Proteomic and Metabolomic Signatures in Prediabetes Progressing to Diabetes or Reversing to Normoglycemia Within 1 Year.

Objective: Progression of prediabetes to type 2 diabetes has been associated with beta cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, we compared the proteomics and metabolomics profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within a year. Research Design and Methods: The fasting plasma concentrations of 1389 proteins and the fasting, 30 min and 120 min post-oral glucose tolerance test plasma concentrations of 152 metabolites were measured in up to 134 individuals with new-onset diabetes, prediabetes or normal glucose tolerance. For 108 participants the analysis was repeated with samples from one-year before, when all had prediabetes. Results: The plasma concentrations of 14 proteins were higher in diabetes compared to normoglycemia in a population with prediabetes one-year before and they correlated with indices of insulin sensitivity. Higher levels of Dicarbonyl/L-xylulose-reductase and Glutathione S-transferase A3 at prediabetic state were associated with increased risk of diabetes one-year later. Pathway analysis pointed towards differences in immune response between diabetes versus normoglycemia that were already recognizable at prediabetic state one-year prior, at baseline. The Area-under-the-curve during OGTT of the concentrations of Intermediate-Density-Lipoprotein (IDL)-particles, IDL-Apolipoprotein B, IDL-Cholesterol was higher in new-onset diabetes compared to normoglycemia. The concentration of glutamate increased in prediabetes progressing to diabetes. Conclusions: We identify new candidates associated with the progression of prediabetes to diabetes or its remission to normoglycemia. Pathways regulating immune response are related to prediabetes trajectories