Q&A #8 | Randle Cycle, Alkaline Diet, and GLUT Drugs
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Welcome everybody to another episode of Dr. Matt and Dr. Mike's Medical Podcast. I'm your host, Dr. Mike Todorovic, and today I'm joined by my co-host, Dr. Matthew Barton. How are you, Matty? I'm so tired of millennials and their attitude. Always walking around like they rent the place. Are you a millennial? I think I just scrape in. Just scrape in as a millennial? Yeah. So we can make this joke because we're one of them.

Exactly. Exactly right. That's right. I was on Instagram before and I, because you know how you and I are doing, we're trying to put out our YouTube videos more consistently, right? So we're trying to put one long form video out every Wednesday night and a short form every Monday and Friday. So I thought, okay, I need some ideas for some of our short form two minute videos. So I went on Instagram and said,

hi, what do you think would make a great physiology topic for two minutes? And so many comments back, which is great, but I would say 90% of them I've already done as a short two-minute video. Some of the comments were videos that I posted up within the last week or two. So it just goes to show that people don't

That's right. People don't always, you know, you think you've got this audience of, you know, on our YouTube page of hundreds of thousands and on Instagram, tens of thousands. And you go, yeah, everyone knows what we're doing. Everyone's up to date. They know all the content that we've released. People don't. It just goes to show that I'm not the center of everyone's universe, Matt, which surprises me because I probably should be. Well, maybe that's the problem. Maybe that's the problem.

Anyway, so we're doing a Q&A. This is actually our eighth Q&A, Matt, just if you wanted to know which number we're up to. We're up to number eight. Thank you. We've got questions. Matt's put his hand deep into the mailbag and he's pulled out a bunch of questions and a bunch of thank yous. Maybe there's going to be a bit of harassment here. We'll see. I haven't read any of the messages yet. I don't know how bad it is.

Well, that's right and how deep you'll have to go. So I'll start first. I'll do our first thank you. Well, let's see. This is from Rose. The subject is, thank you. You were brilliant. So this is a good one. It says, your videos are amazing! I'm currently studying for a very important entrance exam and through your excellent explanations, I'm having so much fun while studying. That's brilliant.

Awesome. I feel like when I do my videos, Matt, my aim is to not let there be a silent moment, almost like this podcast where I don't let you speak. There's no downtime. We're not allowed to be, there's not allowed to be any second.

Of silence. So she also says, I'm making so much process through your help on YouTube and this motivates me a lot. I'm talking mostly about your neuroscience related videos, which must be mine. I never found someone explaining this so well and I'm not even an English native speaker. I'm German. Guten Tag. Guten Tag. Thanks a lot. Many greetings and only the best for you heroes. Rose, how nice is that? Oh, very nice.

Thank you, Rose. Thank you, Rose. Any recommendations as to you, our dear listener? If you have recommendations for videos, please send us an email, admin at drmattdrmike, and we will add it to the list. Matty, what have you got? What's our first question for today? Okay, so this question is from Sabrina, and her message is, hello. The Teenage Witch.

Hello, I'm new to your channel and new to cell biology. Learning a ton, thank you. I searched for a video on the Randall Cycle to see if there is truth to the fact that an excess amount of fatty acids, also known as high fatty diet, can hinder glucose from entering the Krebs Cycle. Thanks. So this is Roger Randall's cycle.

Roger Randall. Isn't that Roger Ramjet? That's right. Roger Ramjet, here's our hero fighting for our freedom. Freedom. Remember that? Yeah. Remember that five-minute propaganda, five-minute cartoon propaganda that we used to watch when we were kids in the early 90s? So the Randall cycle. That and Banana Man.

Yeah, I don't know if that's, I don't know, big banana propaganda. I wonder who's paying for that. Potassium. Oh, big potassium. Of course it is. Just like the spinach with Popeye. Of course. Was that actually made by a spinach company originally? I don't think so. Oh, okay. So, Randall Cycle. Have you heard of it before? To be honest, no.

Yeah, I've heard of the Randall cycle. I didn't know a huge amount about it. But I think the important thing for people to be aware that when you hear of something like the Randall cycle and you're thinking about metabolism, it sounds like, you know, the Krebs cycle, right? Oh, it's another metabolism-based cycle named after some old dead white guy. Claudia Krebs. But in actual fact, Claudia Krebs is a friend of ours. Yeah. Isn't that...

