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 β-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 1 year. Research design and methods: The fasting plasma concentrations of 1,389 proteins and the fasting, 30-min, and 120-min post-oral glucose tolerance test (OGTT) 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 1 year before, when all had prediabetes. Results: The plasma concentrations of 14 proteins were higher in diabetes compared with normoglycemia in a population with prediabetes 1 year before, and they correlated with indices of insulin sensitivity. Higher levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with an increased risk of diabetes 1 year later. Pathway analysis pointed toward differences in immune response between diabetes and normoglycemia that were already recognizable in the prediabetic state 1 year prior at baseline. The area under the curve during OGTT of the concentrations of IDL particles, IDL apolipoprotein B, and IDL cholesterol was higher in new-onset diabetes compared with 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 the immune response are related to prediabetes trajectories.