Biochemistry - Glucose and your brain

Type 1 & LADA New T1/LADA
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There are a lot of different transporters for glucose that allow tissue to use it. I posted about GLUT4 recently.

Today here is a little bit of information about the glucose transporter GLUT3, and why it is used by the brain.

GLUT3 is most abundant in brain, kidney, and placenta. Let’s discuss the brain a little bit. Why does the brain use GLUT3 to get its glucose supply? What is it about GLUT3 that suits the needs of the brain and its high glucose demand?

(Believe it or not, your brain uses a lot of glucose. When at rest, about 60% of the glucose used by your entire body is used by your brain! And the brain does not need insulin to get its glucose!)

GLUT3 is a high-affinity glucose transporter. That means only a small amount of substrate is needed to saturate it. It has a high affinity for glucose.

In very simple and unscientific terms, this means GLUT3 is able to pull in glucose even when it is not available in high quantities.

(The affinity is usually expressed as the Km (Michaelis constant) of the enzyme. It is an inverse measure of affinity, low Km means high affinity.)

Hang with me, there is something important coming up.

The GLUT3 Km for glucose is 1.6 mM. That is much lower than the normal BG, meaning the GLUT3 enzyme is usually saturated with glucose under all but the most extreme low conditions. The high-affinity for glucose of GLUT3 means the brain is usually supplied with a constant glucose source.

According to Biochemistry, 5th Edition (Section 30.2):
Glycolysis slows down when the glucose level approaches the KM value of hexokinase (~50 μM), the enzyme that traps glucose in the cell (Section 16.1.1). This danger point is reached when the plasma-glucose level drops below about 2.2 mM (39.6 mg/dl) and thus approaches the KM value of GLUT3.

And here is a picture of the relevant page in my copy of the book:
image

Yes, low BG impacts you in many ways. And there is no reason to hang with a BG under 60 for days and days.

But I think the general recommendations and fear of brain damage are somewhat overstated for particular BG values, unless you drop below 40. Hopefully this can reduce some of the worry associated with it.

Next time, ask your endo about the Km for GLUT3, and what BG levels still allow it to supply glucose to the brain. Blow his brain a little bit. I would love to hear discussion about it.

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Does this textbook talk about how the body may be affected by high glucose levels both short and long term? This stuff is very interesting.

I don’t necessarily understand all the technical language, but the quoted section was pretty easy to understand.

Thanks for posting this.

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Very interesting reading. Thanks @Eric! I also recently read something from the NCBI that I found interesting, regarding the glucose stores used by the brain. From the site:

"In addition to supply from the circulation, neurons and glia can draw on reserves of glucose stored as glycogen in astrocytes. Initial studies of brain glycogen levels following RH suggested that there might be a ‘supercompensation’ of glycogen storage, which might then act as a buffer against further episodes of interrupted glucose supply [64]. Improvements in technique, allowing for measurements to be taken from awake (rather than anesthetised) animals, however, have recently shown that no such effect occurs.

A further potential adaptation which might act to preserve the brain’s energy supply would be to derive energy not solely from glucose but rather to also metabolise e.g. ketones derived from fatty acids. Such an adaptation is well-known to occur in the brain of animals or humans placed on a ketogenic diet [66], and monocarboxylates have been shown in vitro to support synaptic function in the absence of glucose [67]; Page and colleagues have recently shown that medium-chain fatty acids are capable of attenuating cognitive impairment during hypoglycemia [68]. Preliminary findings in our lab suggest that in our animal model of RH, monocarboxylate transporter expression is increased at both neuronal surface and (possibly) BBB following RH, suggesting a role for use of fuels beyond glucose in adapting to RH."

So, it seems there are many things about the brains requirement of glucose that are very much “self regulated” by the body and the brain, at least where ‘repeated’ hypo events are encountered…EVEN IN people with Type 1 Diabetes, because these processes are outside the whole process that causes diabetes in the first place (immune system killing beta cells responsible for the production of Insulin.)

It’s all very encouraging and helps with “the worry factor”…although, just to be on the safe side, we still want to avoid the lows if at all possible, and as much as possible!

Link to NCBI Mini-review: “Impact of recurrent hypoglycemia on cognitive and brain function.”

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There are so many redundancies for fueling the brain. Even when starving!

I was planning on posting about this at some point.

  • Fatty acids can be converted into ketone and used for energy by the brain. There are 3 types of ketone bodies the brain can use - acetoacetate, beta-hydroxybutyrate, and acetone.

  • The liver can break triglycerides into 3 fatty acid chains and a glycerol molecule which binds them together. The fatty acids are used for energy in the bloodstream and the glycerol is converted into glucose to fuel the brain (this process is called gluconeogenesis).

  • The brain can also use lactate, which is a byproduct of muscle glycogen metabolism.

Sure, lows should still be avoided. Unless it is a well-planned one that coincides with a milkshake or when you are actually doing it on purpose for dessert!
:yum:

But the main point of my post is that the body is so well-designed, and there are multiple safeguards and redundancies in place for all the important things that need to get supplied with fuel!

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No, the book is not specific to diabetes at all. It only has a few paragraphs in the entire book about diabetes.

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And it’s very important to separate diabetes from these functions. In other words, these processes work and are in play in everyone including diabetics.

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