Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory

Abstract

Aims/hypothesis There is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs). Methods Selected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194). Results Eleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family. Conclusions/interpretation The association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes. Graphical Abstract

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes

“…Eleven of the 81 significant biomarkers were higher, and 70 were lower in the T1D cohort compared with Healthy . Cytokines with notable associations to the pathogenesis or prevention of type 1 diabetes included C-type lectin domain family 4 member D (CLEC4D, p<0.0001),13 interleukin (IL)-4 (p<0.0001),14 IL-1215 (p<0.05), IL-1316 (p<0.05), galectin-1 (Gal-1, p<0.0001),17 tumor necrosis factor superfamily member 14 (TNFSF14, p<0.0001),18 islet cell antigen 1 (ICA1, p<0.0001),19 CD40 ligand20 (p<0.05), mannan-binding lectin-associated serine proteases (MASP-1, p<0.0001),21 peroxiredoxin-1 (PRDX1, p<0.01),22 and latency-associated protein transforming growth factor beta 1 (LAP-TGF-beta 1, p<0.001) 23. (figure 4)…”

“…13 PRDX1 22 is an antioxidant with immunoregulatory properties that were lower in T1D. LAP-TGF-beta 1 23 is the upstream pro-protein of immunoregulator TGFbeta 1 and was lower in T1D. Notably, TGF-beta 1 dissociates from LAP and becomes active on interaction with primarily integrin ITGAV:ITGB6 32 and can promote Th17 or Treg differentiation in a concentration-dependent manner.…”

Multi‐omics analysis reveals drivers of loss of β‐cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study

“…The proteomics study 34 found 12 significant associations between peptide expression changes in the initial 12 months after diagnosis and C-peptide glucose ratio slopes, with expression changes in GPX3 being indicative of future C-peptide changes. Because of the cohort and methodological differences, a direct comparison is not possible.…”

“…Two recent single-omics papers have been published on the INNODIA cohort 34,35 with a considerable overlap of patients to our study. There are small differences in the inclusion criteria of patients.…”

Mendelian randomization analysis demonstrates the causal effects of IGF family members in diabetes

“…A review has shown that the high IGF-1 concentrations can prevent or delay the inception of diabetes-related complications in people with diabetes ( 5 ). According to a targeted serum proteomics study, lower levels of IGF1 and IGFBP3 and elevated IGFBP1 level were detected in the sera of T1D youth ( 6 ). There were additionally studies confirmed that adiponectin and INSR were crucial in regulating glucose metabolism and insulin sensitivity ( 7 , 8 ).…”