Fructose Levels Are Markedly Elevated in Cerebrospinal Fluid Compared to Plasma in Pregnant Women

Abstract

BackgroundFructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose→sorbitol→fructose) contributes to brain exposure to fructose.MethodsIn this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section.ResultsAs expected, CSF glucose was ~60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups.ConclusionsThese data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

The human brain produces fructose from glucose

“…Furthermore, the production of sorbitol and fructose was blocked by sorbinil, an inhibitor of the rate-limiting enzyme, aldose reductase (26). Together with the previous finding that fructose and sorbitol are present in human cerebrospinal fluid at markedly higher concentrations than in the periphery (12,14,27), the present observations suggest that endogenous human brain fructose production may be a key underappreciated factor modulating ingested sugar's effect on the brain. While it is possible that plasma fructose may cross the BBB, we observed that the rise of intracerebral fructose occurred much earlier (by 20 minutes) than the modest increase in peripheral fructose levels (at 180 minutes).…”

“…When considered with our recent finding that plasma fructose levels are only 0.1% of plasma glucose levels, compared with CSF in which fructose is 6%-7% of glucose (28), these findings suggest that relative changes in brain fructose may be greater than relative changes in brain glucose levels, potentially making fructose a highly sensitive neuronal signal for carbohydrate ingestion. Interestingly, in Drosophila, any nutritious carbohydrate ingestion results in increased hemolymph fructose levels (through the polyol pathway), which in turn acts on a nutrient sensor in the fruit fly brain (29).…”

“…The polyol pathway is an accessory glucose pathway that bypasses glycolysis (8,9), and in the setting of hyperglycemia, up to 30% of glucose can be metabolized via this alternate pathway (10,11 ). The polyol pathway is present throughout the human body, including the brain (12,13), and it is responsible for the 20-fold higher levels of fructose observed in cerebrospinal fluid compared with blood (14).…”

Fructose metabolism and metabolic disease

“…Physiologically, endogenously synthesized fructose is the primary energy source for sperm and may be important for fertility (104)(105)(106). The placenta may also synthesize sorbitol that the developing fetus may use to synthesize fructose, suggesting a broader role for endogenous fructose in reproductive and developmental biology (107).…”

High Sucrose Diets Contribute to Brain Angiopathy with Impaired Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice

“…Despite the low concentration of fructose in the plasma, fructose has a potential to generate AGEs more readily than the same amount of glucose; in addition, it generates pre-AGE carbonyl compounds, such as glyceraldehyde and methylglyoxal 71 . Moreover, in cerebrospinal fluid (CSF), fructose concentration may be controlled by a mechanism that is distinct from that of the plasma, as fructose levels are increased and glucose levels are decreased in this compartment compared with the plasma 70,72 . Fructose-derived pre-AGE carbonyl compounds were detoxified by GLO1 quickly in astrocytes in wild-type mice and probably even in Glo1 heterozygous mice, because of its strong expression in these cells.…”