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

Area of Science:

• Neuroscience
• Metabolic studies
• Biochemistry

Background:

• Hyperglycemia is known to increase the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter.
• The underlying mechanisms for this observation have remained unexplained.
• Understanding glucose metabolism in the brain is crucial for neurological health.

Purpose of the Study:

• To investigate the mechanisms behind hyperglycemia-induced increases in CMRglc in specific brain regions.
• To determine whether hyperglycemia affects oxidative or non-oxidative glucose metabolism.
• To explore the role of specific enzymes, like hexokinase 2 (HK2), in this process.

Main Methods:

• Utilized positron emission tomography (PET) and pancreatic glucose clamps in 29 healthy adults.
• Measured cerebral metabolic rate of glucose (CMRglc), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) under hyperglycemic and euglycemic conditions.
• Correlated metabolic findings with regional gene expression data, focusing on hexokinase enzymes.

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 the BOLD response.
• Brain regions showing increased CMRglc exhibited higher expression of hexokinase 2 (HK2).
• Simulations indicated that HK2, unlike HK1, is not saturated at euglycemia, allowing for increased aerobic glycolysis during hyperglycemia.

Conclusions:

• Hyperglycemia enhances aerobic glycolysis in specific brain regions, particularly those with low baseline glucose metabolism.
• The enzyme hexokinase 2 (HK2) plays a key role in accommodating increased aerobic glycolysis during hyperglycemia due to its non-saturable kinetics.
• These findings provide a novel explanation for hyperglycemia's effect on brain glucose metabolism and highlight the importance of HK2 in white matter.