Fig 1 - uploaded by Albert Koulman
Content may be subject to copyright.
Design of the study. DIAGRAM, DIAbetes Genetics Replication And Meta-analysis. doi:10.1371/journal.pmed.1002179.g001
Source publication
Background
Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.
Methods and Findings
Genome-wide studies of...
Similar publications
Background
Probiotics have been reported to exhibit positive effects on host health, including improved intestinal barrier function, preventing pathogenic infection, and promoting nutrient digestion efficiency. These internal changes are reflected to the fecal microbiota composition and, bacterial metabolites production. In accordance, the applicat...
Background:
The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preser...
Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in...
Angiopoietin-like-4 (ANGPTL4), a secreted glycoprotein that is mainly known as a regulator in lipid metabolism, now, is also indicated to be involved in the regulation of cancer progression and metastasis. However, little is known about not only biological functions, but also underlying mechanism of ANGPTL4 in the progression of osteosarcoma (OS)....
Arbuscular mycorrhizal fungi (AMF) are a promising tool to improve plant nutrient use efficiency (NUE) and tolerance against abiotic stresses. Moreover, AMF can potentially increase plant productivity and reduce the negative externalities of the agricultural sector. Our study aimed to elucidate whether AMF (containing Rhizoglomus irregulare and Fun...
Citations
... BCAA levels associated with insulin resistance and T2D [75] Genome-wide study of 16,596 patients BCAA levels associated with a higher risk of T2D [76] Case-control study of 2,422 patients in the Framingham cohort BCAA levels associated with a higher risk of T2D [77] Cohort of 1,279 European and 1,007 South Asian patients BCAA levels associated with a 40% higher risk of T2D [78] TGF-β activated kinase-1/p38 mitogen-activated protein kinase (TAK1/P38MAPK); Krüppel-like factor 15 (KLF15); major adverse cardiovascular events (MACE). ...
Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic regulation via specialized signaling networks. Their association with cardiovascular diseases (CVDs) has become a focal point of scientific debate, with emerging evidence suggesting both beneficial and detrimental roles. This review aims to dissect the multifaceted relationship between BCAAs and cardiovascular health, exploring the molecular mechanisms and clinical implications. Elevated BCAA levels have also been linked to insulin resistance (IR), type 2 diabetes mellitus (T2DM), inflammation, and dyslipidemia, which are well-established risk factors for CVD. Central to these processes are key pathways such as mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB)-mediated inflammation, and oxidative stress. Additionally, the interplay between BCAA metabolism and gut microbiota, particularly the production of metabolites like trimethylamine-N-oxide (TMAO), adds another layer of complexity. Contrarily, some studies propose that BCAAs may have cardioprotective effects under certain conditions, contributing to muscle maintenance and metabolic health. This review critically evaluates the evidence, addressing the biological basis and signal transduction mechanism, and also discusses the potential for BCAAs to act as biomarkers versus active mediators of cardiovascular pathology. By presenting a balanced analysis, this review seeks to clarify the contentious roles of BCAAs in CVD, providing a foundation for future research and therapeutic strategies required because of the rising prevalence, incidence, and total burden of CVDs.
... ; https://doi.org/10.1101/2024.05.14.24307378 doi: medRxiv preprint be involved in the pathogenesis of diabetes, which might impair insulin signaling and lead to increased insulin secretion and pancreatic β -cell exhaustion 42 . Furthermore, genetic association studies have shown higher BCAAS resulting from insulin resistance, which may in turn cause diabetes 43,44 . Our study confirmed the vital role of these metabolites in the progression to diabetes among individuals with prediabetes. ...
Background: Identification of individuals with prediabetes who are at high risk of developing diabetes allows for precise interventions. We aimed to determine the role of nuclear magnetic resonance (NMR)-based metabolomic signature in predicting the progression from prediabetes to diabetes.
