A ketogenic diet increases the brain glucose uptake mechanism

When looking into acetoacetone uptake by the brain, I bumped against the following article. I don’t have full access but the abstract showed me the following:

Similar trends were observed for (18)FDG uptake with a 1.9-2.6 times increase on the KD and F(asting), respectively (P < 0.05).

FDG -> radiolabeled glucose such as used to trace cancer. But more importantly, a good doubling of the uptake of glucose! So I started thinking, is it the case that our brain is sucking up so much glucose? Or is this just a side effect of being ketotic and getting a big bolus of glucose administered?

“Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats” https://pubmed.ncbi.nlm.nih.gov/21605500/

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I find it interesting because astrocytes produce more lactate on starvation and I assume on keto as well. Why? To increase the expression of MCT1 transporters on the endothelial cells in the blood-brain-barrier which allows a higher uptake of BHB.

Pyruvate can otherwise be reduced to lactate by lactate dehydrogenase (LDH). This lactate can be released in the extracellular space through monocarboxylate transporters (MCTs).

“Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation” https://www.sciencedirect.com/science/article/pii/S1550413111004207

Astrocytes can store small amounts of glycogen which they, if necessary, break down to glucose and metabolize to lactate (Falkowska et al. 2015). To fulfill this functional characteristic, astrocytes are highly metabolically flexible and can rapidly upregulate glycolysis. In the event of an undersupply, astrocytes thus ensure the survival and function of neurons by providing lactate (Kasischke et al. 2004; Pellerin and Magistretti 1994).

“Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes” https://link.springer.com/article/10.1007/s12031-021-01800-2

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So it seems that astrocytes start to increase lactate production when glucose is running low and they use their little glycogen buffers for that. Cool. So that coincides nicely with an increase in ketones and takes care of the BHB uptake, balancing out low glucose with increased BHB.

I guess it would make sense for the brain to increase its ability to take up glucose which is then indicated by the first link I provided. So I don’t think the brain is actually continuously taking up so much glucose, it is just that it has opened the gates to maximally receive glucose.

Further a reference that shows increased glucose uptake under chronic hypoglycemia

“Chronic hypoglycemia increases brain glucose transport” https://pubmed.ncbi.nlm.nih.gov/3532819/

A first candidate to look at what could cause that increase in uptake is the GLUT1 transporter. And indeed, the following article looked at GLUT1 expression in the BBB under glucose deprivation, hypoxia and the two combined.

r/ketoscience - Keto increases the ability to receive glucose in the brain?

“Glucose deprivation and hypoxia increase the expression of the GLUT1 glucose transporter via a specific mRNA cis-acting regulatory element” https://onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.0022-3042.2001.00756.x

Summary

  • astrocytes sense low glucose availability
  • astrocytes increase lactate production
  • lactate increases MCT1 expression
  • increased MCT1 enables more influx of BHB into the brain
  • low glucose increases GLUT1 expression in the BBB to maximally take up glucose

So this shows a whole balancing mechanism, it allows a shift from purely glucose to glucose and BHB.

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For people who interpret this as ketones being a backup and think this is showing the brain needs glucose… I’d say the truth is somewhere in the middle 😉 Consider the following quote. There may be a point that can be crossed when too much glucose is available and can be considered toxic when that downregulates GLUT1 in the BBB to the point that the brain doesn’t get enough glucose. Also here the astrocytes may start to produce lactate but it won’t do any good because under hyperglycemia, there won’t be any BHB produced.

Glucose transport into the brain is depressed in chronically hyperglycemic (diabetic) rats.

“Chronic hypoglycemia increases brain glucose transport” https://pubmed.ncbi.nlm.nih.gov/3532819/

Compared with normal control rats, the GLUT(1) mRNA was reduced by 46.08%, 29.80%, 19.22% (P < 0.01) in DM1, DM2, and DM3 group, respectively; and the GLUT(3) mRNA was reduced by 75.00%, 46.75%, and 17.89% (P < 0.01) in DM1, DM2, and DM3 group, respectively.

“Influence of blood glucose on the expression of glucose trans-porter proteins 1 and 3 in the brain of diabetic rats” https://pubmed.ncbi.nlm.nih.gov/17935675/

But I find contrasting evidence. In the following article they noted no effect on GLUT1 expression. Different rat models so who knows what the case is for humans..

“Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited” https://pubmed.ncbi.nlm.nih.gov/9886075/

Why is this important? We see reduced expression of GLUT1 in Alzheimer’s. Is it a genetic issue or not and can it be partially prevented or even reverted when going on a low carb diet? Food for thought…

“GLUT1 reductions exacerbate Alzheimer’s disease vasculoneuronal dysfunction and degeneration” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734893/

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