Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.
Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification.
Results: Samples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin.
Conclusions: Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM.
Trial registration NCT02275091
Digital Object Identifier (DOI)
This project has been funded in part with Federal funds (UL1TR001409 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, Dr. Gourgari) and with funds from the Georgetown University “Partners in Research” Award to Dr. Gourgari, funds from Medstar Health Research Institute “Diabetes Award” to Dr. Gourgari, and by the National Heart Lung Blood Institute (NHLBI). The Proteomics and Metabolomics Shared Resources was partially supported by Lombardi Comprehensive Cancer Center Support Grant NCI P30-CA051008. Additional support was provided from Dr. Gordon’s institutional startup funds from the University of Kentucky’s Saha Cardiovascular Research Center. RG was supported in part by R01CA135069 from NCI.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Gourgari, Evgenia; Ma, Junfeng; Playford, Martin P.; Mehta, Nehal N.; Goldman, Radoslav; Remaley, Alan T.; and Gordon, Scott M., "Proteomic Alterations of HDL in Youth with Type 1 Diabetes and their Associations with Glycemic Control: A Case-Control Study" (2019). Saha Cardiovascular Research Center Faculty Publications. 40.