Methods: This prospective study included 13,489 participants with prediabetes who had metabolomic data from the UK Biobank. Circulating metabolites were quantified via NMR spectroscopy. Cox proportional hazard (CPH) models were performed to estimate the associations between metabolites and diabetes risk. Supporting vector machine, random forest, and extreme gradient boosting were used to select the optimal metabolite panel for prediction. CPH and random survival forest (RSF) models were utilized to validate the predictive ability of the metabolites.
Results: During a median follow-up of 13.6 years, 2,525 participants developed diabetes. After adjusting for covariates, 94 of 168 metabolites were associated with risk of progression to diabetes. A panel of nine metabolites, selected by all three machine learning algorithms, was found to significantly improve diabetes risk prediction beyond conventional risk factors in the CPH model (area under the receiver operating characteristic curve [AUROC], 1-year: 0.823 for risk factors + metabolites vs 0.759 for risk factors, 5-year: 0.830 vs 0.798, 10-year: 0.801 vs 0.776, all P <0.05). Similar results were observed from the RSF model. Categorization of participants according to the predicted value thresholds revealed distinct cumulative risk of diabetes.
Conclusions: Our study lends support for use of the metabolite markers to help determine individuals with prediabetes who are at high risk of progressing to diabetes and inform targeted and efficient interventions.
... 30 The PC ae C32:2 was associated with prevalent 19 and incident 20 type 2 diabetes. Although BCAAs have been causally linked with type 2 diabetes risk, 31 it remains elusive whether a causal relationship exists between changes in the valine-to-PC ae C32:2 ratio, measures of insulin resistance and the development of type 2 diabetes. Moreover, it is unknown, whether omentin directly influences levels of serine, valine and PC ae C32:2 or whether the relationship is rather indirect. ...
Introduction
Circulating omentin levels have been positively associated with insulin sensitivity. Although a role for adiponectin in this relationship has been suggested, underlying mechanisms remain elusive. In order to reveal the relationship between omentin and systemic metabolism, this study aimed to investigate associations of serum concentrations of omentin and metabolites.
Research design and methods
This study is based on 1124 participants aged 61–82 years from the population-based KORA (Cooperative Health Research in the Region of Augsburg) F4 Study, for whom both serum omentin levels and metabolite concentration profiles were available. Associations were assessed with five multivariable regression models, which were stepwise adjusted for multiple potential confounders, including age, sex, body mass index, waist-to-hip ratio, lifestyle markers (physical activity, smoking behavior and alcohol consumption), serum adiponectin levels, high-density lipoprotein cholesterol, use of lipid-lowering or anti-inflammatory medication, history of myocardial infarction and stroke, homeostasis model assessment 2 of insulin resistance, diabetes status, and use of oral glucose-lowering medication and insulin.
Results
Omentin levels significantly associated with multiple metabolites including amino acids, acylcarnitines, and lipids (eg, sphingomyelins and phosphatidylcholines (PCs)). Positive associations for several PCs, such as diacyl (PC aa C32:1) and alkyl-alkyl (PC ae C32:2), were significant in models 1–4, whereas those with hydroxytetradecenoylcarnitine (C14:1-OH) were significant in all five models. Omentin concentrations were negatively associated with several metabolite ratios, such as the valine-to-PC ae C32:2 and the serine-to-PC ae C32:2 ratios in most models.
Conclusions
Our results suggest that omentin may influence insulin sensitivity and diabetes risk by changing systemic lipid metabolism, but further mechanistic studies investigating effects of omentin on metabolism of insulin-sensitive tissues are needed.
... The genetic variants associated with plasma BCAA levels were obtained for exposure data from a metaanalysis of GWASs of 16 596 European ancestors. 23 For the reliability of the results, a parallel verification was conducted in this study. The GWAS statistics for BCAAs (valine, leucine, and isoleucine) were collected from the Medical Research Council Integrative Epidemiology Unit OpenGWAS project (https:// gwas. ...
