Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid

BACKGROUND: Gastric bypass surgery for weight reduction often corrects dysglycemia in diabetic patients, but a full understanding of the underlying biochemical pathways continues to be investigated. We explored the effects of weight loss by surgical and dietary interventions on plasma metabolites using both targeted and discovery-oriented metabolomics platforms. SETTING: An academic medical center in the United States. METHODS: Improvement in HOMA-IR, as an index of insulin resistance, was compared at six months in eleven patients that underwent Roux-en-Y gastric bypass (RYGB) against eleven patients that were matched for weight loss in the Weight Loss Maintenance (WLM) program. Metabolites in plasma were evaluated by non-targeted gas chromatography/mass spectrometry (GC/MS) for the potential detection of more than 1100 biochemical markers. RESULTS: Among multiple metabolites detected, 2-hydroxybutyric acid (2-HBA) declined most significantly after six months in comparing patients that underwent RYGB versus those in WLM (P < 0.001), corresponding with declines in HOMA-IR (P = 0.025). Baseline levels of 2-HBA for all patients were correlated with pre-intervention levels of HOMA-IR (R(2) = 0.565, P < 0.001). Moreover, the changes in 2-HBA after six months were correlated with changes in HOMA-IR (R(2) = 0.399, P = 0.0016). CONCLUSIONS: Correlation between insulin resistance and 2-hydroxybutyric acid suggests the utility of the latter as an excellent biomarker for tracking glycemic improvement, and offers further insight into the pathways that control diabetes. This is the first report of a decline in 2-HBA in response to bariatric surgery.