Insulin Signaling on Glucose Metabolism: Study with Video Lessons, Practice Problems & Examples

The insulin receptor tyrosine kinase (RTK) signaling pathway plays a crucial role in glucose metabolism, particularly in decreasing blood glucose levels. Following a high glucose meal, insulin binds to its receptor, activating the insulin receptor substrate (IRS-1). This activates phosphoinositide 3-kinase (PI3K), which converts PIP₂ to PIP₃. PIP₃ then activates protein kinase B (PKB), which inactivates glycogen synthase kinase 3 (GSK-3). This leads to the activation of glycogen synthase (GS), promoting glycogen synthesis and GLUT4 expression, ultimately lowering blood glucose concentration.

Insulin Signaling Decreases Blood [Glucose]

Alright. So here in this video, we're going to introduce our first specific receptor Tyrosine Kinase or RTK signaling pathway. More specifically, we're going to look at the insulin RTK signaling pathway on glucose metabolism, which allows insulin to signal decreased blood glucose concentration. We'll see that there are 6 steps involved in insulin's RTK signaling cascade that allows, again, insulin to decrease blood glucose levels. Notice, in our text below, we're numbering each of these 6 steps in insulin's RTK signaling pathway. The numbers here in our text correspond with the numbers in our image down below right here.

In the very first step of this insulin RTK signaling pathway on glucose metabolism, this occurs after a high glucose meal. After a high glucose meal, there's a high concentration of glucose in our blood. Insulin's job is to help decrease that blood glucose concentration immediately after a high glucose meal. After a high glucose meal, insulin is released into our bloodstream, and it will travel through the blood and diffuse until it binds to its receptor, the insulin receptor. The insulin receptor is going autophosphorylate itself and fully activate its Tyrosine Kinase domains. The fully activated receptor will then phosphorylate and activate its substrate, the insulin receptor substrate 1 or IRS 1. We've already covered this process here in our previous lesson videos, but let’s take a look below at our image for a refresher.

Notice that number 1 is right over here. After a high glucose meal, insulin is going to activate, fully activate its Tyrosine Kinase domains. The Tyrosine Kinase domains here on the insulin receptor will be able to phosphorylate the insulin receptor substrate or IRS 1. In step number 1, notice that we have the phosphorylation of IRS 1. The phosphorylation and the activation, I should say, of IRS 1. Because this is a Tyrosine Kinase domain, IRS 1 is going to be phosphorylated at Tyrosine Residues.

After we get phosphorylation and activation of IRS 1, that leads us to step number 2 in this pathway. In step number 2, the activated IRS 1 is going to bind to the SH 2 domain of a protein called phosphoinositide 3 kinase or PI3K for short. Here we can put in PI3K. When the active IRS 1, which we know is an adapter protein, binds to the SH 2 domain of PI3K, it's actually going to activate PI3K. If we take a look below at our image at step number 2, we can get a better visual of this. After we get a phosphorylated and activated IRS protein, it's going to act as an adapter protein, which again means that it's not going to have enzymatic activity, but it's going to help bring proteins together. More specifically, it's going to help bring in the protein PI3K.

Notice that PI3K here actually has an SH 2 domain, which recall these are domains that will bind to phosphorylated tyrosine residues. And IRS 1 is phosphorylated at tyrosine residues. So, now the binding of PI3K to IRS one activates PI3K. PI3K again is a kinase, and we know that kinases are enzymes that phosphorylate their substrates. We should expect that PI3K is going to phosphorylate its substrate, especially when it is activated. That leads us into step number 3.

In step number 3, we will see that the PI3K or the kinase here is going to phosphorylate its substrate which is phosphatidylinositol 4,5-bisphosphate or PIP2. We've seen PIP2 before act as a substrate in our phosphoinositide GPCR signaling pathway in our previous lesson videos. This is the same PIP2; it's acting as a substrate once again, but for a different enzyme. This time it's acting as a substrate for PI3Ks, which is a kinase. Instead of being hydrolyzed, PIP2 is going to be phosphorylated by this kinase. You can see here that PI3K is acting as the catalyst that will convert PIP2 into phosphatidylinositol 3,4,5-triphosphate or PIP3.

