Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes

Evgenia Gourgari; Kristen J. Nadeau; Laura Pyle; Martin P. Playford; Junfeng Ma; Nehal N. Mehta; Alan T. Remaley; Scott M. Gordon

doi:10.1002/edm2.261

Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes

Evgenia Gourgari, Kristen J. Nadeau, Laura Pyle, Martin P. Playford, Junfeng Ma, Nehal N. Mehta, Alan T. Remaley, Scott M. Gordon

Physiology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown. Objective: To determine the effect of metformin on the HDL proteome. Subjects: Youth (12–20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5. Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined. Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p =.0058) and alpha-2-macroglobulin (A2MG; +29.8%, p =.049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC. Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.

Original language	English
Article number	e00261
Journal	Endocrinology, Diabetes and Metabolism
Volume	4
Issue number	3
DOIs	https://doi.org/10.1002/edm2.261
State	Published - Jul 2021

Bibliographical note

Funding Information:
This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, “Re‐Engineering the Clinical Research Enterprise” (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D‐Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation.

Funding Information:
This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, ?Re-Engineering the Clinical Research Enterprise? (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D-Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation. The authors are grateful to the T1D Exchange Biobank and the participants who provide their time and effort in contributing critical research information. Without participant assistance, this research would not be possible. The T1D Exchange is the source of samples and data for this study, however, the individual authors are solely responsible for the analyses, content and conclusions presented as these have not been reviewed or approved by the T1D Exchange.

Publisher Copyright:
© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

Keywords

cholesterol efflux
high-density lipoprotein
metformin
proteomics
type 1 diabetes

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/edm2.261

Cite this

@article{d4c8a80c0bcc40a08fe0251e853edd29,

title = "Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes",

abstract = "Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown. Objective: To determine the effect of metformin on the HDL proteome. Subjects: Youth (12–20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5. Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined. Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p =.0058) and alpha-2-macroglobulin (A2MG; +29.8%, p =.049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC. Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.",

keywords = "cholesterol efflux, high-density lipoprotein, metformin, proteomics, type 1 diabetes",

author = "Evgenia Gourgari and Nadeau, {Kristen J.} and Laura Pyle and Playford, {Martin P.} and Junfeng Ma and Mehta, {Nehal N.} and Remaley, {Alan T.} and Gordon, {Scott M.}",

note = "Funding Information: This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, “Re‐Engineering the Clinical Research Enterprise” (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D‐Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation. Funding Information: This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, ?Re-Engineering the Clinical Research Enterprise? (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D-Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation. The authors are grateful to the T1D Exchange Biobank and the participants who provide their time and effort in contributing critical research information. Without participant assistance, this research would not be possible. The T1D Exchange is the source of samples and data for this study, however, the individual authors are solely responsible for the analyses, content and conclusions presented as these have not been reviewed or approved by the T1D Exchange. Publisher Copyright: {\textcopyright} 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.",

year = "2021",

month = jul,

doi = "10.1002/edm2.261",

language = "English",

volume = "4",

number = "3",

}

TY - JOUR

T1 - Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes

AU - Gourgari, Evgenia

AU - Nadeau, Kristen J.

AU - Pyle, Laura

AU - Playford, Martin P.

AU - Ma, Junfeng

AU - Mehta, Nehal N.

AU - Remaley, Alan T.

AU - Gordon, Scott M.

N1 - Funding Information: This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, “Re‐Engineering the Clinical Research Enterprise” (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D‐Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation. Funding Information: This project has been funded in part with Federal funds (UL1TR001409, Georgetown University) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, ?Re-Engineering the Clinical Research Enterprise? (KL2 Award and CTSA pilot award to EG), by the National Heart Lung Blood Institute (NHLBI) Intramural Research Program (ATR), and by NHLBI Career Transition Award K22HL141299 (SMG). The Proteomics Shared Resource is partially supported by NIH/NCI grant P30 CA051008. The content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. The T1D-Metformin RCT trial was done with funding provided by the Juvenile Diabetes Research Foundation. The authors are grateful to the T1D Exchange Biobank and the participants who provide their time and effort in contributing critical research information. Without participant assistance, this research would not be possible. The T1D Exchange is the source of samples and data for this study, however, the individual authors are solely responsible for the analyses, content and conclusions presented as these have not been reviewed or approved by the T1D Exchange. Publisher Copyright: © 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

PY - 2021/7

Y1 - 2021/7

N2 - Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown. Objective: To determine the effect of metformin on the HDL proteome. Subjects: Youth (12–20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5. Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined. Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p =.0058) and alpha-2-macroglobulin (A2MG; +29.8%, p =.049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC. Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.

AB - Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown. Objective: To determine the effect of metformin on the HDL proteome. Subjects: Youth (12–20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5. Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined. Results: The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p =.0058) and alpha-2-macroglobulin (A2MG; +29.8%, p =.049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC. Conclusions: Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.

KW - cholesterol efflux

KW - high-density lipoprotein

KW - metformin

KW - proteomics

KW - type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85105399681&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85105399681&partnerID=8YFLogxK

U2 - 10.1002/edm2.261

DO - 10.1002/edm2.261

M3 - Article

C2 - 34277985

AN - SCOPUS:85105399681

VL - 4

IS - 3

M1 - e00261

ER -

Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this