Hi Ningeners, in this video we're going to talk about gluconeogenesis. All right, so let's decipher this word real quick. All right, so gluco is meaning glucose, all right, neo is new, and genesis is to form. So in other words, words we are forming new glucose but to add on that to that little definition of it is it's we're forming new glucose molecules from non-carbohydrate sources so in other words things like amino acids things like glycerol, lactic acid, and we'll discuss all of this.
Okay, so where is gluconeogenesis occurring? What organs would you find this gluconeogenic capability? So one is you would find it within the liver. So you would find it within the liver. And the other one is you could find it within the kidneys, particularly the proximal convoluted tubule of the kidneys.
Okay, so these So these are the two organs. in which this gluconeogenesis activity is occurring. So it's forming new glucose molecules from non-carbohydrate sources like amino acids and glycerol and lactic acid, and it's occurring in organs such as the liver and the kidneys.
Now, the next question is, when is it occurring? So we know what it is, where it's occurring, now why is it occurring? Why is this occurring?
It's occurring because your blood glucose levels are low. So that is one of the primary reasons of why this is happening. So one of the reasons why is because of low blood glucose levels, or we refer to low blood glucose levels as, what do we call this? We call this hypoglycemia. Okay, that's one reason.
Another reason is, it's for the brain. The good old brain. The brain completely relies and depends upon glucose.
So if glucose levels drop the brain becomes affected because the only source of fuel that the brain prefers to run on is glucose so this is the primary source of fuel And you can imagine that any kind of situation where the brain is not getting its fuel, you can imagine the dangerous implications that could potentially develop from this. A secondary source of fuel for this, so this primary source of fuel is glucose. But whenever we're fasting for a while, and if it has to, a secondary source that it can utilize of fuel is ketone bodies. talk about that when we talk about fat metabolism.
Okay, so why is it occurring? It's because of low blood glucose levels, primarily hypoglycemia, and because the brain primarily relies upon glucose as a primary source of fuel. In a situation in which we are having prolonged starvation or certain situations like you're avoiding carbohydrates, then this can become the secondary source of fuel and it's called ketone bodies, but it is dangerous because ketone bodies can cause the actual blood to become acidic so it's not preferred and it can lead to ketoacidosis.
Okay so we know what it is, we know where it's occurring, and we know why it's occurring. Now let's go on to what's actually happening in this gluconeogenic pathway. Okay so you guys know the normal way that glucose is coming into the cell right?
So to recap that let's go ahead and see what happens. Glucose is brought in through some type of glut transporter but specifically we can say that if it's in the liver we know that it's going to be some type of glut 2 transporter, right? We know that this specifically is going to be a glut 2 transporter.
And we also know that in other different organs too, like for example, the kidneys, it can be a glut 3 receptor. So glut 2 receptor for the liver and glut 3 receptor for the kidney. Now, what happens is this glucose is going to come into our cells, right? When the glucose comes into the cell, it actually gets phosphorylated, right? And then it gets turned into glucose.
I'm going to abbreviate them, guys, for the sake of popping through this quick. Glucose 6-phosphate. Then it gets converted into fructose 6-phosphate. Then fructose 1,6-bisphosphate.
Then it gets split into fructose, I'm sorry, and it gets split into glyceraldehyde 3-phosphate. And the other component of that is dihydroxyacetone phosphate. Then it gets converted into 1,3-BPG, then 3-phosphoglycerate, then 2-phosphoglycerate, then phosphoenolpyruvate, and then lastly into pyruvate.
So again, it goes GA3P, 1,3-BPG, 2-PG, phosphoenolpyruvate, and pyruvate. Now this occurs once with the GA3P, but then I told you guys from the glycolysis video that DHAP can't get converted into 1,3-BPG. So he has to get converted into GA3P.
So this pathway occurs twice. And so I can technically represent that by actually if I came all the way down here with this guy, this guy goes into GA3P and then it goes through this process. Okay, now if you remember, I told you there was some important steps. One of them was this step right here. So let me actually draw the rest of this here in pink.
And pink is just representing that it's a very important control step. This step right here is also an important control step. And this step right here is also an important control step.