Yeah, but it's not her cycle, is it? I don't think so. She could take ownership if she wanted. The Randall cycle is, yeah, it's not a metabolic cycle like the Krebs cycle. So remember the Krebs cycle, you know, you've got molecules that are being modified in chemical reactions to basically ultimately produce energy and carbon dioxide and so forth. Instead, the Randall cycle, it's a conceptual model. So basically it's describing...

how two energy sources, which are glucose and fatty acids, how they actually compete for use within tissues of the body. And the tissues that we're talking about are predominantly the liver, the skeletal muscle, and the adipose tissue. So it's based, the Randall Cycle is about fuel selection. And effectively it says that, you know, when you've got one predominant fuel source in the body, it's going to inhibit the use of the other. Right?

If you've just ingested a large fatty acid based meal, it's going to preference fatty acids within the metabolic processes and that will in turn inhibit glucose and vice versa. There's a couple of nuances that need to be discussed, which is where the tissue is and what the circumstance is. Effectively, the Randall cycle is a real cycle, but again, there's nuance.

Do you want to chat about some of the nuance, Matty? Yeah, sure. So what was the first reason for that being discovered, the cycle? Was there something that they were trying to investigate? Yeah, well, it's got to do with the fact that if you're fasting or you're performing some sort of exercise, you're going to preference certain fuel sources. And so off the back of that, it was...

they were looking at, oh, okay, so if fatty acids tend to predominate, glucose tends to be, glucose utilization tends to be inhibited. And if glucose is predominating, fatty acid oxidation, which is the process of pulling its electrons off to ultimately make energy,

that is being inhibited. And so then they did a range of experiments where they basically will, you know, they'll throw fatty acids into the blood and then they'll see, okay, what's happening. And effectively what happens is that when you've got a predominance of fatty acids, the fatty acids will be oxidized because that's the largest fuel source at the moment available in the body. They'll get oxidized to form acetyl-CoA, which we know is the first...

Basically, the first step of the Krebs cycle. And also, it produces huge amounts of NADH, which is an energy-carrying molecule. Now, as we know in metabolism, and I think we've spoken about it before in past episodes,

If you've got high levels of end products, it inhibits earlier stages of that metabolic process. So if you've got high levels of acetyl-CoA and high levels of NADH, it tends to inhibit the use of glucose. So it says, hey, glucose, we don't need to use you right now for energy because we've got these final, well, latter products of these cycles telling us energy is not a problem here.

go store yourself. And so when fatty acids are being utilized, it tells glucose to store itself as glycogen within the muscle and the liver, for example. And that's because high acetyl-CoA and high NADH inhibits an enzyme called pyruvate dehydrogenase. And that's an important enzyme at the very end of the glycolytic process.

Yeah. So it says, stop, glucose stall. And then vice versa, right? If you've got high levels of glucose, it's going to stimulate glucose utilization. Glucose leads to an increased amount of what's called malonyl-CoA, which ends up inhibiting the transporter that transports

fatty acids into the mitochondria to be able to use it for energy. So then your fatty acids can't enter the mitochondria and so the stimulus for them is, hey, you store yourself because we're using glucose. So lipogenesis, which is the storage of fats, that tends to predominate. And again, it depends on what's happening. So if you're fasting, for example, you might go, okay, I haven't eaten, so which one's going to predominate? If you're fasting, we know that we've got

And Matt and I have a book coming out towards the end of this year, and this is one of the chapters, that if you're fasting, you've got a very finite amount of glycogen available in your body, probably about 600 grams worth of available glycogen, but you've got kilograms upon kilograms of fat.

which could effectively be, quote unquote, an endless source of fat. So when you're fasting, your body goes, we've got heaps of fat, let's use that because we know that we've got not enough glycogen, i.e. glucose, and we need to save this for structures like the brain and the retina and the red blood cells and things like that, right? So it says fatty acids,

you're going to predominate in this instance. And so the Randall cycle will occur and it says, okay, fats are used, glucose don't be used for energy, and then we'll tell the liver to actually make new glucose called gluconeogenesis.

So, yeah, that's just sort of like a bit of a summary of what's happening in the Randall cycle. To answer Sabrina the Teenage Witch's question, yes, it is a cycle with some evidence behind it. Did you ever watch Sabrina the Teenage Witch? Yeah, a little bit. I wouldn't say I watched it religiously. Do you remember the cat? Yep. Remember how the cat sometimes was a real cat and then sometimes was a horrible-looking puppet? Yeah, vaguely.

So anyway. So going quickly back to this cycle. So let's say we're focused on the muscle, on the exercise in muscle and early on in regards to an exercise, perform an exercise, presumably depending on the intensity of the exercise, well, let's say it's relatively moderate. Would the –

Early on in the exercise, the muscle is going to be relying on maybe more glucose-like products. And then as it's starting to draw in a longer duration, the muscle will start to be recruiting fatty acids, which have been liberated from adipose tissue. And so that's fine to sustain the energy requirements of the muscle during a moderate exercise in a long duration. But...

