Circulating inflammatory proteins are elevated in type 1 and type 2 diabetes and associated to complications

Abstract

Background: The presence of low-grade inflammation has been reported in people with type 2 diabetes and related to the development of (macro)vascular complications. Whether systemic inflammation is present in type 1 diabetes and linked to long-term complications remains unknown. We used a targeted proteomics approach to compare inflammation in people with type 1 diabetes and type 2 diabetes with control subjects and linked these proteins to diabetes related characteristics and complications.

Methods: We included 233 participants with type 1 diabetes, 387 participants with type 2 diabetes and 150 healthy controls. Plasma was collected and used to determine high sensitive C-reactive proteins (hs-CRP) and an additional 92 inflammatory proteins using the Olink proteomics platform.

Results: Compared to healthy controls, 41 circulating inflammatory proteins were higher in type 1 diabetes (FDR < 0.05) and 64 inflammatory proteins in type 2 diabetes (FDR < 0.05) (including CXCL5, IL-15RA, MCP-4 and AXIN1 for both groups). HbA_1c levels were positively associated with 21 inflammatory proteins (including CDCP1, FGF-21, HGF and IL-18R1) in type 1 diabetes (FDR < 0.05), whereas a positive association existed between body mass index (BMI) and 26 inflammatory proteins (including IL6, IL17C, FGF-23 and CSF-1) in type 2 diabetes. Inflammatory proteins associated with the presences, of complications, particularly nephropathy, were similar in both type 1 and type 2 diabetes. FlT3L and EN-RAGE were associated with the development of cardiovascular disease (CVD) in type 2 diabetes.

Conclusions: Both type 1 diabetes and type 2 diabetes are associated with increased circulating inflammatory protein concentrations, but the increase is more pronounced in type 2 diabetes. These results suggest both differences in drivers of inflammation between type 1 diabetes and type 2 diabetes as well as potential similarities in pathways involved in the development of diabetes-associated complications.

Keywords: inflammation; macrovascular complications; microvascular complications; proteomics; type 1 diabetes; type 2 diabetes.

FIGURE 1

Principal component analysis (PCA) of inflammatory protein levels showing PC1/PC2 or participants with type 1 diabetes (T1DM, green, n = 233), type 2 diabetes (T2DM, blue, n = 387) and healthy controls (HC, n = 147 red) (panel A). Comparison of levels of inflammatory proteins between T1DM (n = 233) and HC (n = 147) (panel B), T2DM (n = 387) and HC (n = 40) (panel C) and T2DM (n = 387) and T1DM (n = 233) (panel D), displayed in Volcano plots showing the logFC/FDR‐corrected p‐value. Red dots indicate proteins that are significantly elevated (Wilcoxon signed‐rank test, FDR < 0.05).

FIGURE 2

Association between clinical characteristics and inflammatory proteins in people with type 1 diabetes (left columns, n = 147) and people with type 2 diabetes (right columns, n = 387). The size of the square indicates the association (Estimate). Yellow/Orange/Red toned squares indicate a positive association, whereas blue toned squares indicate a negative association (linear regression model, FDR‐corrected p‐value < 0.05).

FIGURE 3

Association between diabetes related complications and inflammatory proteins in people with type 1 diabetes (left columns, n = 147) and people with type 2 diabetes (right columns, n = 387). The size of the square indicates the association (Estimate). Yellow/Orange/Red toned squares indicate a positive association, whereas blue toned squares indicate a negative association (linear regression model corrected for age, sex and BMI, FDR‐corrected p‐value < 0.05).

FIGURE 4

Comparison between people with type 2 diabetes that developed cardiovascular disease (CVD) and people that did not develop CVD, displayed in a Volcano plot showing LogFC/p‐value (panel A). Hazard ratios ±SE (cox regression) for the association between increased proteins and the development of CVD corrected for age and BMI (panel B). Red dots indicate proteins that are significantly elevated/associated (n = 347, Wilcoxon signed‐rank test/Cox regression, p‐value < 0.05).