Dysregulation of the Glycolytic Entry Gate and Survival Route by Advanced Lipoxidation End Products in Diabetes Mellitus.

Background: Diabetic retinopathy (DR), a major microvascular complication of Type 2 diabetes mellitus (T2DM), is linked to oxidative and lipoxidative stress-induced metabolic dysfunction. Advanced lipoxidation end products (ALEs) cause metabolic abnormalities, and hexanoyl-lysine (HLY) is a well-known ALE. ALEs may interfere with glycolytic enzymes and disrupt cellular redox balance. Hexokinase (HK), the entry enzyme of glycolysis, and lactate dehydrogenase (LDH), crucial for metabolic survival under hypoxia, may be particularly susceptible to ALE-induced alterations. Nonetheless, the association between circulating ALEs and these glycolytic checkpoints, as well as redox status across DR stages, remains unclear. Methods: A total of 236 consecutively selected subjects were enrolled, including healthy controls (HC, Results: HLY levels increased progressively from HC to HRPDR. The HK activity and the NAD Conclusion: An increase in ALE burden is associated with dysregulation of the glycolytic entry enzyme (HK) and concurrent alterations in LDH activity, which may reflect metabolic adaptation under stress conditions, along with changes in redox status across the stages of DR. The independent association between HLY and HK suggests a link between lipoxidative stress and impaired glycolytic initiation, which may represent a metabolic alteration associated with the progression of DR.