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

Author

Listed:
  • Jonathan M. Dreyfuss

    (Joslin Diabetes Center
    Boston University
    Harvard Medical School)

  • Yixing Yuchi

    (Harvard Medical School
    Joslin Diabetes Center
    Vertex Pharmaceuticals)

  • Xuehong Dong

    (Harvard Medical School
    Joslin Diabetes Center
    Zhejiang University School of Medicine)

  • Vissarion Efthymiou

    (Harvard Medical School
    Joslin Diabetes Center)

  • Hui Pan

    (Joslin Diabetes Center
    Boston University)

  • Donald C. Simonson

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Ashley Vernon

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Florencia Halperin

    (Harvard Medical School
    Brigham and Women’s Hospital
    Form Health)

  • Pratik Aryal

    (Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Anish Konkar

    (MedImmune
    Eli Lilly and Company)

  • Yinong Sebastian

    (MedImmune)

  • Brandon W. Higgs

    (MedImmune
    Genmab)

  • Joseph Grimsby

    (MedImmune
    AstraZeneca)

  • Cristina M. Rondinone

    (MedImmune)

  • Simon Kasif

    (Boston University)

  • Barbara B. Kahn

    (Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Kathleen Foster

    (Joslin Diabetes Center)

  • Randy Seeley

    (University of Michigan)

  • Allison Goldfine

    (Harvard Medical School
    Joslin Diabetes Center
    Brigham and Women’s Hospital
    Novartis Institute for Biomedical Research)

  • Vera Djordjilović

    (Ca’ Foscari University of Venice)

  • Mary Elizabeth Patti

    (Harvard Medical School
    Joslin Diabetes Center)

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.

Suggested Citation

  • 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 , 2021. "High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27289-2
    DOI: 10.1038/s41467-021-27289-2
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    Cited by:

    1. Hirofumi Nagao & Ashok Kumar Jayavelu & Weikang Cai & Hui Pan & Jonathan M. Dreyfuss & Thiago M. Batista & Bruna B. Brandão & Matthias Mann & C. Ronald Kahn, 2023. "Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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