At the same time, so fatty acids, let's just say, are fairly abundant in this position or at this point. Is it still fair to assume that what the liver's doing at this point in time is still wanting to create some glucose to be available to the brain? Because that's still a preference source for the brain in most cases all the time, right? Yeah.

Yeah, so if we're talking exercise, generally speaking, and if our...

wonderful listener has been paying attention to our recent episodes on exercise physiology. We spoke about, you know, moderate versus, you know, high or heavy intensity exercise. So, you know, if you want to do exercise for one to two hours straight, by definition, you can't do it at a high intensity, right? So it has to be a low to moderate intensity. And so because of that,

You don't want to use up your glucose because you'll use it very quickly. So your body will start to preference fatty acids within the longer term exercise, right? Because again, it wants to keep the glucose for the brain and those structures that require the glucose.

If you then want to do high intensity, heavy intensity exercise, which again by definition is short term because you can't do it for a long period of time, we need the energy very quickly. Fatty acids don't cut it. We don't get energy quickly through fatty acids. So then we have to pull upon the glucose in that instance and that glucose will... Now this is the thing, the glucose will tend to inhibit the fatty acids.

However, if you have a big adrenaline dump into the bloodstream, and when I say adrenaline dump, I don't mean what you tend to do after you have your steel cut oats. When you have a big adrenaline dump into the system, what ends up happening is it inhibits the Randall cycle so that you can utilize both glucose and fatty acids in a state of fight or flight. So it's not always activated. Again, there is exceptions to every rule.

Yep. Okay. All right. Should we move on to the next question? Well, you've got another listener now. Yes. Do you want me to have a... I do. This one's from Danielle. Danielle says, hello, both. I just want to let you know you've literally changed my life.

Let's see if it's for the better. I'm currently in prison serving 25 to life. No, it says, I'm currently studying for a master's in science in dietetics and have a huge exam coming up that I was panicking for. I discovered your content on YouTube initially and loved how simple your explanations of the body systems were. Every day I'm at uni, I have a three-hour round trip. Oh, sounds like me. Sometimes four hours with traffic. Oh,

I feel you, Danielle. It is horrendous. I, uh,

So when I found your podcast, I was over the moon. I have a two-year-old, so anytime I have time away from my little one is precious and I always felt like I was wasting time commuting, but not anymore. My routine is watching your shorter YouTube videos to get my head around it and then listening to your podcast during my commute. The podcasts are a dream because I feel incredibly productive and they go into so much depth and now I feel like I could give a lecture on the body systems. That's awesome. Isn't that awesome?

I am also training for a marathon and again, I feel so productive on my long runs. So I just wanted to say a big thank you. Your content is the greatest gift to my learning. On a side note, I have inattentive ADHD and really struggle to concentrate in lectures but now I thoroughly enjoy lectures because I can pre-learn using your content

and actually understand what the teachers are talking about, which means I actually listen and engage. I also really appreciate you, Dr. Mike, opening up about your struggles with ADHD. Your tips have also helped my learning. Sorry for the long email. I'm struggling to keep it concise. That's okay. I'm exactly the same, as I can't quite put into words how grateful I am. P.S., you're both genuinely hilarious, which makes the podcast even better. That's good, because I didn't think anyone thought we were funny. Sending a virtual hug to you both from across the pond, Danielle.

Thank you, Danielle. That is amazing. So is the pond New Zealand or Tasmania? That's a question to you, Michael. Ooh, ooh, great question. It could be, you know, the broader pond. Maybe it's just the Logan River and they're just across from me in the next suburb. But can I just say to Danielle that I think one of the reasons why people with ADHD enjoy what we do is because...

we try and do it in a way that makes sense for people who have difficulty paying attention because both you and I have difficulty paying attention, not just to content but to each other, and we have to say things in a way that just keeps things engaging. Hopefully. That's the aim. That's the aim. Thank you, Danielle. Thank you, Danielle. And maybe you can be whilst you're on your marathon run or practicing for it, you are utilizing your Randall cycle.

There you go. Look at you, Matt, bringing it right back. Wow. What an educator. All right. So this is from Nathan. What are we up to? This is a question from Nathan. And Nathan says, hi, gents. I'm a big fan of your videos. As you know, there is a lot of bollocks out there regarding health and fitness. Is bollocks is a UK term? Yeah, it means balls, Matt. We don't really use it much in Australia. No. Thank you. Thank you.

Just for other listeners out there, they might not be familiar with that term. So it's kind of BS, right? Yeah. Anyway, moving on. A lot of made-up stuff. I was wondering if you could debunk on the alkaline diet or alkaline water and can it change the pH level in your body? I know it possibly can to your saliva and urine, but can it change the pH of the body as a whole?

