Conceptual and Mechanistic Links between glycated hemoglobin and glycosylated RNA: An insight into glycosylation biology in metabolic disease pathophysiology.

Glycated hemoglobin (HbA1c) is a well-established biomarker reflecting chronic glycemic control in diabetes. It accumulates through non-enzymatic glycation of hemoglobin under sustained hyperglycemia and serves as a surrogate of metabolic memory. Emerging in parallel, glycosylated RNA (glycoRNA), small noncoding RNAs bearing covalently attached N-linked glycans, has revealed unexpected roles in immune signaling and glycoimmunomodulation. While glycation and glycosylation represent distinct biochemical processes, both are modulated by glucose availability and cellular stress. This opinion paper aimed to explore the conceptual parallels between HbA1c and glycoRNA, proposing that hyperglycemia-induced metabolic changes may simultaneously influence both processes. In light of these, glycoRNA represents an emerging biomarker as a functional effector in metabolic disease, mirroring the hyperglycemia-driven immunological dimensions of HbA1c with a further advantage of a defined metabolic sequence, which can deepen diagnostics towards disease progression patterns. Though direct experimental evidence is currently limited, we outline plausible mechanistic intersections and suggest methodological frameworks for future research. Therefore, this perspective aims to stimulate interdisciplinary investigation into glycoRNA biology within the broader context of glycemic dysregulation and immune modulation in diabetes.