scholarly journals Exploring mechanistic links between extracellular branched-chain amino acids and muscle insulin resistance: an in vitro approach

2020 ◽  
Vol 319 (6) ◽  
pp. C1151-C1157
Author(s):  
Hannah Crossland ◽  
Kenneth Smith ◽  
Iskandar Idris ◽  
Bethan E. Phillips ◽  
Philip J. Atherton ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Insulin Signaling ◽  
Prolonged Exposure ◽  
Glycogen Synthesis ◽  
Branched Chain Amino Acids ◽  
Increased Risk ◽  
Impaired Insulin ◽  
Branched Chain

Branched-chain amino acids (BCAAs) are essential for critical metabolic processes; however, recent studies have associated elevated plasma BCAA levels with increased risk of insulin resistance. Using skeletal muscle cells, we aimed to determine whether continued exposure of high extracellular BCAA would result in impaired insulin signaling and whether the compound sodium phenylbutyrate (PB), which induces BCAA metabolism, would lower extracellular BCAA, thereby alleviating their potentially inhibitory effects on insulin-mediated signaling. Prolonged exposure of elevated BCAA to cells resulted in impaired insulin receptor substrate 1/AKT signaling and insulin-stimulated glycogen synthesis. PB significantly reduced media BCAA and branched-chain keto acid concentrations and increased phosphorylation of AKT [+2.0 ± 0.1-fold; P < 0.001 versus without (−)PB] and AS160 (+3.2 ± 0.2-fold; P < 0.001 versus −PB); however, insulin-stimulated glycogen synthesis was further reduced upon PB treatment. Continued exposure of high BCAA resulted in impaired intracellular insulin signaling and glycogen synthesis, and while forcing BCAA catabolism using PB resulted in increases in proteins important for regulating glucose uptake, PB did not prevent the impairments in glycogen synthesis with BCAA exposure.

High dietary intake of branched-chain amino acids is associated with an increased risk of insulin resistance in adults

2018 ◽  
Vol 10 (5) ◽  
pp. 357-364 ◽  
Author(s):  
Golaleh Asghari ◽  
Hossein Farhadnejad ◽  
Farshad Teymoori ◽  
Parvin Mirmiran ◽  
Maryam Tohidi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Dietary Intake ◽  
Branched Chain Amino Acids ◽  
Increased Risk ◽  
High Dietary Intake ◽  
Branched Chain

scholarly journals The impact of persistent milk consumption in the pathogenesis of type 2 diabetes mellitus

2019 ◽  
Vol 9 (10) ◽  
pp. 629
Author(s):  
Bodo Melnik
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Type 2 Diabetes Mellitus ◽  
Branched Chain Amino Acids ◽  
Milk Consumption ◽  
Increased Risk ◽  
Branched Chain

Background: Milk and sugar are excessively consumed in a Western diet. There is increasing epidemiological evidence that the intake of unfermented pasteurized cow´s milk is associated with an increased risk of type 2 diabetes mellitus (T2D). It is the intention of this review to provide translational biochemical evidence for milk´s diabetogenic mode of action. Milk proteins provide the highest amounts of branched-chain amino acids (BCAAs) and thus contribute to total BCAA intake, which enhances BCAA plasma levels associated with increased risk of T2D. The consumption of pasteurized milk raises plasma levels of miRNA-29b, which is a diabetogenic miRNA promoting insulin resistance (IR). miRNA29b inhibits the activity of branched-chain-keta acid dehydrogenase, the rate limiting enzyme of BCAA catabolism, which is impaired in patients with IR and T2D. Milk consumption stimulates mTORC1 activity and increases insulin synthesis. -cell mTORC1 is overactivated in T2D patients resulting in impaired autophagy which enhances endoplasmic reticulum (ER) stress associated with a greater risk of early -cell apoptosis, the pathogenic hallmark of T2D. Chronic insulinotropic action of milk-derived BCAAs, IR-promoting mTORC1 overactivity, and miRNA-29b signaling combined with excessive glucose-mediated insulin secretion overburden -cell insulin homeostasis. Epidemiological and translational evidence identifies continued milk intake as a promoter of T2D, the most common metabolic disease of Western civilization. Keywords: Branched-chain amino acids, branched-chain-keto acid dehydrogenase, diabetes mellitus type 2, insulin resistance, milk, miRNA-29b, mechanistic target of rapamycin complex 1.

scholarly journals Impact of Branched Chain Amino Acids on Mitochondrial Metabolism and Insulin Signaling in Mouse Hepatocytes (P08-111-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Meghan Maguire ◽  
Chaitra Surugihalli ◽  
Azuri Hughes ◽  
Nishanth Sunny
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Lipid Metabolism ◽  
Mitochondrial Function ◽  
Insulin Signaling ◽  
Branched Chain Amino Acids ◽  
Turnover Rates ◽  
Alcoholic Fatty Liver ◽  
Gene And Protein Expression ◽  
Branched Chain

Abstract Objectives Plasma branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) are elevated during insulin resistance and are robust predictors of future onset of type 2 diabetes mellitus (T2DM). Further, recent evidence points to a significant cross talk between BCAAs and lipid metabolism, which is disrupted during lipid metabolic disorders. Indeed, dysfunctional mitochondrial lipid metabolism is a central feature of non-alcoholic fatty liver disease (NAFLD). Considering the metabolic and molecular mechanisms of BCAA action on central metabolic pathways, we hypothesized that excess BCAAs during insulin resistance can interfere with mitochondrial function, by altering lipid oxidation, gluconeogenesis, and insulin signaling in the liver. Methods Mice (C57BL/6) were either fed a control (10% kcal from fat) or high fat (HF; 60% kcal from fat) diet for 16 weeks. Mice were then overnight fasted and challenged with either a saline or BCAA infusion (15.59 µmole/hour) for 8-hrs. Glucose and ketone turnover rates were determined from the dilution of [13C6]glucose and [13C4]3-hydroxybutyrate tracers. Plasma and tissues were collected and stored for metabolic profiling and gene and protein expression analysis. Results Infusion of BCAAs in mice resulted in a 2-fold elevation of circulating BCAAs (Control 179 ± 7 µM vs. 375 ± 21 µM, P < 0.01, HF 119 ± 4 µM vs. 265 ± 13 µM, P < 0.01). Elevated levels of BCAAs in circulation were associated with an increase in blood glucose levels in control mice (108 ± 7 µM vs. 127 ± 7 µM, p = 0.09). However, this response was absent in HF-fed mice (152 ± 7 µM vs. 155 ± 10 µM, P = 0.85). Surprisingly, ketone turnover rates (µmoles/min) were significantly reduced with BCAA infusion in the control mice (2.5 ± 0.2 vs. 1.6 ± 0.1, P < 0.01), but remained unchanged with BCAA infusion in HF-fed mice (1.9 ± 0.3 vs. 2.0 ± 0.3). The infusion of BCAAs also induced the phosphorylation of Akt in control mice (P < 0.01), but this effect was blunted in HF-fed mice. Conclusions Our results suggest that excess BCAAs can modulate hepatic mitochondrial function and insulin signaling. Chronic exposure to elevated levels of circulating BCAAs could exacerbate metabolic dysfunction during NAFLD by altering normal hepatic mitochondrial function. Funding Sources National Institutes of Health R01.

scholarly journals Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial

2016 ◽  
Vol 62 (4) ◽  
pp. 582-592 ◽  
Author(s):  
Miguel Ruiz-Canela ◽  
Estefania Toledo ◽  
Clary B Clish ◽  
Adela Hruby ◽  
Liming Liang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Amino Acids ◽  
Cardiovascular Death ◽  
Branched Chain Amino Acids ◽  
Control Group ◽  
Cvd Risk ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Branched Chain

Abstract BACKGROUND The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05–2.76) and 2.09 (1.27–3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.

