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

Jonathan M Dreyfuss ,Yinong Sebastian ,Florencia Halperin ,Allison B Goldfine ,Brandon W Higgs ,Donald C Simonson ,Pei Hui ,Barbara B Kahn ,Cristina M Rondinone ,Kathleen Foster ,Ashley H Vernon ,Joseph Grimsby ,Xuehong Dong ,Simon Kasif ,Vera Djordjilović ,Yixing Yuchi ,Randy J Seeley ,Anish Konkar ,Vissarion Efthymiou ,Pratik Aryal ,Mary Elizabeth Patti

doi:10.1038/s41467-021-27289-2

Abstract

To 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.

Highlights

To improve the power of mediation in high-throughput studies, here we introduce Highthroughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling
Metabolic characteristics of these 35 participants did not differ between groups at baseline (Supplementary Data 1), and HbA1c and BMI of those with proteomics or metabolomics measurements did not differ from the SLIMM-T2D participants within their group at any time point (Supplementary Fig. 1)
Weight-dependent changes included decreases in insulin, leptin, proinflammatory proteins, amino acids, and lipidrelated metabolites; these changes are consistent with improved insulin sensitivity, loss of adipose mass, and reductions in inflammation observed in prior studies of RYGB9,10,48,49

Summary

Introduction

To improve the power of mediation in high-throughput studies, here we introduce Highthroughput 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. To identify mediators of metabolic improvement after surgical vs medical therapy for T2D, we perform a retrospective exploratory analysis of the SLIMM-T2D trial, in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes weight management (DWM), and fasting plasma proteome and metabolome were assayed up to 3 years. The joint significance method was shown to control its false-positive rate in theory and to be more powerful than the commonly-used product significance method for mediation[25] Another popular mediation test not included in these comparative simulations is based on the potential outcomes framework[26]. We identify and validate the growth hormone receptor (GHR) as a mediator of the metabolic impact of RYGB (Fig. 1)

Methods

Results

Conclusion