Now, we want to go in the exact opposite direction of glycolysis. So you can think of gluconeogenesis as the reverse process of glycolysis. But if you remember, I told you that certain pathways are reversible in certain art. Like this pathway is reversible.
This is reversible. That's reversible. Reversible.
Reversible. Reversible, right? All of the ones that are reversible, okay, yeah, you can go right up that pathway, but the ones that are irreversible, you have to go around. And that's what we're going to try to explain what's actually happening here. So the first thing that we need to do is, let's start with the first one that I'm going to talk about, and that's going to be lactic acid.
So if you're, let's say that for some situation, your muscles, your muscles are contracting, right, and they're developing a lot of lactic acid. So out of that, let's say that we have lactic acid come here. So here's our lactic acid.
We're going to represent that as the three carbons because it's going to be similar to pyruvate, right? So now this actual, specifically this lactic acid is going to come into the cell. And then what happens is that lactic acid can get converted into pyruvate, right?
So again, who is this guy up here? This is lactic acid, and this could be coming from the muscles. Okay, now this lactic acid can actually get converted into pyruvate, but pyruvate can't go back up to PEP.
So how does he get around that? He goes into the mitochondria. When he goes, actually before I do that, let's actually show the other things feeding into this. No, I will actually go through this.
So now pyruvate, what's he gonna do? He's gonna move into the mitochondria. When he goes into the mitochondria, what does he begin getting converted into? So here's our pyruvate right there.
This is our pyruvate. If you remember, the pyruvate gets converted into acetyl-CoA. But guess what? Pyruvate's sneaky because you remember there was an enzyme that was controlling this step right here.
And if you remember, the enzyme that was controlling this step, let's actually show it again in pink. What does it represent if it's pink? That means it's a reversible step. I mean, it's an irreversible step. This can't go backwards.
So pyruvate's really sneaky. And he has this special pathway, let's represent it in purple here, that he can actually get converted indirectly, right? I'm sorry, directly.
He can go straight from pyruvate to this guy. What is this guy right here? This guy's name is oxaloacetate. I'm going to abbreviate it OAA, but understand that his name is oxaloacetate. Pyruvate is three carbons.
Oxaloacetate is four carbons. So what had to happen in here? You had to...
put a carbon dioxide or some form of it into this reaction. So the enzyme that's controlling this, if you can imagine, whenever you're carboxylating something, adding a carbon into it, you can imagine what the enzyme is actually called. This enzyme here that's working here in this step is actually called pyruvate carboxylase. So again, what is this enzyme called?
It's called pyruvate carboxylase. And what this enzyme is doing is it's driving this step so that he makes OAA. Now oxaloacetate, he can't get through the membrane.
But guess what? This guy can. This guy here.
So this step is actually reversible. So I'm going to represent this in black here so we can differentiate from all these other ones. So this step is reversible. What is this molecule right here called?
This molecule right here is called malate. Now what happens is OAA can get converted into malate. Then this malate can actually get pushed.
out of the mitochondria. When the malate is pushed out of the mitochondria, this is really cool, it's kind of interesting the way our body does this, but this malate gets pushed out. When he gets pushed out, it's pretty funky what happens, but it's cool.
Now look, here's our actual malate. The malate is going to be acted on by another enzyme and that what's going to happen is This malate is actually going to be converted into, here you go, back to oxaloacetate. So OAA got converted into malate, and then malate gets pushed out.
And then when it gets pushed out, he gets reconverted back into oxaloacetate, OAA. Okay, so now who is this guy right here? Who is this one right here?
This guy specifically, our malate, and this guy right here is our... oxaloacetate. Now what happens is oxaloacetate, we don't want to convert them into pyruvate because that's not a reversible step.
What's the next one right above that? PEP. So now what I'm gonna do is is I'm gonna take OAA and I'm gonna convert that OAA into PEP. But I have to have an enzyme that can do the opposite of what this enzyme did because what does this pyruvate carboxylase do?
He added a carbon because this was three and this was four. Now I'm going from four carbons to three carbons. So what did I have to do?
I had to remove a CO2. So now I'm pushing a CO2 out of this. So now I'm getting rid of CO2.
Just like I put a CO2 into this reaction, I'm getting rid of it. What's another thing that's happening? This one doesn't have a phosphate on it.
