Metabolomic Fingerprints of Medical Therapy vs. Bariatric Surgery in Patients with Obesity and Type 2 Diabetes: The STAMPEDE Trial

Abstract

<p dir="ltr">OBJECTIVE</p><p dir="ltr">Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective procedures to treat and manage type 2 diabetes (T2D). However, the underlying metabolic adaptations that mediate improvements in glucose homeostasis remain largely elusive. The purpose of this study was to identify metabolic signatures associated with biochemical resolution of T2D following medical therapy (MT) or bariatric surgery. </p><p dir="ltr">RESEARCH DESIGN AND METHODS</p><p dir="ltr">Plasma samples from ninety patients (49.9±7.6 years, 57.7% female) randomly assigned to MT (n=30), RYGB (n=30) or SG (n=30) were retrospectively subjected to untargeted metabolomic analysis using UPLC-tandem mass spectrometry at baseline and 24 months of treatment. Phenotypic importance was determined by supervised machine learning. Associations between change in glucose homeostasis and circulating metabolites was assessed by a linear mixed effects model. </p><p dir="ltr">RESULTS</p><p dir="ltr">The circulating metabolome was dramatically remodeled after SG and RYGB, with largely overlapping signatures after MT. Compared to MT, SG and RYGB profoundly enhanced the concentration of metabolites associated with lipid and amino acid signaling, while limiting xenobiotic metabolites, a function of decreased medication usage. Random forest analysis revealed 2-hydroxydecanoate as having selective importance to RYGB and as the most distinguishing feature between MT, SG, and RYGB. To this end, change in 2-hydroxydecanoate correlated with reductions in fasting glucose after RYGB but not SG or MT. </p><p dir="ltr">CONCLUSIONS</p><p dir="ltr">We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to MT, RYGB, and SG. Notably, the metabolomic profile of both RYGB and SG procedures were distinct, indicating equivalent weight loss may be achieved by divergent effects on metabolism.</p>