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

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.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00377.2020 ◽

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.

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

Clinical Chemistry ◽

10.1373/clinchem.2015.251710 ◽

2016 ◽

Vol 62 (4) ◽

pp. 582-592 ◽

Cited By ~ 91

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.

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Dietary intake of branched-chain amino acids in relation to depression, anxiety and psychological distress

Nutrition Journal ◽

10.1186/s12937-021-00670-z ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Glareh Koochakpoor ◽

Asma Salari-Moghaddam ◽

Ammar Hassanzadeh Keshteli ◽

Hamid Afshar ◽

Ahmad Esmaillzadeh ◽

...

Keyword(s):

Amino Acids ◽

Psychological Distress ◽

Dietary Intake ◽

Psychological Disorders ◽

Branched Chain Amino Acids ◽

Inverse Association ◽

Depression And Anxiety ◽

Lower Odds ◽

Significant Inverse Association ◽

Branched Chain

Abstract Background There is no previous study that examined the association between branched-chain amino acids (BCAAs) intake and odds of psychological disorders. The aim of this study was to investigate the association between dietary BCAAs and odds of psychological disorders including depression, anxiety, and psychological distress in a large sample of Iranian adults. Methods In this cross-sectional study on 3175 Iranian adults aged 18–55 years, a validated food frequency questionnaire was used to assess dietary intakes. BCAAs intake was computed by summing up the amount of valine, leucine, and isoleucine intake from all food items in the questionnaire. Psychological health was examined through the use of Iranian validated version of the Hospital Anxiety and Depression Scale (HADS). Psychological distress was assessed using General Health Questionnaire (GHQ). For depression and anxiety, scores of 8 or more on either subscale were considered as psychological disorders and scores of 0–7 were defined as “normal”. In terms of psychological distress, the score of 4 or more was defined as psychological distress. Results Mean age of study participants was 36.2 ± 7.8 years. Overall, 26.4% (n = 837) of study subjects had depression, 11.9% (n = 378) had anxiety and 20.9% (n = 665) were affected by psychological distress. After controlling for potential confounders, participants in the highest tertile of total BCAAs intake had lower odds of depression (OR: 0.76; 95% CI: 0.60–0.96) and anxiety (OR: 0.66; 95% CI: 0.47–0.91) compared with those in the lowest tertile. Participants in the top tertile of valine intake had a lower odds of depression (OR: 0.76; 95% CI: 0.60–0.96) and anxiety (OR: 0.65; 95% CI: 0.47–0.90) compared with those in the bottom tertile. A significant inverse association was also seen between leucine intake and depression (OR: 0.77; 95% CI: 0.61–0.98) and anxiety (OR: 0.66; 95% CI: 0.47–0.91). In addition, a significant inverse association was observed between isoleucine intake and odds of depression (OR: 0.75; 95% CI: 0.59–0.95) and anxiety (OR: 0.62; 95% CI: 0.45–0.86). There was no significant association between isoleucine intake and odds of psychological distress. Conclusion Evidence indicating an inverse association between dietary intake of BCAAs and odds of depression and anxiety was found. Prospective studies are required to confirm these findings.

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Branched-chain amino acids in metabolic signalling and insulin resistance

Nature Reviews Endocrinology ◽

10.1038/nrendo.2014.171 ◽

2014 ◽

Vol 10 (12) ◽

pp. 723-736 ◽

Cited By ~ 490

Author(s):

Christopher J. Lynch ◽

Sean H. Adams

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Branched Chain Amino Acids ◽

Metabolic Signalling ◽

Branched Chain

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Food consumption of branched chain amino acids and insulin resistance: A systematic review of observational studies in humans

Clinical Nutrition ESPEN ◽

10.1016/j.clnesp.2020.09.007 ◽

2020 ◽

Vol 40 ◽

pp. 277-281

Author(s):

Eduardo Emanuel Sátiro Vieira ◽

Irislene Costa Pereira ◽

Amanda Ferraz Braz ◽

Marcus Vinicius Nascimento-Ferreira ◽

Lucillia Rabelo de Oliveira Torres ◽

...

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Amino Acids ◽

Food Consumption ◽

Observational Studies ◽

Branched Chain Amino Acids ◽

Branched Chain

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Insulin resistance and the metabolism of branched-chain amino acids

Frontiers of Medicine ◽

10.1007/s11684-013-0255-5 ◽

2013 ◽

Vol 7 (1) ◽

pp. 53-59 ◽

Cited By ~ 69

Author(s):

Jingyi Lu ◽

Guoxiang Xie ◽

Weiping Jia ◽

Wei Jia

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Branched Chain Amino Acids ◽

Branched Chain

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Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y04-067 ◽

2004 ◽

Vol 82 (7) ◽

pp. 506-514 ◽

Cited By ~ 105

Author(s):

Enoka P Wijekoon ◽

Craig Skinner ◽

Margaret E Brosnan ◽

John T Brosnan

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Plasma Concentrations ◽

Branched Chain Amino Acids ◽

Insulin Resistant ◽

Branched Chain

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, α-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.Key words: plasma amino acids, liver amino acids, muscle amino acids, gluconeogenesis.

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