The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation. Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose–induced cognitive impairment, a prevalent complication of diabetes. A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes. High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene Ldha , which encodes the enzyme lactate dehydrogenase. As a result, lactate production was increased during glycolysis, triggering neuronal apoptosis and cognitive dysfunction in mouse models of type 1 and 2 diabetes. Expression of a Creb3 mutant that could not be O-GlcNAcylated at Ser 325 or competitive blockade of the O-GlcNAcylation of Ser 325 in Creb3 with a short peptide alleviated these effects. This study elucidates a mechanistic link between high glucose–induced Creb3 O-GlcNAcylation and Ldha-mediated lactate production, offering a potential therapeutic strategy for managing diabetes-related cognitive dysfunction.
Xu et al. (2026) studied this question.