High glucose impairs cognitive function through Creb3 O-GlcNAcylation and increased lactate production

Area of Science:

• Biochemistry
• Neuroscience
• Endocrinology

Background:

• Diabetes is characterized by high glucose levels, leading to increased glycolysis, lactate production, and O-GlcNAcylation.
• Cognitive impairment is a prevalent complication of diabetes, with underlying molecular mechanisms requiring elucidation.

Purpose of the Study:

• To identify the molecular mechanisms linking high glucose to cognitive impairment in diabetes.
• To investigate the roles of O-GlcNAcylation and lactate production in diabetes-related cognitive dysfunction.

Main Methods:

• A prospective observational study correlated plasma lactate levels with mild cognitive impairment in diabetic patients.
• Experiments on mouse hippocampal neurons and diabetic mouse models (type 1 and 2) were conducted.
• O-GlcNAcylation of transcription factor Creb3 and its downstream effects on Ldha expression were analyzed.

Main Results:

• Elevated plasma lactate independently predicted mild cognitive impairment in diabetic patients.
• High glucose increased O-GlcNAcylation of Creb3, stabilizing it and up-regulating Ldha expression.
• Increased lactate production led to neuronal apoptosis and cognitive dysfunction in diabetic mouse models.
• Modulating Creb3 O-GlcNAcylation alleviated these detrimental effects.

Conclusions:

• O-GlcNAcylation of Creb3 and subsequent Ldha-mediated lactate production are key mechanisms in high glucose-induced cognitive impairment.
• This pathway represents a potential therapeutic target for managing cognitive dysfunction associated with diabetes.