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

• Published in: Endocrinology, diabetes & metabolism Vol. 4; no. 3; pp. e00261 - n/a
• Main Authors: Gourgari, Evgenia, Nadeau, Kristen J., Pyle, Laura, Playford, Martin P., Ma, Junfeng, Mehta, Nehal N., Remaley, Alan T., Gordon, Scott M.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2021; John Wiley and Sons Inc; Wiley
• Subjects: Adolescent; Antidiabetics; Child; Cholesterol; cholesterol efflux; Cholesterol, HDL; Chromatography; Clinical trials; Diabetes; Diabetes Mellitus, Type 1 - drug therapy; Double-Blind Method; High density lipoprotein; Humans; Insulin resistance; Laboratories; Libraries; Lipids; Lipoproteins; Lipoproteins, HDL - metabolism; metformin; Metformin - pharmacology; Metformin - therapeutic use; Original; Original s; Peptides; Proteins; Proteome; Proteomics; Software; Triglycerides; type 1 diabetes; Young Adult; high‐density lipoprotein; metformin; type 1 diabetes; proteomics; cholesterol efflux
• ISSN: 2398-9238; 2398-9238
• DOI: 10.1002/edm2.261

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. We hypothesized that metformin could change the protein cargo on HDL and subsequently improve HDL function in youth with T1D. We analysed samples from a large RCT metformin‐placebo trial and we found that 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 cholesterol efflux. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.