See this as a bit of a myth-busting episode. Cheers, Nathan. Cool. Well, I think broadly speaking, no, it can't. I mean, if we talk about when you say the body, I think would you interpret that as like your blood plasma? Yeah, well, I guess either or really. You've got your plasma, you've got your extracellular fluid and your intracellular fluid, and in any regard, they have to be tightly regulated in a very tight way.

pH range. So you don't really want to go fluctuating the pH too much, but what I'm going to get you to do, because you do it so well and so succinctly, just generally speaking, pH, we know it's a measurement of hydrogen ions and

But why do we use, and it's a concentration of hydrogen ions in a fluid or in something. Why do we have to use the pH scale? Why can't we just do millimoles per litre like we do with everything else?

Well, if I were to take your blood and measure the concentration of the ions in your blood, right, sodium, potassium, magnesium, chloride, and hydrogen, they're all charged atoms or elements. I would measure it and I would get the output, which would mostly be in millimoles per litre, right? And so I'd go, oh, okay, you're at a potassium, let's say your sodium is at 140,

40 millimoles per litre. 135 millimoles.

135, 140. You're right, 140. That's the middle ground. Let's say 140 millimoles per litre for your potassium. And you can go through all of them. You're like 5 millimoles per litre for your potassium, 140 for sodium and so forth. Then when you get to hydrogen, the number's like 0.00007 millimoles per litre, right? So it's a small number.

And there's too many zeros. If you were to write this down, you can make a mistake, right? And if you miss a zero, add a zero, that's 10 times difference. So too many zeros there because we have such a low concentration of hydrogen. So we needed to figure out another way to write it. So what they did was they did a whole bunch of mathematical equations where I did a video on it. So you're welcome to watch the video on how we get pH from millimoles.

And ultimately they turned the millimoles into pH and the pH effectively simply the concentration. Yeah, it's the concentration of the hydrogen. So it's just another way to write millimoles per litre. And so what we've got is that a pH of 7.4, which is our blood pH on average, is equivalent to the 0.00007 millimoles per litre. That's the same thing. Okay.

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We got you. Visit Verizon today. Price guarantee applies to then current base monthly rate. Additional terms and conditions apply for all offers.

But

But there is a solution. A new proposal before Congress would close this loophole and ensure these foreign investors pay taxes, just like the actual plaintiffs have to. It's a common sense move that discourages frivolous and abusive lawsuits and redirects resources back into American jobs in

innovation, and growth. Only President Trump and congressional Republicans can deliver this win for America and hold these foreign investors accountable. Contact your lawmakers today and demand they take a stand to end foreign-funded litigation abuse. Yep. Okay. So just to get a couple of terms down pat here. So you may have heard the term like acidosis and

And so there's distinctions here. When you hear the term acidosis, that's just generally meaning a process, let's just say within the body, that's forming more hydrogen ions. So it's acid forming process. Whereas an acidemia is kind of the collective average of the acidosis. So it's only when the acidosis becomes such that it changes the pHs

the pH of the blood to be out of the 7.35 range and going below that it then quantifies as an acidemia and then that becomes more problematic to the body because it's out of a homeostatic range and that can start to cause effects.

Just quickly, I made a mistake. I said 0.00007 millimoles per litre. It's actually 0.00004 millimoles per litre. So I was off by a little bit. I got the right zeros. I got the right amount of zeros, but I said seven instead of four. But anyway, just wanted to clarify. Keep going, Matty.

And so then you've got on the other side of the coin, you've got the alkalosis, which is a process of hydrogen ions being removed out of a solution. So that's a process of, but it's only again when it becomes...

within the blood, measured in the blood, that it's an alkalemia. So it's just important for those terms that we can – because you could have multiple processes happening all at the same time in your body. You could be having acidosis occurring in multiple parts, but you could also be having alkalosis happening in multiple parts. But it's only when one becomes –

or more dominant that you may then see an acidemia or alkalemia that then becomes problematic because that is likely to cause serious fluctuations in our physiology.

Our body doesn't really want to go through this because fluctuating our hydrogen ion levels can be quite problematic and particularly to the function of proteins in the body because proteins don't like to be outside that range because if they start to be outside that range, they're going to start to change their shape and therefore function. So it's in our best interest within our body to keep the pH in a very tight range. However, so like Mike said...