PIP3 differs from PIP2 in just one phosphate group, again, because the PI3K kinase is phosphorylating PIP2 into PIP3. If we take a look at our step number 3 down below in our image, we can get a better visual of this. Notice that in our step number 3, what we have is PIP2, once again, is acting as a substrate. But this time for the enzyme PI3K, which is again a kinase. So it's going to take the substrate PIP2 and phosphorylate it, and that's what we see here in step number 3. That generates PIP3, of course. Notice that PIP3 has one additional phosphate group at this position right here, sorry, that PIP2 does not have.

Now that we have PIP3 formation, that leads us into step number 4. Notice that PIP3 is membrane-bound. It is bound to that membrane, and so it can only laterally diffuse in the membrane. PIP3 is going to laterally diffuse and bind to yet another kinase called protein kinase B or PKB here for short. We can put PKB here in this blank. What's important to note is that in some of your textbooks, PKB is sometimes referred to as AKT. But really, PKB and AKT are referring to the same exact protein. If we take a look at our image down below at our step number 4, notice that PIP3 once generated, is bound to this membrane. So it can only laterally diffuse in the membrane, but it will laterally diffuse and bind to another kinase over here, this protein over here called again, PKB or AKT, depending on your textbook.

This is going to lead us to step number 5. In step number 5, what's important to know is that yet another kinase is going to come into play. A kinase called PIP3 Dependent Kinase 1 or PDK1 for short. PDK1, again, is a kinase, so it's also going to phosphorylate its substrate, and its substrate is actually going to be PKB. PDK1 is going to phosphorylate and activate PKB. But notice that PDK1 is a PIP3-dependent kinase, which means that it also needs to bind to PIP3 because it's dependent on PIP3. If we take a look at our step number 5 down below, over here, what you'll notice is that we have another PIP3 molecule right over here. PIP3s can convert multiple PIP2 molecules into PIP3. One of those PIP3 will bind to PKB, and the other PIP3 over here is going to bind to this other enzyme, PDK1 that you can see right here, this green structure. PDK1 is again another kinase that's going to phosphorylate its substrate, and the substrate is PKB. Notice that because PDK1 is a kinase, it will use ATP to phosphorylate its substrate. You can see that now PKB has been phosphorylated in our step number 5 right here.

This leads us into step number 6, and that is that now that PKB has been phosphorylated by PDK1, it is now active. The active PKB, again, is a kinase. So protein kinase B is a kinase itself. So it's going to phosphorylate its target substrates as well. The active PKB is going to regulate targets that control GLUT4 expression as well as glycogen synthesis. Of course, we know that GLUT4 expression is going to increase and glycogen synthesis is also going to increase. Both of these events, the increase in GLUT4 expression, and the increase in glycogen synthesis, are going to help decrease blood glucose concentration.

If we take a look at our image down below at step number 6, what you'll notice is that PKB is going to phosphorylate a bunch of targets that we're not going to get into the details of in this video. In step number 6, you can see that PKB will phosphorylate targets that lead to vesicle fusion here, vesicles that contain GLUT4. And GLUT4 in this vesicle will fuse with the plasma membrane to express GLUT4 in the membrane, and so we get an increase in GLUT4 expression in the membrane. Notice that down below over here, in step number 6, we also get an increase in glycogen synthesis. So glucose, free glucose that's within the cell, is going to be converted into glycogen because PKB is going to activate very specific enzymes.

What this glycogen synthesis is going to lead to relatively low glucose inside the cell. After eating a meal, the glucose concentration in the bloodstream, which we're showing up here, is going to be quite high. So high glucose in the blood, low glucose in the cell because it's being converted into glycogen. That's going to allow for glucose to be transported down its concentration gradient and into the cell. The GLUT4 is going to facilitate that transport of glucose from the blood and into the cell. Again, this is going to lead to decreased blood glucose concentration.