This one does. So that means that by some mechanism, I had to add phosphate into this. So what is the enzyme that's catalyzing this whole step right here? The enzyme that's driving this step is called phosphoenolpyruvate carboxykinase. They refer to it as PEPCK.
So again what is this enzyme here called? It's called phosphoenolpyruvate carboxykinase. So this phosphoenolpyruvate carboxykinase is stimulating this step here.
What is he doing again? He's putting a phosphate onto OAA and he's getting rid of a carbon in the form of carbon dioxide and then converting it into PEP. And then where can PEP go? He can go to 2-phosphoglycerate, 3-phosphoglycerate, 1,3-bisphosphoglycerate, back up to GA3P, back up to fructose 1,6-phosphate.
Oh, he's stuck. Now what do you have to do? Well thankfully, God has provided another enzyme at this point right here.
And this enzyme is called Fructose 1,6-bisphosphatase. And what this enzyme does is, is he helps to trigger the opposite reaction. So you know how this was fructose 1,6-bisphosphate?
This enzyme fructose 1,6-bisphosphatase will cut the phosphate off of the one carbon. So what comes out of this reaction? What will actually be released as a result of this? You'll release that phosphate.
That's representing our phosphate. This will go up to this point. So now you go to fructose 6-phosphate and then fructose 6-phosphate can convert it into glucose 6-phosphate.
But this glucose 6-phosphate, he can't get out. Where does he have to go? He comes over here. So now this glucose 6-phosphate comes over here. What is this guy right here called?
This guy right here is called the smooth Endoplasmic reticulum. So over here you're gonna have your smooth endoplasmic reticulum. In the smooth endoplasmic reticulum you have a special enzyme. Look at this enzyme here.
It's inside of this actual smoothie R. So if it's inside of the smoothie R you have to bring the glucose inside of the smoothie R in order for this enzyme to be able to function. This enzyme is going to rip that phosphate off of the 6 carbon of glucose.
So look what happens. Glucose, 6 phosphate is going to come in. It's going to come in through this channel.
This is a glut transporter, or T1 they call it. It's going to move across this enzyme. What is this enzyme going to do?
It's going to rip a phosphate out. So now we got rid of that phosphate off of that guy. So now what do we have here? What will be remaining out of this?
One, two, three, four, five, six. And then if you remember... There's six of these guys that is our glucose. Where's that glucose going to go? That glucose is actually going to exit out through this other glucose transporter they even call it T2.
So again this is T1 this is T2. It's going to come out and then where? Then it can actually go out through a glucose transporter. So maybe it can come out through this one and be put into the bloodstream.
So again, what's being put into the bloodstream here? If we draw it here. One, two, three, four, five. One, two, three, four, five, six.
Sorry, I'm messing up my counting here sometimes. All right, so there's our glucose. And then we have into the blood our glucose.
What was the original problem, guys? What was the problem of why we had to do this? Let's come over here.
Why did we have to do it? Because the blood glucose levels were low. What did we just do to the blood glucose levels? We brought it up. So now, now that we've started this whole process, we did it specifically showing how that works with this lactic acid being converted into pyruvate.
And then that pyruvate gets pushed in here. Then what happens to him? He goes and gets acted on by pyruvate carboxylase, gets into OAA, then he gets converted into malate. Malate gets pushed out here, back into OAA, worked on by PEPCK to PEP, all the way up until it gets stuck at this point. Fructose 1,6-bisphosphatase rips that phosphate off, takes them up to the next problem, which is G6P.
If you're in the liver and the kidneys, you have this enzyme, which is called, what is this enzyme here called? This enzyme is called glucose 6-phosphatase. So this enzyme is called glucose 6-phosphatase.
Okay, then it gets converted into glucose because it rips the phosphate off. That glucose goes out of the smoothie R and out back through T2 into this cytoplasm and then gets pushed out of a glucose transporter into the blood and the blood glucose levels goes up. What else can contribute to this?
You see this guy right here? This is triglyceride right? So this is our triglyceride. What is this triglyceride gonna do?
So here is our triglyceride and if you know about triglycerides, they're actually composed of two components. You see this head part of it? The head part of this triglyceride is consisting primarily of what's called glycerol.
