylic acid (BCH) in white adipocytes. System L appears to be a major pathway of iodothyronine and large neutral amino acid entry into these cells in the euthyroid state. We also demonstrate expression of the CD98hc peptide subunit of the System L transporter in adipocyte cell membranes. Experimental hypothyroidism (28-day propylthiouracil treatment) has no significant effect on Systeml-like transport of the amino acid tryptophan in adipocytes. In contrast, uptake of T3 and especially T4 is substantially reduced in adipocytes from hypothyroid rats, partly due to reduction of the BCH-sensitive transport component. Transport of iodothyronines and amino acids in adipocytes therefore becomes decoupled in the hypothyroid state, as occurs similarly in liver cells. This may be due to downregulation or dissociation of iodothyronine receptors from the System L transporter complex. Regulation of iodothyronine turnover in fat cells by this type of mechanism could contribute significantly to modulation of T4-T3/rT3 metabolism in the hypothyroid state.

scholarly journals Metabolomics and Type 2 Diabetes: Translating Basic Research into Clinical Application

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Matthias S. Klein ◽  
Jane Shearer
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Aromatic Amino Acids ◽  
Predictive Biomarkers ◽  
Basic Research ◽  
New Approach ◽  
Branched Chain ◽  
Small Biomolecules ◽  
Overt Disease

Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids andα-hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine.

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