Truncated Albumins as Novel Surrogate Biomarkers in Diabetes Therapy: Epiphenomena and Potential Clinical Applications.

Aims/Hypothesis: Among various albumin posttranslational modifications (PTMs), N- and C-terminal truncations (HSA-DA and HSA-L) have also shown biomarker potential in disease states. We examined albumin truncation longitudinal trends and correlations during diabetes therapy toward possible future clinical applications. Methods: In a preliminary longitudinal therapy investigation, mass spectrometry was employed to track PTMs of human serum albumin (HSA), including glycation (GA), cysteinylation (CA or HNA1; reversible), di/trioxidation (OA or HNA2; irreversible), and truncation (TA). These modifications were correlated with ongoing therapy in four distinct subject groups: type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity (PDOB), and healthy controls (NORM), observed over a follow-up period extending up to 280 days. Results: Diabetes was associated with significant reduction ("deficiency") of measured albumin truncations (For HSA-DA: T2DM = 0.32 ± 0.3%, p = 2E-08; T1DM = 1.02 ± 0.4%, p = 3E-05; PDOB = 1.61 ± 0.2%, p = 0.004; compared to NORM = 2.08 ± 0.2%). Albumin truncation reduction was more striking in T2DM (HSA-DA: T2DM vs. T1DM: p = 0.004). Improvements in glycemic control and decrease of albumin glycation during diabetes therapy were associated with concomitant increase of albumin truncations toward the "healthy" normal ranges, and vice versa ("mirror image" trends). Accordingly, albumin truncation correlated inversely with albumin glycation (HSA-DA vs. GA: R = -0.53, p = 1E-09). Conclusions: The "epiphenomenon" of albumin truncation (reflecting the severity of mean hyperglycemia and also insulin resistance) can possibly provide novel, sensitive, and complementary biomarkers (e.g., via simpler HSA-DA peptide fragment immunoassays) to monitor efficacy of diabetes therapy and also progression from "healthy" to prediabetes and type 2 diabetes, highlighting potential diagnostic and prognostic utility in clinical diabetes care.