... Six independent SNPs (P<5×10 −8 ) related to circulating BCAAs levels were selected from the GWAS metaanalysis of exposure data. 23 The studies included in the GWAS were approved by the relevant institutional review committees, and participants provided informed consent. The selection of IVs is exhibited in Data S1. ...
Background
This study aimed to investigate the causal relationships between branched‐chain amino acids (BCAAs) and the risks of hypertension via meta‐analysis and Mendelian randomization analysis.
Methods and Results
A meta‐analysis of 32 845 subjects was conducted to evaluate the relationships between BCAAs and hypertension. In Mendelian randomization analysis, independent single‐nucleotide polymorphisms associated with BCAAs at the genome‐wide significance level were selected as the instrumental variables. Meanwhile, the summary‐level data for essential hypertension and secondary hypertension end points were obtained from the FinnGen study. As suggested by the meta‐analysis results, elevated BCAA levels were associated with a higher risk of hypertension (isoleucine: summary odds ratio, 1.26 [95% CI, 1.08–1.47]; leucine: summary odds ratio, 1.28 [95% CI, 1.07–1.52]; valine: summary odds ratio, 1.32 [95% CI, 1.12–1.57]). Moreover, the inverse variance‐weighted method demonstrated that an elevated circulating isoleucine level might be the causal risk factor for essential hypertension but not secondary hypertension (essential hypertension: odds ratio, 1.22 [95% CI, 1.12–1.34]; secondary hypertension: odds ratio, 0.96 [95% CI, 0.54–1.68]).
Conclusions
The increased levels of 3 BCAAs positively correlated with an increased risk of hypertension. Particularly, elevated isoleucine level is a causal risk factor for essential hypertension. Increased levels of leucine and valine also tend to increase the risk of essential hypertension, but further verification is still warranted.
... Although the role of Bifidobacterium in BCCA metabolism remains to be determined, supplementation of Bifidobacterium plus fructooligosaccharide has been found to reduce serum levels of BCAAs in obese women 45 . Our results, together with previous observations 46 , support a potential role of BCAA metabolites in increasing risk of T2D. In addition, our MR analyses suggest a putative causal relationship between γ-glutamylvaline, a metabolite from leucine and glutamate metabolism, and T2D; but how gut microbiota, especially Bifidobacterium species, may influence circulating levels of γ-glutamylvaline is largely unknown 27 . ...
Cow’s milk is frequently included in the human diet, but the relationship between milk intake and type 2 diabetes (T2D) remains controversial. Here, using data from the Hispanic Community Health Study/Study of Latinos, we show that in both sexes, higher milk intake is associated with lower risk of T2D in lactase non-persistent (LNP) individuals (determined by a variant of the lactase LCT gene, single nucleotide polymorphism rs4988235) but not in lactase persistent individuals. We validate this finding in the UK Biobank. Further analyses reveal that among LNP individuals, higher milk intake is associated with alterations in gut microbiota (for example, enriched Bifidobacterium and reduced Prevotella) and circulating metabolites (for example, increased indolepropionate and reduced branched-chain amino acid metabolites). Many of these metabolites are related to the identified milk-associated bacteria and partially mediate the association between milk intake and T2D in LNP individuals. Our study demonstrates a protective association between milk intake and T2D among LNP individuals and a potential involvement of gut microbiota and blood metabolites in this association.
... We included 20 hematologic traits, 12 anthropometric traits, 18 body composition traits, renal function (urea), liver function (alkaline phosphatase (ALP), alanine transaminase (ALT), bilirubin and total protein), and lung function (forced expiratory volume in the first second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, peak expiratory flow (PEF), the mid-forced expiratory flow at 25-75% of the pulmonary volume (FEF 25-75%)). We also included other metrics from NMR metabolomic panel, i.e., amino acids, fatty acids, fluid balance, glycolysisrelated metabolites, inflammation, and ketone bodies as safety outcomes given some of these metabolites (e.g., branched chain amino acid) may be related to cardiometabolic diseases [21,22] (Additional file 1: Table S2). ...