Now you can see that these 6 steps that we've talked about here in this video really do lead to decreased blood glucose levels, and insulin does signal decreased blood glucose concentration. This is the pathway, the insulin RTK signaling pathway that allows it to do that. Moving forward, we are not going to get into the specific enzymes that are going to be phosphorylated by PKB that lead to vesicle fusion here. We're not going to get into that moving forward. However, what we are going to get into is the specific enzymes that lead to glycogen synthesis and how they get affected by PKB. In our next video, we'll be able to talk more ab

Insulin Signaling on Glucose Metabolism Example 1

Alright. So here we have an example problem that says, if you delete the PKB gene from insulin responsive cells, what would you likely observe in insulin's presence? And we've got these 4 potential answer options down below. Now recall from our previous lesson video that PKB is protein kinase B, and depending on your textbook, it may also be referred to as AKT. And so AKT and PKB are referring to the same exact enzyme. And again, we're looking at a deletion here, in the PKB gene. And so, notice option A says that PI3K would not be activated if we deleted the PKB gene. And so if we go back up and revisit our pathway here, notice that PKB is this protein that we see right here, and again recall that it can also be referred to as AKT. And so we're talking about a deletion in this, the gene that codes for this protein right here. And so option A again says that PI3K is not activated, but notice PI3K is way over here, and really PI3K activation does not rely on PKB at all. And so what that means is that PI3K, would still be activated and PI3K not being activated is not something that we would likely observe. And so for that reason, we can eliminate option A.

Now option B says PDK1 is not activated, but notice that PDK1 is over here. And again, PDK1 really doesn't rely on PKB to activate it. PDK1 is a PIP₃ dependent kinase 1. So really it relies on PIP₃, which is right here. And so again, it says PDK1 is not activated, but that is not something that we would likely observe in insulin's presence. So once again, we can eliminate answer option B. So now we're between either answer option C or answer option D, and notice answer option D says phosphatidylinositol is cleaved by phospholipase C, but phospholipase C is not in this pathway that we see right here. Phospholipase C, you might recall, is the effector enzyme in the phosphoenositide GPCR signal transduction pathway. And so for that reason, this is just the wrong pathway here, so it's not going to apply. And so that must mean that option C here is the correct answer.

And so if you delete the PKB gene in insulin responsive cells, we would likely observe in insulin's presence that GLUT4 is not going to be expressed and is going to be retained in intracellular vesicles. And so notice that if PKB is mutated, PKB will not be able to phosphorylate the enzymes that lead to GLUT4 fusing with the membrane and being expressed. And so, deleting the PKB gene will not allow for GLUT4 expression and so it's going to remain retained in the intracellular vesicle. And so that's exactly what answer option C here is referring to. So we can go ahead and indicate that C here is the correct answer to this example problem, and I'll see you guys in our next video.

Insulin Signaling Activates Glycogen Synthesis

So in our last lesson video, we introduced the 6 steps that are needed in insulin signaling on glucose metabolism. And so here in this video, we're actually going to continue that same exact insulin signaling pathway from our last lesson video. And more specifically, we're going to take a closer look at how insulin signaling actually activates glycogen synthesis. And so what you guys need to know is that there's an enzyme known as Glycogen Synthase, which is commonly abbreviated as just GS. And, of course, we know that it ends in ASE, so it is an enzyme. And if we read this enzyme backwards, it tells us what it does. And so this is an enzyme that synthesizes glycogen. And so that's exactly how we're defining glycogen synthase or GS as an enzyme that synthesizes glycogen. And, of course, when we're referring to glycogen synthesis, we're really just referring to the ability to convert free glucose into Glycogen.

Now there's also another very important enzyme that you guys need to know called Glycogen Synthase Kinase 3 or GSK3. And so GSK3, again, is a kinase. And because it's a kinase, we know that it's going to phosphorylate its substrate. And its substrate is actually going to be Glycogen Synthase itself, which is again this enzyme that we just introduced up above. And so what's important to note is that usually, glycogen synthase kinase 3 or GSK3 is going to be active and so it's going to phosphorylate its substrate, glycogen synthase. However, when GSK3 is active and phosphorylates Glycogen Synthase, it actually ends up inactivating Glycogen Synthase or GS. And so this is really important because in our previous lesson videos, remember we mentioned that you should never associate phosphorylation with either activation or inactivation. Instead, you should associate phosphorylation with an alteration in activity. And whether or not that alteration be an increase in activity or decrease in activity is actually going to be on a case-by-case basis. It will be different, depending on the scenario. And so although in some of our previous videos, we had seen that, kinase phosphorylation led to activation. Here, we're seeing that kinase phosphorylation is leading to inactivation of GS.

And so again, we're saying that usually, GSK3 will phosphorylate and inactivate GS. So usually, GS Glycogen Synthase is inactive. However, when PKB, protein kinase B, becomes active during insulin signaling on glucose metabolism, the active PKB is actually going to phosphorylate and inactivate GSK3. And so again, this is pretty much like inactivating the inactivator GSK3. And when you inactivate an inactivator, that's pretty much going to allow for the activation of GS.

And so essentially what we're saying is that insulin signaling is going to activate Glycogen Synthesis. And so if we take a look at our example image down below, we can see how insulin activates glycogen synthesis.

And so notice over here on the right-hand side, at the top, we're actually showing you a little snapshot of the same insulin signaling pathway on glycogen synthesis from our last lesson video. However, we're starting from the point of PIP3 production just to save us some space here. And so recall from our last lesson video that upon PIP3 production, PIP3 would actually laterally diffuse in the membrane and bind to the enzyme protein kinase B or PKB, which in some of your textbooks is referred to as just AKT. Also recall that PIP3 would also laterally diffuse and bind to PDK1, which we have over here. And, that would activate PDK1 and PDK1 is a PIP3-dependent kinase, so it's going to phosphorylate PKB just like we talked about in our last lesson video.

And so notice that we have step number 5 and step number 6 here shaded in this grayish color because these are steps that we already talked about in our last lesson video. So really there's nothing new here with step number 56. And so what you'll see here is that, in step number 6, it would lead to GLUT4 transport, decreasing glucose concentration because the GLUT4 would have been expressed into the plasma membrane. But, that's not really the main focus of this video. Instead, notice that we're focusing in on this portion, in this video, and this is the portion that, leads to insulin activating glycogen synthesis.

And so notice that we're continuing the process here with step 7, 8, and step 9, which corresponds with 7, 8, and 9 steps over here on the left-hand side. And so, again, as we indicated up above, when there is an active PKB such as the one that is right here upon being phosphorylated by PDK1, the active PKB is going to phosphorylate and inactivate GSK3. And so notice, right here in step number 7, what we're seeing is that PKB inhibits GSK3.

In step number 8, what we're seeing is that the inactive GSK3 right over here can no longer inhibit GS. And when it can no longer inhibit GS, GS becomes active, and so the active GS then goes on to synthesize glycogen. And so, this here, is really, the conclusion of our video. And the main takeaway here is really that insulin signaling ultimately is going to stimulate or activate glycogen synthesis through this pathway step 7, 8, and 9, that we introduced here in this video. And so this here concludes our lesson on how insulin signaling activates Glycogen synthesis by inactivating the inactivator GSK3. And that here, we'll be able to get some practice applying these concepts as we move forward in our course. So I'll see you guys in our next video.

Place the following insulin signaling transduction events in order of occurrence (event 9 is provided).

a) Full activation of PKB/Akt ______.

b) Activated PI3K converts PIP₂ to PIP₃ ______.

c) GLUT4 expressed in the cell membrane ___9___.

d) Ligand/insulin binding to the insulin receptor ______.

e) GSK3 is phosphorylated & inactivated ______.

f) Activated PDK1 phosphorylates & activates of PKB/Akt ______.

g) IRS-1 is phosphorylated & activated by the insulin receptor ______.

h) Autophosphorylation of the insulin receptor ______.

i) PI3K is activated upon its SH2 domain binding phosphorylated IRS-1 ______.

j) Glycogen synthase converts glucose to glycogen ______.

k) PIP₃ molecules laterally diffuse to bind PKB/Akt & PDK1 ______.

Alright. So here we have a practice problem that's really testing our memories of the insulin signaling pathway on glucose metabolism. It's asking us to place the following insulin signaling transduction events that we see down below right here in order of occurrence, and it tells us that event 9 is already provided for us, as you can see right here. And so, of course, we're going to need to recall a lot of information from our previous lesson videos, and for this particular practice problem, I would encourage you to actually go back to our previous lesson videos and your previous notes to answer this practice problem. And as we move forward in our course, we're actually going to share with you guys an interesting memory tool to help you answer practice problems like this one. But for now, you can go ahead and use your notes to help you answer this problem. And so, of course, the very first event that's going to take place in insulin signaling transduction is that the ligand, which is of course going to be insulin, is going to bind to the insulin receptor. This will be our step number 1. Now moving on, after the ligand binds the insulin receptor, because the insulin receptor is a receptor tyrosine kinase or an RTK, that is going to trigger the autophosphorylation of the insulin receptor. And so, that will be step number 2 here. The autophosphorylation of the insulin receptor fully activates the insulin receptor's Tyrosine Kinase domains and that allows it to target its substrate, the insulin receptor substrate 1 or IRS-1. The insulin receptor substrate 1 is going to be phosphorylated and activated by the insulin receptor, and that will be our step 3. Then, the enzyme referred to as phosphinositide 3-kinase or PI3K is going to get activated by IRS-1 upon its SH2 domain binding to the phosphorylated IRS-1. This will be our step number 4. PI3K is phosphinositide 3-kinase. So it's a kinase, so we expect it to phosphorylate its substrate. Its substrate is going to be PIP2. Notice that our step number 5 is that this activated PI3K is going to convert its substrate PIP2 into PIP3, again phosphorylating PIP2 into PIP3. This will be our step number 5. Upon the generation of PIP3, the PIP3 molecules are going to laterally diffuse to bind to the enzyme protein kinase B, which in some of your textbooks is referred to as AKT. So, PKB and AKT are referring to the same thing. And also, PIP3 molecules will also diffuse and bind to the enzyme PIP3 dependent kinase 1 or PDK1. This will be our step number 6. That means our step number 7 is that this PDK1 enzyme is going to be activated and because it is a PIP3 dependent kinase, it's going to phosphorylate its substrate, which is PKB or AKT. So this will be our step number 7. The phosphorylation and the activation of PKB or AKT are going to lead to its full activation, and this will be our step number 8. PKB is a protein kinase B, so it's another kinase. It's also going to phosphorylate its substrates. Step number 9 here was already given to us. Some of those targets that PKB is going to phosphorylate will ultimately lead to step number 9, which is that GLUT4 is going to get expressed in the cell membrane, allowing the cells to bring in the blood glucose into the cell and decrease blood glucose concentration. Notice that we only have 2 steps here that are remaining. Step E here says GSK3 is phosphorylated and inactivated. Recall, GSK3 is Glycogen Synthase Kinase 3. It is a kinase that regulates the activity of Glycogen Synthase, and normally GSK3 will inactivate Glycogen Synthase. However, upon full activation of PKB, GSK3 is actually going to get phosphorylated and inactivated by PKB. This will actually be our step number 10 here since, again, step number 9 was already taken by this. Our last step down below here is going to be our final step, which is that now that GSK3 has been phosphorylated and inactivated, it can no longer inactivate Glycogen Synthase. Glycogen Synthase is now free to convert glucose into glycogen, and that is step number 11. Really, all of the numbers that you see here are the answers to this practice problem, and this is the correct order of events. That concludes this practice. Again, as we move forward in our course, we're going to share with you guys some helpful memory tools to help you memorize these steps, the most important steps of this pathway. That concludes this practice problem, and I'll see you guys in our next video.

How to Remember Insulin RTK Signaling on Glucose Metabolism?

So as you guys have probably noticed from our previous lesson videos, when it comes to insulin signaling on glucose metabolism, there's quite a lot for you guys to remember. And so how is it that you guys are supposed to remember the most important components and the most important events in the correct order when it comes to insulin RTK signaling on glucose metabolism. Well, that's exactly what this video is all about right here. And so here at Clutch Prep, we've come up with a really interesting and unique story to help you guys remember, again, the most important components and the most important events in the correct order when it comes to insulin RTK signaling on glucose metabolism.

Now the story is not a perfect story. It's not fully bulletproof. But again, it was intentionally designed only to help you guys memorize the most important components and the most important events in the correct order. And so notice up above right here, what we have is an image that shows you the most important components and the most important events of insulin RTK signaling on glucose metabolism, and it's shown in the correct order. Now notice what we're not showing you here in this image is the insulin receptor and ligand binding to the insulin receptor, insulin binding to the insulin receptor. We're not showing you the autophosphorylation of the insulin receptor, but we did cover all of those things in our previous lesson video. So hopefully those things come naturally to you.

And so here, we're really just picking up with the insulin receptor substrate or IRS₁. And so, of course, we know from our previous lesson videos that IRS₁ is going to get phosphorylated and activated by the insulin receptor. And so upon IRS₁ phosphorylation and activation, the SH₂ domain of the enzyme called phosphoinositide 3-kinase or PI3K is going to bind to the activated and phosphorylated IRS₁. And when PI3K binds to IRS₁, that leads to the activation of PI3K. And PI3K is a kinase, so we know that it's going to phosphorylate its substrate. More specifically, it phosphorylates the substrate PIP₂ into PIP₃.

And so PIP₃ is going to remain membrane-bound and laterally diffuse and associate itself with PKB or Protein Kinase B, as well as with PDK1 or PIP3-dependent kinase 1. Now PDK1, when it is bound to PIP₃, that activates PDK1, and then PDK1 is a kinase that phosphorylates its substrate which is PKB. And so PDK1 phosphorylates PKB and when it phosphorylates PKB, PKB is activated and PKB goes on to increase glycogen synthesis and to increase GLUT4 expression in the membrane, and ultimately both of these events lead to decreased blood glucose concentration.

If you take a look at our text down below, notice that we're numbering each of the steps of our story, and so there are 6 steps to our story. And of course, the numbers that you see here corresponding with the steps of our story correspond with the numbers from our previous lesson videos where we first introduce insulin signaling on glucose metabolism steps. And of course, the numbers that you see here in our text also correspond with the numbers that you see down below throughout our image. And so the very first step of our story is that the IRS is going to get activated, the insulin receptor substrate 1. Now in our story, the IRS stands for the Internal Revenue Service, and so the Internal Revenue Service is going to give a tax refund to the cell.

And so the cell is pretty much getting a nice little paycheck, a nice little cash influx, if you will. And so again, the IRS giving the cell a nice tax refund represents IRS₁ activation. And so if we take a look at our image down below, notice over here on the left what we have is the IRS giving a tax refund, a nice little pile of cash here that the cell can use to spend on something. And so again, the IRS, tax refund represents IRS₁ activation.

And so this leads us to the second step of our story, which is the cell is going to use that tax refund, that cash influx to buy a pie and it's going to put a fake 3 K label on it, a fake $3,000 label on it. And the reason for that is to prank the evil villain that we know is Pip. And so the pie with the fake 3 K label on it represents the enzyme PI 3 K, which is Phosphoenositide 3 Kinase. And so really the cell buying a pie to prank Pip represents the activation of the enzyme PI3K. And so if we take a look down below at our step number 2, which is right here, notice that the cell uses this cash influx to buy a pie, looks like a cherry pie here, and the pie, the cell goes and puts a fake 3 K label on it, fake $3,000 label on it, and the reason that the cell does this is, again, to prank the evil villain that we know is Pip. And so notice over here we have Pip. And so again the pie with the fake 3 K label on it represents PI3K or phosphoinositide 3 kinase.

And so this leads us to step number 3 of our story. And in step number 3, this evil villain named Pip, of course, because he's so slick and so sly and evil, he's always trying to undervalue things, including this pie with the price tag, the fake 3 K label on it. So he sees, even though Pip sees that 3 K label on it, first because he's so slick and so sly and so evil, he tries to undervalue it and he offers only 2 K for a bite. But then, ultimately, Pip comes to his senses and he's like, you know what? There's a 3 K label on it. He doesn't know it's fake. But, he sees the 3 K label and then he just agrees to pay 3 K for that pie. And so PIP first offering 2 K for a bite and then agreeing to pay 3 K for a bite represents PIP₂ conversion to PIP₃. And so if we take a look down below at our image, notice that Pip over here, this sly evil villain, is first offering a byte for 2 K even though he clearly sees the 3 K label on it. And so then, eventually, Pip comes to his senses and says, fine, you know what, I'll give him 3 K for the pie since there's 3 K label on it. And so pretty much the cell's prank is working on Pip. And so, now that we have PIP₃ here, this leads us to step number 4 of our story.

And in step number 4, as you can see in our image down below, the bank tellers are shocked, absolutely shocked when they hear that the prank actually worked on Pip and that Pip actually did pay thousands of dollars for a byte of that pie. And so Pip paying thousands of dollars for a byte represents PKB, and really the bank tellers are associated with PKB in this story. And so if we take a look down below at our image, notice that our bank tellers are right here at this position with step number 4. And these bank tellers again are completely shocked that the prank actually worked, and so they're gossiping to each other saying, you know what? I can't believe Pip paid thousands of dollars for a bite. And so again, these bank tellers here represent PKB, the enzyme Protein Kinase B.

And so this leads us to step number 5, and in step number 5, Pip decides to take the remainder of his money, which it turns out to be $1,000, 1 K. And so Pip decides to take the remainder of his money and deposit that 1 K at the bank. And so Pip depositing 1 K represents the enzyme PDK1 or PIP-dependent kinase 1. However, when Pip goes to deposit that 1 K at the bank, the bank tellers, of course, are going to be involved, and recall the bank tellers are PKB. And so the bank tellers have to handle the transaction when Pip decides to deposit his 1 K. And so this here represents where PDK1 activates PKB, where PDK1 activates PKB. And so if we take a look down below at our step number 5 in our image, notice that Pip is depositing the remainder of his money, which is 1 K, at the bank. And so, this represents PDK1 over here. But, of course, when Pip decides to deposit his 1 K at the bank, the bank tellers are going to get involved. And so, again, this represents PDK1, activating PKB here. And again, the bank tellers are going to handle the transaction when Pip deposits his 1 K.

And so this leads us to step number 6, which is the final step of our story. And so in step number 6, the bank tellers who are handling the transaction are going to increase Pip's savings since they're depositing his money into the bank. And so they increase Pip's savings and increasing the savings here, you can see the G S at the end of savings, represents glycogen synthesis, increasing glycogen synthesis. And then also, the bank tellers decide to express order some gluten free donuts, and the gluten-free donuts here represent GLUT4 expression. And so if we take a look at our step number 6 down below, which is right here, notice that the bank tellers have to handle the transaction where Pip is depositing his 1 K. So when they handle that transaction, they're actually increasing Pip's savings, and so you can see Pip is depositing his cash into his bank and increasing his savings and this represents glycogen synthesis where glucose is converted into glycogen. And also the bank tellers decide to express order some gluten-free donuts over here, and so you can see that embedded in our gluten-free donut we have the GLUT4 transporter. And so this represents GLUT4 expression in our plasma membranes. And so really, this is a really crazy, really silly story, but hopefully, if you guys go over the steps of this story and, practice it a couple of times, it'll help you remember the most important components and the most important events, of insulin RTK signaling on glucose metabolism, and help you put them in the correct order.

And so this here concludes our introduction to our story and we'll be able to get some practice applying what we've learned here moving forward in our course. So I'll see you guys in our next video.

Insulin Signaling on Glucose Metabolism Example 2

Alright. So here we have an example problem that wants us to place the following insulin signal transduction events that we have down below right here in order of occurrence, placing event 1 through to event number 8. And so, of course, after taking a read through each of these events, the very first event that must occur is binding of insulin to the receptor. That's basically ligand binding to the receptor. And so, we can put that as one here.

And then of course, the binding of the ligand to the receptor is going to allow for the autophosphorylation of the insulin receptor or the activation of the insulin receptor, and so that will be step number 2. And then of course, recall from our last lesson video that, the binding of insulin to the receptor and the activation of the insulin receptor itself was actually not included in our crazy story to help you guys memorize this specific pathway. However, we did pick up here with step number 3 in our story. And so, step number 3 is going to be the phosphorylation of IRS 1 or the activation of IRS 1. And so IRS, recall in our story, was the Internal Revenue Service, which provided a tax refund or a cash influx.

And then, of course, we know that the cell is going to use that cash to buy a pie and then place a ₃k label on it. And so that reminds us of the activation of PI₃K. So that will be step number 4. And then of course, Pip is going to see that pie and try to undervalue it, and so that, he only offers ₂k at first, and so that's PIP₂. But then he comes to his senses, and then he decides to pay what's on the label, on the actual tag, which is ₃k. So that is PIP₃. And so that reminds us of the conversion of PIP₂ to PIP₃. So that's gonna be our step number 5 here.

And then, of course, at that point, Pip is going to decide to deposit the rest of his money into the bank. And so Pip depositing $1,000 into the bank, $1,000 into the bank reminds us of PDK1, so that reminds us of the activation of PDK1, which is step number 6 here. And then, of course, Pip can't deposit his money into the bank without the bank tellers which are the protein kinase B. And so that would be full activation of PKB here, and so that would be our step number 7.

And then of course last but not least, what we have is the final step here, which is that the bank tellers decide to express order some gluten free doughnuts or that, is gonna be GLUT4 transporter expression in the cell membrane. And so this one here will be step number 8. And so, these numbers that you see here in these blanks are really the answers to this example problem. And that concludes this example, so I'll see you guys in our next video.

All of the following are true of the reaction catalyzed by PI3K EXCEPT:

• A. Phosphatidylinositol bisphosphate is a substrate of PI3K.
• B. Inositol triphosphate is a substrate of PI3K.
• C. ATP is a substrate of PI3K.
• D. Phosphatidylinositol triphosphate is a product of PI3K.
• E. ADP is a product of PI3K.

Which of the following results would you predict to occur if a mutation changes a Tyr residue of the Insulin Receptor to Ala?

• A. Inability to take up glucose from the bloodstream.
• B. Constant uptake of glucose from the bloodstream.
• C. Upregulated glycogen synthesis and GLUT4 transport to the membrane.
• D. B and C.

IRS-1 is an essential adaptor protein in the insulin signaling pathway. If IRS-1 was under expressed in muscle cells, what effect would you expect to see on glycogen synthesis?

• A. Protein kinase B would remain inactive, resulting in increased glycogen synthesis.
• B. Protein kinase B would be overstimulated, resulting in increased glycogen synthesis.
• C. Protein kinase B would remain inactive, resulting in decreased glycogen synthesis.
• D. Protein kinase B would be overstimulated, resulting in decreased glycogen synthesis.

Here’s what students ask on this topic:

What are the steps involved in the insulin RTK signaling pathway for glucose metabolism?

The insulin RTK signaling pathway for glucose metabolism involves six key steps:

1. Insulin binds to its receptor, activating the receptor's tyrosine kinase domains.
2. The activated receptor phosphorylates insulin receptor substrate 1 (IRS-1).
3. IRS-1 activates phosphoinositide 3-kinase (PI3K), which converts PIP2 to PIP3.
4. PIP3 activates protein kinase B (PKB), also known as AKT.
5. PKB phosphorylates and inactivates glycogen synthase kinase 3 (GSK-3).
6. Inactivation of GSK-3 leads to the activation of glycogen synthase (GS) and increased GLUT4 expression, promoting glycogen synthesis and glucose uptake, thereby lowering blood glucose levels.

How does insulin signaling lead to glycogen synthesis?

Insulin signaling leads to glycogen synthesis through a series of phosphorylation events. When insulin binds to its receptor, it activates IRS-1, which in turn activates PI3K. PI3K converts PIP2 to PIP3, which activates PKB. Active PKB phosphorylates and inactivates GSK-3. Normally, GSK-3 inhibits glycogen synthase (GS) by phosphorylation. When GSK-3 is inactivated, GS remains active, allowing it to convert free glucose into glycogen, thus promoting glycogen synthesis.

What role does GLUT4 play in insulin signaling and glucose metabolism?

GLUT4 is a glucose transporter that plays a crucial role in insulin signaling and glucose metabolism. Upon insulin signaling, PKB is activated and promotes the translocation of GLUT4-containing vesicles to the plasma membrane. This increases the number of GLUT4 transporters on the cell surface, facilitating the uptake of glucose from the bloodstream into the cells. This process helps lower blood glucose levels, especially after a high-glucose meal.

What is the function of protein kinase B (PKB) in the insulin signaling pathway?

Protein kinase B (PKB), also known as AKT, plays a pivotal role in the insulin signaling pathway. Once activated by PIP3, PKB phosphorylates and inactivates glycogen synthase kinase 3 (GSK-3). This inactivation prevents GSK-3 from inhibiting glycogen synthase (GS), thereby promoting glycogen synthesis. Additionally, PKB facilitates the translocation of GLUT4 to the plasma membrane, enhancing glucose uptake into cells and contributing to the reduction of blood glucose levels.

How does the phosphorylation of IRS-1 affect the insulin signaling pathway?

The phosphorylation of insulin receptor substrate 1 (IRS-1) is a critical step in the insulin signaling pathway. When IRS-1 is phosphorylated by the activated insulin receptor, it serves as a docking site for phosphoinositide 3-kinase (PI3K). This interaction activates PI3K, which then converts PIP2 to PIP3. The production of PIP3 is essential for the subsequent activation of protein kinase B (PKB) and other downstream signaling events that lead to glucose uptake and glycogen synthesis, ultimately lowering blood glucose levels.