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. 2018 Feb 10:172:100-110.
doi: 10.1016/j.jprot.2017.10.004. Epub 2017 Oct 7.

Temporal expression profiling of plasma proteins reveals oxidative stress in early stages of Type 1 Diabetes progression

Chih-Wei Liu  1 , Lisa Bramer  2 , Bobbie-Jo Webb-Robertson  2 , Kathleen Waugh  3 , Marian J Rewers  3 , Qibin Zhang  4
Affiliations

Temporal expression profiling of plasma proteins reveals oxidative stress in early stages of Type 1 Diabetes progression

Chih-Wei Liu et al. J Proteomics. .

Abstract

Blood markers other than islet autoantibodies are greatly needed to indicate the pancreatic beta cell destruction process as early as possible, and more accurately reflect the progression of Type 1 Diabetes Mellitus (T1D). To this end, a longitudinal proteomic profiling of human plasma using TMT-10plex-based LC-MS/MS analysis was performed to track temporal proteomic changes of T1D patients (n=11) across 9 serial time points, spanning the period of T1D natural progression, in comparison with those of the matching healthy controls (n=10). To our knowledge, the current study represents the largest (>2000 proteins measured) longitudinal expression profiles of human plasma proteome in T1D research. By applying statistical trend analysis on the temporal expression patterns between T1D and controls, and Benjamini-Hochberg procedure for multiple-testing correction, 13 protein groups were regarded as having statistically significant differences during the entire follow-up period. Moreover, 16 protein groups, which play pivotal roles in response to oxidative stress, have consistently abnormal expression trend before seroconversion to islet autoimmunity. Importantly, the expression trends of two key reactive oxygen species-decomposing enzymes, Catalase and Superoxide dismutase were verified independently by ELISA.

Biological significance: The temporal changes of >2000 plasma proteins (at least quantified in two subjects), spanning the entire period of T1D natural progression were provided to the research community. Oxidative stress related proteins have consistently different dysregulated patterns in T1D group than in age-sex matched healthy controls, even prior to appearance of islet autoantibodies - the earliest sign of islet autoimmunity and pancreatic beta cell stress.

Keywords: Longitudinal profiling; Oxidative stress; Pediatric plasma proteome; TMT10; Temporal proteome change; Type 1 Diabetes.

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Figures

Fig. 1
Fig. 1
Schematic representation of experimental workflow. The plasma samples of 9 serial time points from each subject were longitudinally collected and immunodepleted by removing the top 14 abundant proteins prior to tryptic digestion. The peptides of serial 9 time points plus one common reference were labeled by TMT-10plex, and the high-pH RPLC was used to fractionate the pooled TMT-labeled peptide mixtures before nanoLC-MS/MS analysis. All of raw files were searched together using MaxQuant for protein identification and quantification. The quantification data matrix was further used for statistical trend analysis and visualization by Trelliscope. Finally, ELISA experiments were conducted for trend verifications. This modified workflow was adopted from Liu et al. [17] with permission.
Fig. 2
Fig. 2
The sampling time points in healthy subjects (NP, n = 10) and T1D patients (TD, n = 11). The filled circles/squares/triangles indicate the sampling time points. Large filled squares and triangles indicate the seroconversion time and T1D clinical diagnosis, respectively.
Fig. 3
Fig. 3
(A) Summary and Venn diagram of plasma proteins identified in healthy subjects (NP) and T1D patients (T1D). (B) Overlap comparison between the proteins identified in this study, in cultured human islet cells by Schrimpe-Rutledge et al. [35], and in human pancreatic tissues by Liu et al. [16]. Venn diagram was calculated based on the reported gene name.
Fig. 4
Fig. 4
The temporal expression patterns of protein CAT (A–C) and SOD1 (D–F) observed by LC-MS/MS analysis from healthy subjects (NP, A and D) and T1D patients (T1D, B and E) as well as their corresponding verification by ELISA (C and F). The dots and triangles indicate the sampling time points from female and male, respectively, and the lines with different colors indicate each individual subject. X- and Y-axis are the real age and protein relative abundance (Log 2 scale), respectively. CAT: Catalase; SOD1: Superoxide dismutase [Cu-Zn]. Pearson Correlation values between ELISA and LC-MS data (CAT: 0.92 for NP, 0.98 for T1D; SOD1: 0.87 for NP, 0.89 for T1D).
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