Branched chain amino Acids as in vitro and in vivo Anti-Oxidation Compounds

2021 ◽  
pp. 3899-3904
Author(s):  
Moath Alqaraleh ◽  
Violet Kasabri ◽  
Ibrahim Al-Majali ◽  
Nihad Al-Othman ◽  
Nihad Al-Othman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Amino Acids ◽  
Branched Chain Amino Acids ◽  
Raw 264.7 ◽  
Raw 264.7 Cell ◽  
Branched Chain ◽  
Raw 264.7 Cell Line

Background and aims: Branched chain amino acids (BCAAs) can be tightly connected to metabolism syndrome (MetS) which can be counted as a metabolic indicator in the case of insulin resistance (IR). The aim of this study was to assess the potential role of these acids under oxidative stress. Material and Methods: the in vitro antioxidant activity of BCAAs was assessed using free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) scavenging assays. For further check, a qRT-PCR technique was madefor detection the extent of alterations in gene expression of antioxidative enzymes (catalase and glutathione peroxidase (Gpx)) in lipopolysaccharides (LPS(-induced macrophages RAW 264.7 cell line. Additionally, BCAAs antioxidant activity was evaluated based on plasma H2O2 levels and xanthine oxidase (XO) activity in prooxidative LPS-treated mice. Results: Different concentrations of BCAAs affected on DPPH radical scavenging activity but to lesser extent than the ascorbic acid. Besides, BCAAs obviously upregulated the gene expression levels of catalases and Gpx in LPS-modulated macrophage RAW 264.7 cell line. In vivo BCAAs significantly minimized the level of plasma H2O2 as well as the activity of XO activity under oxidative stress. Conclusion: our current findings suggest that BCAAs supplementation may potentially serve as a therapeutic target for treatment of oxidative stress occurs with atherosclerosis, IR-diabetes, MetS and tumorigenesis.

A1151 EFFECT OF BRANCHED CHAIN AMINO ACIDS (BCAA) ON DIAPHRAGM FATIGUE IN VITRO

1990 ◽  
Vol 73 (3A) ◽  
pp. NA-NA
Author(s):  
H. Yamada ◽  
Y. Ohta ◽  
I. Chaudhry ◽  
H. Nagashima ◽  
J. Askanazi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Branched Chain Amino Acids ◽  
Branched Chain ◽  
Diaphragm Fatigue

scholarly journals Molecular Mechanisms Underlying the Positive Stringent Response of the Bacillus subtilis ilv-leu Operon, Involved in the Biosynthesis of Branched-Chain Amino Acids

2008 ◽  
Vol 190 (18) ◽  
pp. 6134-6147 ◽  
Author(s):  
Shigeo Tojo ◽  
Takenori Satomura ◽  
Kanako Kumamoto ◽  
Kazutake Hirooka ◽  
Yasutaro Fujita
Keyword(s):  
Amino Acids ◽  
Bacillus Subtilis ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Stringent Response ◽  
Branched Chain Amino Acids ◽  
Base Substitution ◽  
Branched Chain

ABSTRACT Branched-chain amino acids are the most abundant amino acids in proteins. The Bacillus subtilis ilv-leu operon is involved in the biosynthesis of branched-chain amino acids. This operon exhibits a RelA-dependent positive stringent response to amino acid starvation. We investigated this positive stringent response upon lysine starvation as well as decoyinine treatment. Deletion analysis involving various lacZ fusions revealed two molecular mechanisms underlying the positive stringent response of ilv-leu, i.e., CodY-dependent and -independent mechanisms. The former is most likely triggered by the decrease in the in vivo concentration of GTP upon lysine starvation, GTP being a corepressor of the CodY protein. So, the GTP decrease derepressed ilv-leu expression through detachment of the CodY protein from its cis elements upstream of the ilv-leu promoter. By means of base substitution and in vitro transcription analyses, the latter (CodY-independent) mechanism was found to comprise the modulation of the transcription initiation frequency, which likely depends on fluctuation of the in vivo RNA polymerase substrate concentrations after stringent treatment, and to involve at least the base species of adenine at the 5′ end of the ilv-leu transcript. As discussed, this mechanism is presumably distinct from that for B. subtilis rrn operons, which involves changes in the in vivo concentration of the initiating GTP.

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