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, Mary Elizabeth Patti, 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, Mary Elizabeth Patti
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.
Conflict of interest statement
For the parent study (SLIMM-T2D) from which samples were derived for analysis in the current study, D.S., A.V., F.H., and A.B.G. received unrestricted funding from the Herbert Graetz Fund and from Covidien, to support surgical procedures for research participants with BMI 30-35 (not covered by insurance). Some supplies for the SLIMM-T2D clinical study were received from Lifescan, a division of Johnson and Johnson, Nestle Inc, and Novo Nordisk. M.E.P. received unrestricted investigator-initiated research grant funding from Medimmune to support the present work, and funding to support assay costs from SomaLogic. ABG served on advisory boards for Baranova, and Kowa. DCS received funds from PCORI and is a stock/shareholder of GI Windows. A.K., B.H., C.M.R., J.G., and Y.S. were employees of Medimmune when the work was initiated. Y.Y. is now employed at Vertex, F.H. at Form Health, A.K. at Sanofi, B.H. at Immunocore, J.G. at AstraZeneca, and A.B.G. at Novartis Institutes of Biomedical Research. All other authors declare no competing interests.
© 2021. The Author(s).
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