So let's say I put it like a dividing line down here. So this component of this side right there is the glycerol. That's the head. Over here, all of these little tails, all of these three tails here, one, two, three, that is for your fatty acids.
Okay, so triglycerides are broken into two parts. Glycerol fatty acids. What I'm gonna do is I'm gonna activate some enzyme and that enzyme is gonna break this Triglyceride into two components one component is gonna be the fatty acids.
So now let's draw here. Here's our one fatty acid There's our two fatty acid. There's our three fatty acids. Okay? What's the other component?
The other component is going to be the Glycerol so you have two components here. One is the glycerol that we broke it down into and the other one is the fatty acids. What is this process called whenever you break down triglycerides into fatty acids and glycerol?
They call this, okay, lipolysis. Okay, this glycerol is going to contribute to this process. How? He bypasses this step.
He's kind of lucky. So what the glycerol does is he actually gets acted on by a special enzyme. And he gets converted, so now let's actually show the glycerol as a result of this reaction.
Here's our glycerol, and then what we're going to do is we're going to put, glycerol is three carbons, so what we're going to do is we're going to put on the third carbon, we're going to chain a glucose on there. So what had to happen in this part here? There had to be some type of glycerol kinase, which puts a phosphate into this reaction, usually in the form of ATP. But now we got this glycerol 3-phosphate.
So what is this molecule here called? This molecule is called glycerol. Specifically it's called glycerol 3-phosphate. That glycerol 3-phosphate is going to get converted into dihydroxyacetone phosphate.
You see dihydroxyacetone phosphate? There's just a little NADH mechanism that works here. But DHAP, where can he go?
He can go up to fructose 1,6-phosphate. Then from fructose 1,6-bisphosphate, if he's acted on by the fructose 1,6-bisphosphatase, he's converted into fructose 6-phosphate. Then from fructose 6-phosphate, he's converted into glucose 6-phosphate. Oh, he's stuck. Where does he go?
Smoothie R. What happens in the smoothie R? He gets taken into the smoothie R by... T1 acted on inside of the smoothie R by the glucose 6 phosphatase enzyme and converted back into glucose taken out of the smoothie R through T2 and then put out of the blood through the glucose transporter. Okay now technically I'm not going to mention it but these fatty acids they can be involved in it but generally they're not going to be they're actually going to get pushed into another pathway I'm just going to show here with a straight line they will be involved in being converted into acetyl-CoA.
And this is called beta-oxidation, but we'll talk about this. There is a phenomenon where the fatty acids, if you have what's called odd-chain fatty acids, so I'll put here as an exception, it's insignificant because the amount of odd-chain fatty acids that contribute to specifically gluconeogenesis is insignificant. But some of these odd-chain fatty acids, they can.
actually be pushed into this guy right here called succinyl-CoA and then eventually to malate and then that malate can get pushed out and be Contributed to this process, but it's so insignificant that it's really not even considered to be a part of that mainly just glycerol Okay, one more inside of our cells you have proteins. That's where a good portion of our actual Proteins are going to be primarily found now when you need glucose Sometimes your body might have to use some of the amino acids from these proteins. So you know what happens whenever you break down proteins? So let's say I take this actual protein and I catabolize this protein. So I undergo catabolism of this protein.
If this protein is catabolized, what is that called when you have this? This is called again, protein catabolism. In this process, now what I'm going to do is I'm going to break this actual protein into its individual amino acids.
What I'm going to do now is I'm going to zoom in on one specific amino acid and look at how it's affecting this process. So let's say here I have an amino acid, but I talk about really some specific ones, okay? So actually no, we won't do that.
We'll talk about that individually with protein metabolism. So what happens with this amino acid? This amino acid can react with another molecule.
This molecule that it's going to react with is going to be some type of keto acid. What do I mean by keto acid? Usually this keto acid is called alpha-ketoglutarate.
There can be another one which is called oxaloacety, but generally these are usually Krebs cycle intermediates. What happens is this amino acid and this keto acid are going to react with one another and then as a result so let's say this amino acid reacts with the keto acid. The keto acid is going to be converted into a new molecule. This new molecule is now going to be a new amino acid.
