Dataset Information

5-Aminovaleric acid betaine predicts impaired glucose metabolism and diabetes.

ABSTRACT:

Background

5-Aminovaleric acid betaine (5-AVAB) has recently been identified as a diet and microbial-dependent factor inducing obesity and hepatic steatosis in mice fed a Western diet. Accumulating evidence suggests a role in metabolic dysfunction associated with obesity, diabetes, and fatty liver disease. However, whether 5-AVAB plays a role in human disease is unclear, and human data are sparse.

Methods

We measured circulating 5-AVAB serum levels in 143 individuals with overweight or obesity participating in a randomized intervention study (NCT00850629) investigating the long-term effect of a weight maintenance strategy after diet-induced weight reduction.

Results

Higher 5-AVAB serum levels correlate with worse estimates of obesity, glucose metabolism, and hepatic steatosis after weight loss. Furthermore, higher 5-AVAB levels after weight loss independently predict detrimental changes in glucose metabolism 18 months after the successful weight reduction.

Conclusion

Our human data supports previous findings in rodents indicating a relevant, potentially disadvantageous function of 5-AVAB in the context of metabolic dysbalance.

SUBMITTER: Haberbosch L

PROVIDER: S-EPMC10511423 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

5-Aminovaleric acid betaine predicts impaired glucose metabolism and diabetes.

Haberbosch Linus L Kierszniowska Sylwia S Willmitzer Lothar L Mai Knut K Spranger Joachim J Maurer Lukas L

Nutrition & diabetes 20230920 1

<h4>Background</h4>5-Aminovaleric acid betaine (5-AVAB) has recently been identified as a diet and microbial-dependent factor inducing obesity and hepatic steatosis in mice fed a Western diet. Accumulating evidence suggests a role in metabolic dysfunction associated with obesity, diabetes, and fatty liver disease. However, whether 5-AVAB plays a role in human disease is unclear, and human data are sparse.<h4>Methods</h4>We measured circulating 5-AVAB serum levels in 143 individuals with overweig ...[more]

PMID: 37730732

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Project description:BackgroundPer- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown.ObjectiveThe aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults.MethodsA total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated.ResultsHigher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006).ConclusionsIncreased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.

Project description:Aims/hypothesisIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified.MethodsPlasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation.ResultsImpairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37-56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes.Conclusions/interpretationMetabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent.

Dataset Information

5-Aminovaleric acid betaine predicts impaired glucose metabolism and diabetes.

Background

Methods

Results

Conclusion

Publications

5-Aminovaleric acid betaine predicts impaired glucose metabolism and diabetes.

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