It's fair that the pH in your blood, which is the plasma, which is basically equivalent to the extracellular fluid in your body, is kept between 7.35 and 7.45. However, there are other parts of your body where it won't be in this range. So for instance, there's your skin, particularly on the epidermis, there's what we term the acid mantle, and this could be

low as four for probably between a four six ph and there's a reason for that it's it's protective it stops certain organisms being able to grow in that particular environment so it's

There's a purpose behind that being that particular pH. Urine is also generally a little bit more acidic because it can also be used, so the pH of urine can be also used to limit growth of certain microorganisms. And then when we go to the stomach, that's the best example where we have a very low pH and that is done for a couple of reasons. Again, as an immune instrument,

innate immune barrier or chemical barrier but it's also there to denature proteins to help with protein digestion when we get past the stomach and we go into the small intestine and we have bile and pancreatic juices that's going to be alkaline so it's actually going to do the opposite

So if you ingest, let's just say the first example of an alkali water, so this would be a water, what would you reckon, Mike? Somewhere between eight and 10, maybe not quite 10, maybe eight and nine. I would say that the standard tap water would make maybe slightly basic water.

I'd have to check that, but I think it's slightly basic. What comes straight out of your tap, but if alkaline water would be something more. It's between 6.5 to 8.5. It goes between. It's obviously going to be closest to 7, but the alkaline water is between 8 to 10.

Therefore, ingesting alkaline water, which has got a pH of, like you said, 8 to 10, as soon as it hits your stomach, you're in an environment of a pH of 1 to 3. So that's all of a sudden changed everything. And once that's processed through your stomach, then you go back to a more basic environment because your pancreas and the bicarbonate secreted from your pancreas but also the bile is going to change it more quickly.

at a higher pH and then ultimately things will be absorbed across the intestinal wall into the blood. But the take-home point here is, well, alkaline water won't overly change things. You may get a slight drop in acidity in the stomach initially, a bit like you would if you had an antacid, but that probably would be transient and it wouldn't be overly profound in that area. But then...

Going to more of Nathan's questions, which is the alkaline diet, it gets a little bit more complicated because depending on...

the diet itself, what the foods that you have can change in terms of why these molecules are then metabolized and broken down elsewhere in the body. They can change the way that the body needs to buffer those, the area where the metabolism has taken place.

The one thing I did forget to mention a bit earlier was if we do have fluctuations in our pH in the body, the body has very tightly regulated processes which come into play very quickly to keep it in that 7.35, 7.45 range. So we've got probably the most important buffer system, which is the carbonic acid buffer.

which is sometimes the bicarbonate system. We've got the physiological systems which play at either end of the carbonic acid buffering system, which is your kidneys at one end and your respiratory centre at the other end. So that's very tightly regulated and it's a very efficient buffering system. We also have phosphate buffering capacity within phosphate ions. We also have protein buffers, which could be albumin, red blood cells or...

maybe hemoglobin is more accurate in that regard. And then you have intracellular buffers, which again, certain things are happening within the cell to buffer it because again, you don't want these fluctuations because it's going to cause changes in protein functions, enzyme functions, so that can be quite problematic. So again, there's buffers there purposely to keep these things in check. So when we eat certain foods...

Once the foods are broken down, digested and absorbed across the intestinal wall into the blood, they can be utilized in different tissues in the body. And depending on the types of chemical molecules that the foods have, they do have the potential to change, I guess you could say, the pH in that environment that they're being metabolized. Now, from the bit of research that I did, there is a fairly...

I wouldn't say common because I don't know, but there is a scale that they use and it's called the Potential Renal Acid Load Scale or PRALS. And this looks at...

I guess you would say the potential of the food being more acid-like or being more alkaline-like. And that's got to do... So, for instance, dairy, meats, eggs can be considered more acid-forming because they have certain chemical constituents, particularly in amino acids, that can...

hydrogen ions into that area. And so when amino acids are being broken down, let's say in the liver or muscle or something like that, these, um, side groups could then, um,

release hydrogen and therefore be acid forming, I guess you'd say, in those regions. But again, it's important to note that your body has all these buffer systems to keep it in that tight range. So in terms of it affecting or changing your blood pH, unless you're consuming so significant amount of this, which I don't think would be possible, you're not really going to pull it out of range completely.

in an acute period. Do you think that's fair, Mike? Yeah, yeah. Basically, to answer Nathan's question, no, it can't change the pH of your blood plasma because we've got half a dozen buffer systems that are there and their whole job is to make sure that things don't

the pH of our blood plasma. We've got excretory pathways like the digestive tract and the kidneys. It's okay for their pH to be off a little bit because that's not the blood, they're the excretion pathways. So it's fine for the urine to be of a different pH and for the poop to be of a different pH

But effectively, as long as the blood isn't, and because we've got the bicarbonate buffer, protein buffers, hemoglobin buffers, phosphate buffers, we've got all these different buffers of the body. Effectively, that will keep us in check. Now, if parts of these buffers are broken, so maybe you've got a problem in regards to your respiratory system because part of the bicarbonate buffer system is...

using carbon dioxide as a way to get rid of the acid, then you might accumulate more acid. But luckily, we've got the kidneys and the kidneys will help excrete the acid. Or if your kidneys are damaged, you might accumulate acid. But this is a failure of organs or a product of disease states as opposed to a product of diet. And so

I would say as maybe a final point is that generally speaking, and again, when it's biology, you can't give definitives, but generally speaking, diet is not going to change your blood plasma unless you are chronically exposing yourself to something highly acidic or highly alkaline over a long, long, long period of time. Because generally, these buffers are bloody fantastic. How's that, Matty? Yeah.