Background
With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics.
Methods
A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong’s “Children of 1997” birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the “Children of 1997” birth cohort and coronary artery disease from Biobank Japan.
Results
Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], − 1.06 [− 1.52 to − 0.60]; PCSK9: − 0.93 [− 1.56 to − 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid − 0.79 [− 1.25 to − 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed.
Conclusions
Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.
... animal versus plant protein. Animal protein provides higher amounts of branched-chain amino acids compared to plant proteins, and circulating leucine, isoleucine, and valine may be risk factors for T2D [51]. Furthermore, circulating glycine was found to be associated with a higher risk of T2D; as it is abundant in animal protein, it has been considered as a potential mediator which links higher intake of red meat to T2D [52]. ...
Purpose
Protein-rich foods show heterogeneous associations with the risk of type 2 diabetes (T2D) and it remains unclear whether habitual protein intake is related to T2D risk. We carried out an umbrella review of systematic reviews (SR) of randomised trials and/or cohort studies on protein intake in relation to risks of T2D.
Methods
Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and T2D risk published between July 1st 2009 and May 22nd 2022, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria.
Results
Eight SRs were identified of which six contained meta-analyses. The majority of SRs on total protein intake had moderate or high methodological quality and moderate outcome-specific certainty of evidence according to NutriGrade, however, the latter was low for the majority of SRs on animal and plant protein. Six of the eight SRs reported risk increases with both total and animal protein. According to one SR, total protein intake in studies was ~ 21 energy percentage (%E) in the highest intake category and 15%E in the lowest intake category. Relative Risks comparing high versus low intake in most recent SRs ranged from 1.09 (two SRs, 95% CIs 1.02–1.15 and 1.06–1.13) to 1.11 (1.05–1.16) for total protein (between 8 and 12 cohort studies included) and from 1.13 (1.08–1.19) to 1.19 (two SRs, 1.11–1.28 and 1.11–1.28) (8–9 cohort studies) for animal protein. However, SRs on RCTs examining major glycaemic traits (HbA1c, fasting glucose, fasting insulin) do not support a clear biological link with T2D risk. For plant protein, some recent SRs pointed towards risk decreases and non-linear associations, however, the majority did not support an association with T2D risk.
Conclusion
Higher total protein intake was possibly associated with higher T2D risk, while there is insufficient evidence for a risk increase with higher intakes of animal protein and a risk decrease with plant protein intake. Given that most SRs on plant protein did not indicate an association, there is possibly a lack of an effect.
... The accumulation of related metabolites and branched-chain ketone acids after elevated insulin levels may lead to further insulin resistance (52). High levels of BCAA polymorphisms are linked to a high risk of type 2 diabetes, according to a Mendelian randomization study that used genes related to BCAA metabolism to evaluate the causality of an influence on insulin resistance (53). Another possible mechanism is related to the activation of mTOR. ...
Diabetic Kidney Disease (DKD) is one of the significant microvascular consequences of type 2 diabetes mellitus with a complex etiology and protracted course. In the early stages of DKD, the majority of patients experience an insidious onset and few overt clinical symptoms and indicators, but they are prone to develop end-stage renal disease in the later stage, which is life-threatening. The abnormal amino acid metabolism is tightly associated with the development of DKD, which involves several pathological processes such as oxidative stress, inflammatory response, and immune response and is also closely related to autophagy, mitochondrial dysfunction, and iron death. With a focus on taurine, branched-chain amino acids (BCAAs) and glutamine, we explored the biological effects of various amino acid mechanisms linked to DKD, the impact of amino acid metabolism in the early diagnosis of DKD, and the role of amino acid metabolism in treating DKD, to offer fresh objectives and guidelines for later early detection and DKD therapy.
