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

doi:10.1038/s41467-021-27289-2

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

Nat Commun. 2021 Nov 29;12(1):6951. doi: 10.1038/s41467-021-27289-2.

Authors

Jonathan M Dreyfuss^#^{1

2

3}, Yixing Yuchi^#^{3

4

5}, Xuehong Dong^{3

4

6}, Vissarion Efthymiou^{3

4}, Hui Pan^{1

2}, Donald C Simonson^{3

7}, Ashley Vernon^{3

8}, Florencia Halperin^{3

7

9}, Pratik Aryal^{3

10}, Anish Konkar^{11

12}, Yinong Sebastian¹¹, Brandon W Higgs^{11

13}, Joseph Grimsby^{11

14}, Cristina M Rondinone¹¹, Simon Kasif², Barbara B Kahn^{3

10}, Kathleen Foster⁴, Randy Seeley¹⁵, Allison Goldfine^{3

4

7

16}, Vera Djordjilović¹⁷, Mary Elizabeth Patti^{18

19}

Affiliations

¹ Bioinformatics and Biostatistics Core, Research Division, Joslin Diabetes Center, Boston, MA, USA.
² Biomedical Engineering, Boston University, Boston, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA.
⁵ Vertex Pharmaceuticals, Boston, MA, USA.
⁶ Department of Endocrinology, Diabetes & Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁷ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Form Health, Boston, MA, USA.
¹⁰ Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹¹ MedImmune, Gaithersburg, MD, USA.
¹² Eli Lilly and Company, Indianapolis, IN, USA.
¹³ Genmab, Plainsboro, NJ, USA.
¹⁴ AstraZeneca, Gaithersburg, MD, USA.
¹⁵ Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Novartis Institute for Biomedical Research, Cambridge, MA, USA.
¹⁷ Department of Economics, Ca' Foscari University of Venice, Venice, Italy.
¹⁸ Harvard Medical School, Boston, MA, USA. [email protected].
¹⁹ Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers / blood
Blood Glucose / metabolism
Body Mass Index
Carrier Proteins / blood
Carrier Proteins / genetics
Diabetes Mellitus, Type 2 / blood*
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / pathology
Diabetes Mellitus, Type 2 / surgery
Dipeptidases / blood
Dipeptidases / genetics
Fasting / physiology
Gastric Bypass*
Gene Expression Regulation
Glycated Hemoglobin / genetics
Glycated Hemoglobin / metabolism
Hepatocytes / metabolism
Hepatocytes / pathology
Human Growth Hormone / blood
Human Growth Hormone / genetics
Humans
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
Liver / metabolism*
Liver / pathology
Metabolome*
Obesity / blood*
Obesity / genetics
Obesity / pathology
Obesity / surgery
Primary Cell Culture
Proteome*
Rats
Retrospective Studies

Substances

Biomarkers
Blood Glucose
Carrier Proteins
Glycated Hemoglobin A
IGFBP1 protein, human
IGFBP2 protein, human
Insulin-Like Growth Factor Binding Protein 1
Insulin-Like Growth Factor Binding Protein 2
Proteome
hemoglobin A1c protein, human
Human Growth Hormone
CNDP1 protein, human
Dipeptidases
somatotropin-binding protein

Associated data

ClinicalTrials.gov/NCT01073020

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding