Biochemistry - what does insulin actually do?!

Tim asked about this yesterday. How does insulin work, exactly? What does it do?

It is basically a key that opens the door to the cells for glucose to get in. I tried to put it into words, but then I thought some pictures would make it easier to understand.
(There are a number of different glucose transporters, but GLUT4 is the major glucose transporter in fat and muscle, so that is what I am showing.)

Sorry about the low-grade drawings. These are mine!

  1. A glucose molecule is too large to pass through a cell membrane by itself. It can’t get through the external boundary of the cell by itself, it needs help. (Since it needs help, it is called “facilitated diffusion”.) Glucose is in the blood but can’t get into the cell. No insulin means glucose can’t get into the cells and that means high blood sugar!

  2. Insulin binds to the Tyrosine Kinase Receptor in the cell.

  3. This causes a big cascade of steps. You can see notes below on “Insulin signaling pathway”, if you are curious.

  4. The GLUT4 transporter goes to the plasma membrane, the external boundary of the cell. This is a door for glucose to get into the cell. It can finally get into the cell. Thanks insulin. Come on in, glucose!

  5. The glucose has moved from the blood into the cell. Notice the blood sugar is now lower! Now that glucose is in the cell, it can be used for energy or storage of energy - that’s what glucose is used for. It can undergo glycolysis and glycogen synthesis.

Just a very simple and basic explanation. Here are notes on the insulin signaling pathway if you are interested.

Insulin signaling pathway:
(Here are the steps. Nothing in here is very important to know, except for the bold parts. Just wanted to list it out for everyone in case people were curious. Only read it if you want to be bored!)

  • Insulin binds to the Tyrosine Kinase Receptor and causes it to auto-phosphorylate (introduce a phosphate group into the molecule)

  • The phosphorylation is a reaction catalyzed by kinases that activates proteins by donating a phosphate group

  • The activated insulin receptor recruits an insulin receptor substrate 1 protein, IRS-1

  • IRS-1 activates protein PI3K which catalyzes the phosphorylation of a phospholipid called PIP2, and converts it to PIP3

  • PIP3 recruits and activates Protein kinase B (PKB, also known as Akt)

  • Protein kinase B phosphorylates Protein TBC1D1

  • TBC1D1 travels deeper toward the cellular storage compartment

  • TBC1D1 activates RabGDP, converting it to Active RabGTP

  • This releases GLUT4 vesicles to the cell surface

  • Fusion of the phospholipid bilayers of the vesicles and the cell adds glucose transporter proteins to the plasma membrane

  • Glucose can then enter the cell and undergo glycolysis and glycogen synthesis

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Isn’t it wild that we all rely, day-to-day, on this lifesaving molecule and yet few of us have a clear idea of how it works in the body??

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But that’s the same as driving a car. We know that gas (or battery) and pushing the right pedal makes the car go or stop. But most, including me, could not describe all that happens in between. We take it for granted every day.

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@Eric Thanks for the graphics. They make it easier to understand for us visual learners. :sunglasses:

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@Eric
I am getting lost with the detailed steps after:
Insulin binds to the Tyrosine Kinase Receptor

Would you be able to simplify that a little? That area sounds like it may be interesting.

Also I am wondering about the quantity of insulin. How does more or less insulin binding have an impact on the next step? Also what causes the insulin to bind to the Tyrosine Kinase Receptor or is it just like a magnet where it is drawn and it binds whether it is needed or appropriate to bind or not? ie - is the “binding” in any way related to high or low BG or is that irrelevant in terms of binding and is how “much” binding is occurring related to how much insulin is currently in the bloodstream?

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It is just a cascade of reactions. I can try to find some better stuff, but it is just a chain sequence of chemistry. Adding phosphates, activating one thing which triggers another. Just a crazy sequence of dominoes. All the pictures look kind of like this:

image

Really, the important stuff is insulin binds to the receptor and GLUT4 binds to the plasma membrane.

I can see if there are more detailed descriptions of each step.

At a basal insulin level, GLUT4 cycles slowly back and forth between the plasma membrane (external wall) and the interior of the cell. Activation of the insulin receptor triggers a large increase in the rate of GLUT4 vesicles binding to the membrane.

Basically more open doors.

Glucose flows into the cells based on the difference in concentration. Since there is usually more glucose in the blood than in the cell, it will flow into the cells more rapidly with more GLUT4 vesicles - i.e. more open pathways.

The receptor is just a large protein. The binding is not based on need. The insulin is released into the blood based on need. The binding just happens when the insulin is released in the blood. More insulin means more binding, more GLUT4 movement, more glucose moving into the cells. All of that is based on the amount of insulin and the amount of glucose. None of that stuff is “smart”. The only smart part is the beta cells knowing how much insulin to put into the blood.

Here is a picture of it. The insulin is in red and the receptor is in blue.

image

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Awesome !!!

Thanks for the additional pictures and the info.
:smile:

There is a lot going on there !!!

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Another question if you don’t mind.

With the GLUT4 vesicle, is that really in one place as shown on the picture or is that just for illustrative purposes? Or does does GLUT4 impact the entire surface of the cell? Point I am getting at does the glucose molecule that is sitting outside and not able to get in, does that have to happen to physically align on the outside at the same location where the GLUT4 appears from the inside?
Or does the GLUT4 impact the entire surface so the glucose can migrate in from any point? Or is it more like polka dots where there would be many GLUT4 all over the cell and the glucose still has to hit the point where a GLUT4 is but there are many all over so it is more likely to match up plus more insulin creates more GLUT4 so as to further increase the probability of a glucose happening to line up with a GLUT4 ?

I was just trying to make it simple in the picture with just one GLUT4 vesicle shown. In reality, there is a pool of them available, not just a single one and not just a single place. The glucose flows in from a place of more density (the blood) to less density (the cell). And it doesn’t really need alignment, because there are multiple glucose molecules in the blood and multiple cells and multiple locations where it can go. The body has about 37 trillion cells, so the glucose will find a place to go! :wink:

Now that the basic idea has been discussed, this picture is a little more detailed, but not overwhelming. And this one doesn’t even list all the crazy steps between the insulin binding to the receptor and the translocation of the GLUT4 vesicles.

image


All the pictures are crappy because the GLUT4 vesicles are not easy to identify by light microscopy. Which is somewhat of an excuse for the crayon-type drawing I did.

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I am a math person. The reality is it is tough to wrap your mind around numbers that large. So large numbers simply exceed any typical point of reference.

Nice drawings !!!

Appreciate the additional info and explanations.
:smile:

This is not trivial stuff.

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Thanks. The last one is not my drawing, BTW. But I thought it was a bit more complicated than the one I did originally, so I chose to not use it in my initial post.

What happens to the insulin itself after it binds to the tyrosine kinase receptor and sparks the chain reaction? Does it get broken down in the phosphorylating steps? Or does the receptor release it, and, now ineffective, it gets disposed of some other way?

After binding with the receptor and triggering its action, insulin is degraded by the insulin-degrading enzyme (IDE) (also called insulysin or insulin protease). It is no longer functional and is cleared from the body as a waste-product by the liver and kidneys.

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