Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow

Area of Science:

• Neuroscience
• Metabolic studies
• Brain imaging

Background:

• Hyperglycemia is known to increase the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter.
• The underlying mechanisms for this observed increase in CMRglc during hyperglycemia remain unexplained.

Purpose of the Study:

• To investigate the specific pathways of glucose metabolism affected by acute hyperglycemia in the brain.
• To determine if hyperglycemia influences non-oxidative glucose metabolism, such as aerobic glycolysis (AG).

Main Methods:

• Utilized positron emission tomography (PET) combined with euinsulinaemic glucose clamps to measure brain metabolism.
• Assessed regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and blood-oxygen-level-dependent (BOLD) responses.
• Analyzed regional gene expression, specifically focusing on hexokinase enzymes (HK1 and HK2).

Main Results:

• Acute hyperglycemia significantly increased non-oxidative CMRglc (aerobic glycolysis) in subcortical white matter, medial temporal lobe, cerebellum, and brainstem.
• No significant changes were observed in regional CBF, CMRO2, or BOLD response.
• Brain regions with increased CMRglc showed higher expression of hexokinase 2 (HK2).

Conclusions:

• Hyperglycemia enhances aerobic glycolysis in specific brain regions, particularly those with low baseline glucose metabolism.
• The increased expression and non-saturated activity of hexokinase 2 (HK2) at euglycemia explain the enhanced AG during hyperglycemia.
• This finding provides a novel mechanistic insight into brain glucose utilization under hyperglycemic conditions.