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.

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Published in Endocrinology, Diabetes & Metabolism, v. 4, issue 3, e00261.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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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.

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