Yeah, that's fine. And just to add final, the cherry on top there, however, the diet can, because the kidney is an excretory organ that's trying to balance the hydrogen and the bicarbonate, there is the possibility that the urine pH will change depending on the food intake or the types of foods used.

and the buffering capacity that's happening in the body and in the kidneys. So there is that possibility that the pH of the urine can change with dietary intake. And the only other thing that I came across was

because there is a phosphate buffer system and only a small fraction of phosphate is available. So a significant amount of phosphate is held within the bone alongside calcium as stores for mineralisation but also to be released at a later date if you need it in your body, in your blood. If you are utilising phosphate as a buffer, and your kidney may be doing so as well,

the bones may be drawing upon some of this phosphate. And if this is drawn out over long, long periods of time, it is plausible that that can potentially change density of bone, but that would have to be fairly long-standing chronic effects. And like Mike said, this would probably also be...

or predisposed by having a respiratory disease or maybe a kidney disease which also changes the handling ability of phosphate.

All right, next message. We've got a message from Jason, and this message says, Dear Dr. Mike and Dr. Matt, see how they put my name first, even though our company name is Dr. Matt and Dr. Mike? Thank you, Jason. Dear Dr. Mike and Dr. Matt, I wanted to take the time to thank you both, well, I don't know about that, for all the help you provide us viewers and nonetheless fans of your physiology content. I'm currently enrolled in BIOL 472 at Penn State University. That's a great university, which is an advanced physiology class.

I'll tell you what, I think Jason's going to have a better understanding of physiology than us after he's finished his advanced physiology class at Penn State. And I cannot put into words how much your videos have aided me in my journey to become a physician. I wish you both the absolute best and please understand how much you are helping aspiring physiologists around the globe. Much love, Jason. Thank you, Jason. We love hearing from our international audience, even though Matt and I have a terrible understanding of geography, which is...

become more and more apparent as we do these episodes. But thank you so much again, Jason. If you've got any suggestions for episodes, let us know. All right, Maddie, what do you got?

You know, Pennsylvania, Penn State's Pennsylvania, by the way, and it's located fairly close to New York State, just so you know. Tell me how you know this, Matt. Just quickly, you're pulling this out of just your brain, obviously. This is something you already know. I think I've driven very quickly through Pennsylvania. Why did you drive so quick through it?

Because I was at the top near the Great Lakes, so I think I just nicked it before I went from New York into Ohio. All right. Thank you, Jason. It was a very quick – so I had technically been there. Got to Penn State though. Okay. I've never been that way. I've been to New York, but I've never been to Pennsylvania. Aren't our friends from Ninja Nerd, aren't they in Pennsylvania or are they in Philadelphia? Yeah.

I can't remember. I'm going to have to ask. Well, Philadelphia is a city in Pennsylvania. Is it really? Okay. Well, I'm showing my ignorance. All right, Matty, what's the final question? Okay, so this is from Asia. Asia says, hello. Thank you for unlocking the complexities of...

You've helped me a lot and still do. So I have a question about the glucose transport or GLUT. I was wondering if these transporters become malfunctioned, is there a medication that can fix them? In other words, is there anything that can target these channels or transporters?

All right, Matt, let me ask you a question in the front end of this. So glucose transporters are sometimes termed gluts, right? Or some people term them glutes because glucose transporters, right? G-L-U-T, that's what it stands for, glucose transporters. I say glutes. Okay, I say glutes. Maybe you say glutes because you don't have any. So we've got all these different gluts, right? Yeah.

There's what glut 9 to like glut 14 or something. There's a whole bunch. And basically these are the channels that help bring glucose in from the plasma or the extracellular fluid into the tissue. So different tissues have different glucose transporters. Now,

Am I right that out of all the 10 to 14 or whatever they are, that only one of them actually requires insulin to bring the glucose in? And that's going to be the GLUT4 transporter, which is used for skeletal muscle and adipose tissue. Is that correct? Yeah. Okay.

