“The human brain produces fructose from glucose” Summary and Points of Consideration

A recent study entitled “The human brain produces fructose from glucose” published in JCI Insight sought to examine whether peripheral hyperglycemia can drive intracerebral production of fructose through the polyol pathway [glucose –(aldose reductase)à sorbitol –(sorbitol dehydrogenase)à fructose] in an exploratory study. Researchers at Yale selected 4 male and 4 female participants (mean: age 28.8, BMI 23.4mg/k², HbA1c 2.9%) to participate in the study. Following an overnight fast, each participant was given one IV catheter in one arm to draw labs and a second IV catheter in the other arm to administer 20% dextrose every 5-10 minutes to achieve and maintain plasma glucose of 12 mmol/l. Blood was collected at baseline and at 30, 60, 120, 180 and 240 minutes during the hyperglycemic trial and ¹H MRS spectrometer scans were used to measure intracerebral concentrations of fructose and glucose at the same time points.

As expected, plasma glucose rapidly increased during the dextrose infusion. Plasma fructose levels were only significantly greater than baseline after 180 minutes and 240 minutes of dextrose infusion. There were no differences in plasma sorbitol levels during the entire hyperglycemic clamping trial.

Intracerebral glucose levels rose significantly over time, beginning at 10 minutes after infusion initiation. Similarly, intracerebral fructose levels rose significantly overtime beginning at 20 minutes after infusion initiation. Intracerebral sorbitol was not measured. The magnitude of the change for intracerebral fructose was approximately 30% that of the change of intracerebral glucose.

Because intracerebral fructose concentrations levels rose more rapidly than plasma (20 minutes versus 180 minutes), researchers conclude that the increase in brain fructose is not a result of peripheral fructose crossing the blood brain barrier but is rather created endogenously from glucose through the polyol pathway.

Points of Consideration

• Researchers had a small sample size (n=8) and this was a pilot study.
• Participants were characterized as “healthy” based on smoking status, drug use status, BMI and hemoglobin A1c. Researchers did not conduct oral glucose tolerance tests, measure HOMA-IR, or gather data on family history of diabetes.
• The ¹H MRS scan only measured changes in concentration and not absolute concentration of glucose and fructose in the human brain.
• Researchers were unable to measure changes in sorbitol levels because sorbitol’s spectra overlaps glucose and fructose and is therefore indistinguishable.

o   Furthermore researcher were unable to confirm that the observed results were a direct result of the polyol pathway. In rodent studies, this mechanism was demonstrated by administering sorbinil, an inhibitor of the rate limiting enzyme (aldose reductase), and observing subsequent decrease in the production of sorbitol and fructose following glucose administration.

• Researchers only scanned the occipital lobe and therefore, did not account for regional variability in glucose utilization in different areas of the brain.
• Researchers did not control for insulin or other hormonal effects which could have indirectly affected the polyol pathway.

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