Hemoglobin A1C: Intracellular Heterogeneity and Functional Implications in Prediabetic and T2 Diabetic Erythrocytes

Hemoglobin A1C (HbA1C), a non-enzymatically glycated form of adult hemoglobin (HbA0), is a widely used biomarker for diabetes. Its concentration is strongly correlated with the long-term glycemic state and the risk of diabetes development. However, beyond its diagnostic role, its physiological functions remain poorly understood. To fill this gap, we investigated the intracellular distribution of HbA1C and its potential impact on red blood cell (RBC) functions. Specifically, the differences in cytosolic and membrane pools of HbA1C in RBCs from individuals with prediabetes, overt type 2 diabetes (T2D), and healthy controls were explored. Our cross-sectional findings confirmed the intracellular heterogeneity of HbA1C and revealed a strong correlation between fluctuations in HbA1C and those of other hemoglobin isoforms, specifically HbA2 and HbA0. This correlation was particularly evident in the context of diabetes or acute exposure to Ca²⁺-depleted environments. We also observed that short-term hyperglycemia does not significantly alter HbA1C intracellular localization. Furthermore, we found that the intracellular distribution of HbA1C is correlated with several physiological properties of RBCs, with these links varying according to the specific pathological abnormalities associated with pre- and overt diabetes. Further research is required to fully understand the mechanisms and implications of these observations.