Bariatric surgery has emerged as a potent approach to improve obesity-related metabolic comorbidities including type 2 diabetes (T2D). However, molecular mechanisms responsible for metabolic improvement after bariatric surgery remain incompletely understood. We profiled and integrated the fasting plasma proteome (aptamer-based Somalogic platform) and metabolome (MS, Metabolon) from patients with T2D at baseline and up to 3 years after randomization to either gastric bypass (GB) or nonsurgical diabetes/weight management (DMW) within the SLIMM-T2D longitudinal clinical trial (random subset, n=19 per group). To identify top-ranking pathways encompassing both proteomic and metabolomic data, we developed a systems approach employing two interdependent programs: ezlimma (for differential analysis) and Pathway Analysis via Network Smoothing (PANTS). PANTS smooths differential statistics over a large network of interacting proteins/metabolites, calculating significance by permutation. Top-ranking pathways were phospholipid (e.g., choline), retinol (e.g., retinol-binding protein 4, RBP4), and histidine metabolism (e.g., carnosine dipeptidase 1, CNDP1). Quantitative Western blot confirmed 26% reduction in RBP4 in GB vs. DWM; ELISA confirmed 66% reduction in CNDP1 in GB vs. DWM (both p<0.05, 3 months). CNDP1 change at 3 months was associated with improved metabolism at 1 year (BMI r=0.67, p<10-5; HbA1c r=0.61, p<10-4). Causal inference analysis in the entire cohort identified CNDP1 change at 3 months as the most likely protein to cause improved HbA1c at 1 year (p=0.01). Decreased CNDP1 occurred before significant weight loss, suggesting weight-independent impact on glycemia. Investigating modulation of CNDP1 activity, its enzymatic products Ala/His, and related metabolites will be important to determine if these pathways may serve as targets for T2D therapy.
J. Dreyfuss: None. Y. Yuchi: None. H. Pan: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A.H. Vernon: None. P. Aryal: None. B. Kahn: Advisory Panel; Self; Janssen Research & Development. Research Support; Self; Janssen Research & Development. Advisory Panel; Self; Alterna Biotech. K. Foster: None. S. Kasif: None. A. Goldfine: Employee; Self; Novartis AG. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.