High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

Author:

Dreyfuss Jonathan M.ORCID,Yuchi YixingORCID,Dong Xuehong,Efthymiou VissarionORCID,Pan HuiORCID,Simonson Donald C.ORCID,Vernon Ashley,Halperin Florencia,Aryal PratikORCID,Konkar Anish,Sebastian Yinong,Higgs Brandon W.,Grimsby Joseph,Rondinone Cristina M.,Kasif SimonORCID,Kahn Barbara B.ORCID,Foster Kathleen,Seeley RandyORCID,Goldfine AllisonORCID,Djordjilović VeraORCID,Patti Mary ElizabethORCID

Abstract

AbstractTo improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.

Funder

MedImmune

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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