Well, actually, I don't know beyond four. I don't know beyond five, to be honest, because I didn't go into that extra level. I think most of the cells in the body fit within one to five. When you go beyond five, it gets quite obscure. So I didn't really go beyond that. But I think generally speaking, yes, you're correct. So when we look at it, it means that

So if we have a high amount of glucose in the bloodstream, that's going to stimulate the pancreas to release insulin. And the insulin will specifically help the GLUT4 transporters to bring the glucose into the tissues that have the GLUT4 transporters.

and that's going to be skeletal muscle and adipose tissue. And if we take that by pure mass, right, by a percentage of mass of the body, the skeletal muscle and adipose tissue is the majority of our body by mass.

So even though there's only one out of the dozen or so glute transporters that require insulin, insulin is obviously very important because that's the main way that we get rid of or lower our blood glucose, using insulin, throwing it into those tissues. But the question that Asia asked, tell me if I got it correctly, is that she wants to know if there's any drugs that specifically target insulin

glucose transporters. And so my question to you, Matt, is, well, is there, and is it going to, will it have to be a drug that targets the glut4? Okay. Good question. And thank you, Asia, for your question as well. So let me give a couple of

Backstory points here. So as you said, Mike, we need to have a transporter for glucose. Glucose, I mean, it's very important as an energy source for all cells or most cells, but it's a very large polar molecule and it can't cross cell membranes by simple means.

diffusion. So therefore we need to have transporters in the body. Now these transporters are generally categorized into two types. There's the gluts which you've already spoken about but there's also the SGLTs or sodium glucotransporters. Now there's kind of two main types of those or two main locations for those. So how they work a little bit different to the gluts is that or the glutes

as I call them, they are symporters. So they require the gradient, the pushing gradient of sodium. So they actually require sodium to do the driving force to get glucose to jump on board with it. So this is the analogy that we usually use is those revolving doors that you see at the bottom of expensive hotels that spin. What spins those transporters is the sodium gradient.

So sodium follows its gradient, spins the door, but glucose jumps on board with it. Now, the two common locations of those are the small intestine and the PCT in the kidney. So in the small intestine, that's a big way that we can transport glucose

glucose and galactose from the lumen of the small intestine across the intestinal wall into the blood, but that's through the gradient of sodium. But we also do that in the PCT to get glucose to be absorbed from the filtrate back into the blood. In terms of the gluts, like you said, one, two, three, four, the only one that's insulin dependent is four, but there is different affinities on the one, two, and three. So one,

is located on the blood-brain barrier, which becomes important for the disorder, which I'll go through in a second, and there's also on red blood cells. So GLUT1 or GLUT1 transporters located in the blood-brain barrier and the RBCs doesn't need insulin, fairly good at sucking the glucose across it. GLUT2, it hasn't got such a strong affinity, even though it's still insulin-rich.

It's not super sensitive to glucose, so it doesn't transport it across as efficiently as GLUT1 and GLUT3. And that's located in the liver, the pancreas, and the kidney. GLUT3 is the brain, and this has got the highest affinity, so it's really good at transporting glucose.

even low levels of glucose across into neurons, which makes sense because that's one of its primary energy source. So it needs to be really good at extracting it out of the blood. And like you said, GLUT4 is muscle, adipose and heart tissue and that's insulin dependent. Now, when we go to the disorders, I just quickly found a couple of the most common ones. Interestingly, the first one I found was the deficiency to the SGLT,

SGLT1 deficiency, which is the one on the small intestine. And so what happens here is as a transporter, it becomes dysfunctional and it no longer can transport glucose and galactose. Now, where that's a problem is these are important proteins

Both of these monomers, glucose and galactose, are broken down from milk. So lactose is glucose, galactose. So the baby, so this is first seen in babies. And so the baby is, or the infant, days after birth, will be starting to ingest milk, either bottle or breastfed.

And what will happen is they're breaking down glucose and galactose, but this transporter is broken or not working well. So glucose and galactose is remaining in the intestine. Therefore, it's generating an osmotic diarrhea and the infant is going to lose a lot of fluid very rapidly. So significant diarrhea.

And it's very difficult for those parents to know if that's urine or feces because of how profuse it is. So they're going to lose fluid quite quickly. And if it's not rectified very fast, they can die pretty quickly from loss of fluids and hypovolemic shock. So the way around this... Just quickly, so this is a mutation in the SGLT1 gene.

gene that allows for this transporter to be produced. And so that means that they'll take in the milk, which will have the milk sugar lactose. They've got the enzyme to break the lactose down into glucose and galactose, which is what makes up lactose. But unfortunately the enzyme, the transporter SGLT1 can't transport it because it's, and then has those effects that you said that the diarrhea causes.

the osmotic diarrhoea dragon water with it. So what do they do? Correct. Well, they need to get IV fluids or parental fluids pretty quickly. Otherwise, they're just going to lose everything and they'll die from hypovolemic shock. But interestingly, if this is...

diagnosed soon after, the feeds will change to a fructose-based feed and then fructose is transported differently to the galactose and glucose and that can be then rectified and so all the feeds from then onwards will be using fructose-based formulas and then they will be able to

get enough nutrition that way and thrive. But if it wasn't, then they would have issues with their nutrition. All right. So that's... Let me...

