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

• Published in: Nature communications 2021-11, Vol.12 (1), p.6951-6951, Article 6951
• Main Authors: Dreyfuss, Jonathan M., Yuchi, Yixing, Dong, Xuehong, Efthymiou, Vissarion, Pan, Hui, Simonson, Donald C., Vernon, Ashley, Halperin, Florencia, Aryal, Pratik, Konkar, Anish, Sebastian, Yinong, Higgs, Brandon W., Grimsby, Joseph, Rondinone, Cristina M., Kasif, Simon, Kahn, Barbara B., Foster, Kathleen, Seeley, Randy, Goldfine, Allison, Djordjilović, Vera, Patti, Mary Elizabeth
• Format: Article
• Language: English
• Subjects: 631/114/2415; 692/163/2743/137/773; 82/80; Animals; Bayesian analysis; Biomarkers - blood; Blood glucose; Blood Glucose - metabolism; Body Mass Index; Carrier Proteins - blood; Carrier Proteins - genetics; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - surgery; Dipeptidases - blood; Dipeptidases - genetics; Disease control; Empirical analysis; Fasting - physiology; Gastric Bypass; Gastrointestinal surgery; Gene expression; Gene Expression Regulation; Glucose; Glycated Hemoglobin - genetics; Glycated Hemoglobin - metabolism; Growth factors; Growth hormones; Heart surgery; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Homeostasis; Human Growth Hormone - blood; Human Growth Hormone - genetics; Humanities and Social Sciences; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1 - blood; Insulin-Like Growth Factor Binding Protein 1 - genetics; Insulin-Like Growth Factor Binding Protein 2 - blood; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-like growth factor-binding protein 1; Liver - metabolism; Liver - pathology; Metabolome; multidisciplinary; Obesity - blood; Obesity - genetics; Obesity - pathology; Obesity - surgery; Physical growth; Primary Cell Culture; Proteome; Proteomes; Rats; Receptors; Retrospective Studies; Science; Science (multidisciplinary); Surgery
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27289-2

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. Factors underlying the effects of gastric bypass surgery on glucose homeostasis are incompletely understood. Here the authors developed and applied high-throughput mediation analysis to identify proteome/metabolome mediators of improved glucose homeostasis after to gastric bypass surgery, and report that improved glycemia was mediated by the growth hormone receptor.