Abstract
Background and aimsAn association between hypoglycaemia and adverse cardiovascular events has been suggested from longitudinal and retrospective cohort studies. The complement pathway proteins in hypoglycemia are not well studied. Here, we hypothesized that these circulating proteins would be elevated in response to hypoglycemia in type 2 diabetes (T2D) through the inflammatory response. MethodsA prospective, parallel study in T2D (n = 23) and controls (n = 23). Subjects underwent insulin-induced hypoglycemia with blood sampling at baseline, hypoglycemia and post-hypoglycemia; SOMAscan proteomic analysis of complement pathway-related proteins, cytokines and inflammatory proteins was undertaken. ResultsAt baseline: Complement C2 (p < 0.05) and Factor B (p < 0.05) were elevated in T2D. At hypoglycemia: Complement C2 (p < 0.05) and Factor B (p < 0.01) remained elevated, whilst Factor I became elevated (p < 0.05) in T2D; Complement C4b became elevated in controls (p < 0.05). In the post-hypoglycemia follow up period, Complement C2, Factor B and Factor I remained elevated in T2D; in addition, Factor D, Factor H and mannose-binding protein C showed elevations in T2D, whilst properdin, complement C3b, Factor H-related protein 5, complement C1q and decay-accelerating factor (DAF) showed elevations in controls. Granger causality analysis showed that inflammatory proteins appeared to drive complement protein changes in T2D; conversely, in controls, complement proteins drove inflammatory protein changes. ConclusionsBaseline elevations in C2 and Factor B indicate upregulation of the complement pathway in T2D. Changes in complement pathway-related protein levels in response to hypoglycemia suggest both intrinsic and alternative pathway activation at 2-h that appears driven by the underlying inflammation in T2D and could contribute to a cardiovascular event.ClinicalTrials.gov NCT03102801. Date of registration April 6, 2017, retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03102801?term=NCT03102801&draw=2&rank=1.
Highlights
1 joint first authors. 2 joint senior authors
Complement C2 (p < 0.05) and Factor B (p < 0.01) remained elevated, whilst Factor I became elevated (p < 0.05) in the type 2 diabetes (T2D) cohort (Fig. 2C); by contrast, Complement C4b became elevated in controls (p < 0.05) (Fig. 2D)
We have previously shown that a number of inflammatory proteins are affected by hypoglycaemia [34] and these include C-XC motif chemokine ligand 10 (CXCL10), interleukin 1 alpha (IL-1A), interleukin 10 (IL-10), interleukin 12 alpha (IL-12A), CeC motif chemokine ligand 19 (CCL19), tumour necrosis factor alpha (TNFalpha) and TANK-binding kinase 1 (TBK1) and these specific proteins were correlated with the complement proteins
Summary
The complement pathway proteins in hypoglycemia are not well studied. Subjects underwent insulin-induced hypoglycemia with blood sampling at baseline, hypoglycemia and post-hypoglycemia; SOMAscan proteomic analysis of complement pathway-related proteins, cytokines and inflammatory proteins was undertaken. At hypoglycemia: Complement C2 (p < 0.05) and Factor B (p < 0.01) remained elevated, whilst Factor I became elevated (p < 0.05) in T2D; Complement C4b became elevated in controls (p < 0.05). Conclusions: Baseline elevations in C2 and Factor B indicate upregulation of the complement pathway in T2D. Changes in complement pathway-related protein levels in response to hypoglycemia suggest both intrinsic and alternative pathway activation at 2-h that appears driven by the underlying inflammation in T2D and could contribute to a cardiovascular event. Date of registration April 6, 2017, retrospectively registered. https:// clinicaltrials.gov/ct2/show/NCT03102801?term1⁄4NCT03102801&draw1⁄42&rank1⁄41
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