Effect of Insulin Sensitizer Therapy on Amino Acids and Their Metabolites
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Diabetes
PROVIDER: ST000168 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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| mwtab | Other |
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Project description:AimsPrior studies have reported that elevated concentrations of several plasma amino acids (AA), particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes.MethodsWe performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI ~30kg/m(2)) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45mg per day) plus metformin (1000mg twice per day, N=12 participants) or placebo (N=13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention.ResultsInsulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/α-aminoadipic acid.ConclusionsReductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites.
| S-EPMC4525767 | biostudies-literature
Project description:ContextAmino acids (AAs) and their metabolites are altered with obesity and may be predictive of future diabetes in adults, but there are fewer studies on AAs, as well as conflicting findings on how they vary with obesity, in adolescents.ObjectiveTo determine whether plasma AAs vary with body composition and insulin sensitivity and are altered in response to exercise training.DesignCross-sectional, and an exercise intervention.SettingTribal wellness center.ParticipantsAmerican Indian boys and girls, 11 to 17 years of age with obesity (Ob, n = 58) or normal weight (NW, n = 36).InterventionThe Ob group completed 16 weeks of aerobic exercise training.Main outcome measureA panel of 42 plasma AAs.ResultsCompared with the NW group, the Ob group had lower aerobic fitness and insulin sensitivity (interactive homeostasis model assessment 2), 17 AAs that were higher, and 7 AAs that were lower. Branched-chain AAs (+10% to 16%), aromatic AAs (+15% to 32%), and glutamate were among the higher AAs; all were positively correlated with body fat and negatively correlated with insulin sensitivity. The lysine metabolite 2-aminoadipic acid (2-AAA) and the valine metabolite β-aminoisobutyric acid (BAIBA) were 47% higher and 29% lower, respectively, in the Ob group, and were positively (2-AAA) and negatively (BAIBA) correlated with insulin sensitivity. Exercise training increased aerobic fitness by 10%, but body composition, insulin sensitivity, and AAs were not significantly changed.ConclusionsSeveral plasma AAs are altered in American Indian adolescents with obesity and are associated with insulin sensitivity, but they were not altered with this exercise intervention.
| S-EPMC6584131 | biostudies-literature
Project description:Postoperative insulin resistance refers to the phenomenon that the body’s glucose uptake stimulated by insulin is reduced due to stress effects such as trauma or the inhibitory effect of insulin on liver glucose output is weakened after surgery.
There is a clear link between postoperative insulin resistance and poor perioperative prognosis. Therefore, exploring interventions to reduce postoperative stress insulin resistance, stabilize postoperative blood glucose, and reduce postoperative complications are clinical problems that need to be solved urgently. In recent years, research on branched-chain amino acids and metabolic diseases has become a hot spot. Studies have found that in the rat model, preoperatively given a high branched-chain amino acid diet can inhibit postoperative insulin resistance and stabilize blood glucose levels. This research plan is to try to add branched-chain amino acids before surgery to observe the occurrence of postoperative insulin resistance in patients.
| 2744698 | ecrin-mdr-crc
Project description:Interventions: Control group:Drink pure water before surgery;Experimental group1:Drink low-dose BCAA before surgery;Experimental group2:Drink high-dose BCAA before surgery
Primary outcome(s): Postoperative blood glucose level
Study Design: Parallel
| 2760516 | ecrin-mdr-crc
Project description:Despite technological advances in metabolomics, large parts of the human metabolome are still unexplored. In an untargeted metabolomics screen aiming to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), we identified a class of mammalian metabolites, N-lactoyl-amino acids. Using parallel protein fractionation in conjunction with shotgun proteomics on fractions containing N-lactoyl-Phe-forming activity, we unexpectedly found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. N-lactoyl-amino acids are ubiquitous pseudodipeptides of lactic acid and amino acids that are rapidly formed by reverse proteolysis, a process previously considered to be negligible in vivo. The plasma levels of these metabolites strongly correlate with plasma levels of lactate and amino acid, as shown by increased levels after physical exercise and in patients with phenylketonuria who suffer from elevated Phe levels. Our approach to identify unknown metabolites and their biosynthesis has general applicability in the further exploration of the human metabolome.
| S-EPMC4450436 | biostudies-literature
Project description:In order to assess the efficiency of photo-labeling, total HeLa cell lysates treated with photo-amino acids were subjected to proteome analysis.
2017-04-10 | PXD005346 | Pride
Project description:ObjectiveRecent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.Research design and methodsIn 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.ResultsElevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = -0.0012 [95% CI -0.0018, -0.00059], P < 0.001 for SI; β = -0.0013 [95% CI -0.0018, -0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.ConclusionsPlasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.
| S-EPMC4806771 | biostudies-literature
Project description:Amino acids (AAs) are well known to be involved in the regulation of glucose metabolism and, in particular, of insulin secretion. However, the effects of different AAs on insulin release and kinetics have not been completely elucidated. The aim of this study was to propose a mathematical model that includes the effect of AAs on insulin kinetics during a mixed meal tolerance test. To this aim, five different models were proposed and compared. Validation was performed using average data, derived from the scientific literature, regarding subjects with normal glucose tolerance (CNT) and with type 2 diabetes (T2D). From the average data of the CNT and T2D people, data for two virtual populations (100 for each group) were generated for further model validation. Among the five proposed models, a simple model including one first-order differential equation showed the best results in terms of model performance (best compromise between model structure parsimony, estimated parameters plausibility, and data fit accuracy). With regard to the contribution of AAs to insulin appearance/disappearance (kAA model parameter), model analysis of the average data from the literature yielded 0.0247 (confidence interval, CI: 0.0168 - 0.0325) and -0.0048 (CI: -0.0281 - 0.0185) μU·ml-1/(μmol·l-1·min), for CNT and T2D, respectively. This suggests a positive effect of AAs on insulin secretion in CNT, and negligible effect in T2D. In conclusion, a simple model, including single first-order differential equation, may help to describe the possible AAs effects on insulin kinetics during a physiological metabolic test, and provide parameters that can be assessed in the single individuals.
| S-EPMC9519856 | biostudies-literature
Project description:Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.
| S-EPMC4424797 | biostudies-literature
Project description:The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream, where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.
| S-EPMC5850949 | biostudies-literature