... To demonstrate utility and to increase confidence in our results, we explored mediated effects of known obesity-associated genes. For this purpose, we created a catalogue of 52 genes reported for association with BMI (Supplemental Table S3) [60,61]. We screened our mediation results for these genes and selected mediations with a high mediated effect proportion (PM ≥ 0.2). ...
... We retrieved 51 such genes from Srivastava et al. [61]. Additionally, we included one gene that was both genetically associated to metabolites (BCAA) and T2D, namely PPM1K [60]. In our meta-analysis, we detected 87 associated metabolite-transcript pairs of 27 catalogue genes with 32 metabolites. ...
Investigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC–MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases.
Key messages
Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations.
A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs.
Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms.
... Previous MR studies have shown branchchained amino acids (BCAAs), including leucine, isoleucine and valine, may increase T2D risk whereas alanine and tyrosine, an aromatic amino acid, may decrease T2D. [8][9][10] However, these MR studies may be flawed due to the use of limited number of instruments derived from small genome wide association studies (GWAS) of amino acids, 11 12 and the use of a single instrument (e.g. variants in protein phosphatase Mg 2+ /Mn 2+ dependent 1K [PPM1K] locus) to estimate the causal relationship between multiple amino acids and T2D and hence constitute horizontal pleiotropy. ...
... To the best of our knowledge, this is one of the first MR studies which comprehensively assessed the role of nine amino acids in T2D risk and glycemic traits using respective large genetic consortia where earlier MR studies have only investigated BCAAs and tyrosine, and may suffer from methodological issues such as the use of smaller amino acid GWAS, the use of a single variant for investigation of multiple BCAAs. [8][9][10] We showed, for the first-time using MR, that alanine likely increases T2D risk, and hence confirmed the positive findings in previous observational studies. [31][32][33] Consistent with previous studies, our study showed that isoleucine (one of the BCAAs) likely increases T2D risk. ...
... 41 The positive association of BCAAs with T2D risk was well studied in observational studies. 3 35 41 42 With the inclusion of more genetic instruments, our study clarified that amongst the BCAAs, isoleucine may be more relevant to the development of T2D, consistent with findings from various analyses and data sources, 9 although it is noted that the association did not pass correction for multiple testing and hence requires replications. Nevertheless, previous studies suggested that BCAAs could lead to persistent mammalian target of rapamycin complex 1 (mTORC1) activation, causing insulin resistance. ...
Background: Previous observational and Mendelian randomization studies suggested different amino acids associated with type 2 diabetes (T2D). However, these studies may suffer from confounding or the use of invalid instruments, respectively.
Methods: We extracted strong (p < 5 x 10-8), independent (r2 < 0.001) genetic variants associated with nine amino acids (alanine, glutamine, glycine, histidine, phenylalanine, tyrosine, isoleucine, leucine, and valine) from summary statistics of UK Biobank (N =< 115,075), with exclusion of potentially pleiotropic variants. We then applied them to T2D summary statistics from DIAMANTE Consortium (without UK Biobank participants) (N = 455,313) and FinnGen study (N = 365,950), and glycemic traits (MAGIC consortium, N =< 209,605). Inverse variance weighed (IVW) method was the main analysis, with multiple sensitivity analyses to assess robustness of findings.
Results: Alanine was associated with higher T2D risk, correcting for multiple testing (Odds Ratio (OR) 1.50 per SD; 95% CI 1.16 to 1.95). At nominal significance, isoleucine was associated with higher T2D risk (OR 1.13; 95% CI 1.00 to 1.27) and tyrosine was associated with lower T2D risk (OR 0.89; 95% CI 0.80 to 0.99). Alanine was also associated with lower insulin, higher glycated hemoglobin and glucose whereas isoleucine and leucine were associated with lower insulin. These associations were consistent in most sensitivity analyses.
Conclusion: Alaine likely contributed to higher T2D risk whilst the associations for isoleucine and tyrosine requires further verification. Whether these findings explain health effects of sources of amino acids, such as diet, should be further explored.
