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

Jonathan M. Dreyfuss, Yixing Yuchi, Xuehong Dong, Vissarion Efthymiou, Hui Pan, Donald C. Simonson, Ashley Vernon, Florencia Halperin, Pratik Aryal, Anish Konkar, Yinong Sebastian, Brandon W. Higgs, Joseph Grimsby, Cristina M. Rondinone, Simon Kasif, Barbara B. Kahn, Kathleen Foster, Randy Seeley, Allison Goldfine, Vera Djordjilović and Mary Elizabeth Patti ()
Additional contact information
Jonathan M. Dreyfuss: Joslin Diabetes Center
Yixing Yuchi: Harvard Medical School
Xuehong Dong: Harvard Medical School
Vissarion Efthymiou: Harvard Medical School
Hui Pan: Joslin Diabetes Center
Donald C. Simonson: Harvard Medical School
Ashley Vernon: Harvard Medical School
Florencia Halperin: Harvard Medical School
Pratik Aryal: Harvard Medical School
Anish Konkar: MedImmune
Yinong Sebastian: MedImmune
Brandon W. Higgs: MedImmune
Joseph Grimsby: MedImmune
Cristina M. Rondinone: MedImmune
Simon Kasif: Boston University
Barbara B. Kahn: Harvard Medical School
Kathleen Foster: Joslin Diabetes Center
Randy Seeley: University of Michigan
Allison Goldfine: Harvard Medical School
Vera Djordjilović: Ca’ Foscari University of Venice
Mary Elizabeth Patti: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27289-2

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