Okay? Generally this new amino acid is usually glutamate. Okay, then this amino acid is actually going to be converted into some type of modified keto acid. Or just in general, a keto acid.
What do I mean by this? It depends upon the amino acid. But some of these amino acids inside of our body, some of them, mainly one of them is actually specifically called alanine.
I'll write it here. Specifically, one is called alanine. This right here, this modified keto acid, can actually get converted into pyruvate.
What happens here again? Specifically. This modified keto acid can actually go and be converted into pyruvate.
Where can pyruvate go? It can go into forming oxaloacetate via the pyruvate carboxylase. Then it can get converted into malate. Then from malate, it can go back into OAA. Then it can go to PEP, and then eventually you know the whole process.
It can go back up and make glucose. That's one mechanism. Look what else can happen with these keto acids. This is pretty cool. It can come into a specific point of the Krebs cycle.
Maybe one of them is acetyl-CoA. Okay, so maybe one of them is specifically acetyl-CoA. Maybe he can actually, one of the amino acids can get converted into acetyl-CoA. Some of them can actually be converted into...
Specifically, other Krebs cycle intermediates. One of them, for example, is this guy right here. This guy right here is actually called alpha-ketoglutarate. He can be converted into him.
There's some of them that can be converted into other different Krebs cycle intermediates, like succinyl-CoA or oxaloacetate, but you get the point. the overall point of this then? These modified keto acids they can be converted into different points.
One point is they can be converted into pyruvate. If it's converted into pyruvate, where can that pyruvate go? It can eventually be used to make glucose.
What if this is actually converted into acetyl-CoA? Where does acetyl-CoA go through? It goes through all of this process and eventually it goes to OAA or it goes to this malate, right?
And where can this malate go? It can go out here. Let's say it gets converted into alpha-ketoglutarate. Where will that eventually go?
It'll go to malate. Where will that malate go? Out here. Let's say it goes to succinyl-CoA.
Succinyl-CoA goes to eventually malate and goes out here and helps with the making of glucose. So it's amazing the way our body performs these processes. So now...
To finish it all off, what are the actual substances that can be contributors of gluconeogenesis? What are our contributors here? One of them we said was lactic acid, which is coming from the muscles.
The other one is going to be glycerol, which is coming from the actual triglycerides. The other one is going to be amino acids. And then technically, if you want to throw this one in there, I'm going to do it in a different color because it's not as significant. But it would be the odd chain fatty acids. Okay?
But again, these are not as significant because very little amounts of these are actually contributing to gluconeogenesis. Last but not least, what hormones are helping this process? Because it's not just good to know all the things.
that are involved but what hormones are actually assisting in this process. So now let's write down specifically what hormones are involved in gluconeogenesis. Who's helping this process occur? So the main hormone is going to be glucagon, which is made by your pancreatic alpha cells, norepinephrine, epinephrine, so your catecholamines, cortisol, and I'm going to put a star.
next to this guy because his prime metabolic effect is going to be gluconeogenesis. And we can even say thyroid hormone. So even thyroid hormone. So I'm going to put thyroid hormone.
And then we'll put one more and that's going to be growth hormone, GH, right? So again, what hormones are contributing to this actual process here? Glucagon, norepinephrine, cortisol, thyroid hormone, and growth hormone.
These are the main ones that are contributing to the actual gluconeogenesis. So we know what gluconeogenesis is. What kidney neogenesis is, it's the formation of glucose from non-carbohydrate sources. We know that it's occurring in the liver and in the kidneys, primarily the proximal convoluted tubule.
We know it's occurring because your blood glucose levels are low, hypoglycemia, so maybe below 70 or 80 milligrams per dl. And it's also occurring because the brain needs glucose. It's its primary source of fuel. And you don't want it to make ketone bodies because they're acidic. And you understand this whole process of how gluconeogenesis is occurring.
And you understand the actual three main gluconeogenic factors, lactic acid, glycerol, amino acids, and chain fatty acids. All right, engineers, I hope all of this made sense. I hope you guys really enjoyed it. If you did, hit the like button, subscribe, leave a comment. down in the comment section.
We look forward to being able to hear from you guys. Alright Ninja Nerds, until next time.