title: Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss.
abstract: OBJECTIVE
  Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss.
  
  
  METHODS
  Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, β-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n = 22).
  
  
  RESULTS
  Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was -0.80 ± 1.73, range -28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r = 0.50, p < 0.0001) and independently associated with ∆HOMA-IR (p < 0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (r = 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (p = 0.007).
  
  
  CONCLUSIONS
  A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.
authors: Department of Medicine, DUMC, Duke University Medical Center, Box 3445, Durham, NC 27710, USA. svati.shah@duke.edu
authors: S H
authors: SH
authors: Shah
authors: D R
authors: DR
authors: Crosslin
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authors: CS
authors: Haynes
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authors: Nelson
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authors: Turer
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authors: Laferrère
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authors: Teixeira
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authors: Brantley
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authors: Stevens
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authors: Hollis
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authors: Appel
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authors: Lien
authors: B
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authors: Batch
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authors: Newgard
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authors: Svetkey
mesh_terms: D000328:Adult; D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D000597:Amino Acids, Branched-Chain / Q000737:chemistry*; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D001835:Body Weight; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D025341:Principal Component Analysis; D015431:Weight Loss
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D015415:Biomarkers