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

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.