Yeah. Let me get you back on track here. So she said, are there drugs for the glucose transport? I just like going through these ones. No, no, wait a minute, wait a minute. So this is fine. This is actually all very interesting. So basically to get glucose from one side of a membrane to another, we've got the multiple glute transporters, right? Yeah.

And we've also got the SGLT transporters. I know that the T, it means transporter, so it's redundant saying transporter. But we've got the GLUTs and we've got the SGLTs, right? Now, so my first question is to you, we know that probably the most important SGLT is going to be SGLT2, right? Because it's...

Let's just say I drink a liter of Coke. My bloodstream is filled with the glucose. We know that if I didn't drink that Coke, that all the glucose that I have in my bloodstream, the five millimoles, right, or whatever it might be of glucose in my bloodstream, it will get filtered by my kidneys, but I need to reabsorb pretty much 100% of it back into my body.

into the body, right? And that reabsorption is mostly done by the SGLT2 transporter, right? So that's really important. So my point is that's really important to bring the glucose back into the body, right? So my question to you is, because I'm thinking here, here's an opportunity for a drug. Is there a drug that targets this SGLT2 transporter?

right? And if so, what does it do? And then translate that to what glut transporters do, which is simply to absorb it in the opposite direction, right? To allow for glucose to go into the tissues effectively, to stay in the, right, to be utilized. Let's just talk about that. SGLT2.

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Yeah. So like you said, there is some disorders where this one malfunctions and again, the person has issues absorbing or reabsorbing the glucose from the filtrate back into the blood. And as a result, they have glycosuria, which is just glucose in the urine. That's generally not so much of a problem to them.

they'll be able to still maintain normal blood sugar fairly well. So that's a mutation in a scale of T2. There's no real treatment for that because it's not really required. But as you said, in diabetes, particularly type 2, individuals who have issues...

Oh, okay. Sorry. Well, diabetes just meaning high sugar. So high sugar in the blood. So in diabetes type 2, now I'm going to get to your point or what you're referring to. If there are drugs, so it's not repairing it, but it's actually blocking it. So there are drugs that block this transporter, this SGLT2,

that stops the reabsorption of sugar from your filtrate back into your blood and that then just means the diabetic is expelling more glucose in their urine. So they're getting glycosuria but they're also losing water with it so they're getting a bit of polyuria and that helps them stabilise their blood sugar levels, probably also loses a bit of weight because they are losing calories and that can be a means of maintaining or...

been a little bit better with their blood sugar levels. So there is a set of drugs and these generally end with the suffix glyphosate, which I try to find the tongue Mac. Yeah. Glyphosate, which I think sounds like something from glucose flux, glucose flux. So you lose glucose flux and that's professor Frank for you. So, um,

There is a set of drugs. They wouldn't be the first line of drugs for type 2 diabetes. I mean, metformin would be one of those, but it can be still used to help stabilize sugars and so forth in diabetes type 2. So are you saying that the... So these SGLT2 inhibitors, because diabetes is a problem with too much glucose in the blood...

that simply by blocking the reabsorption of the glucose back into the body through these receptors, you just pee it out. And that's its quote-unquote method of treatment. Correct. Okay, so... That's exactly right. That makes sense. But when I start thinking about all the gluts, right, not the SGLTs, but the gluts, their job is to bring it from the blood into the tissues. So, I mean, would it... Well, I would think...

Would there be a benefit to have a drug that isn't an SGLT? What you spoke about just then was an SGLT inhibitor.

would it be worth having a glut activator a glut stimulator like a glut force stimulator because then that would help pull glucose from the blood into the muscle and into the fat to again effectively lower high blood sugar levels and drops it not by letting it leave the body but by pulling it into the tissues do we have well one would that be worth doing and two do we have one

Good question. I think this probably partly works in the space of type 2 diabetes as well, where over time the efficiency of insulin on its receptor, because when insulin binds to its receptor on these locations, the fat tissue and the muscle, it would then lead to

the glut-4 transported to be then moved from the cytoplasm up onto the cell membrane which improves efficiency of glucose being transported into the cell. And I think in the complicated condition that diabetes is, there can be a desensitization to that whole process and glut-4s aren't being brought up to the membrane as efficiently. So there may be some drugs that kind of do work in that, its ability to become more...

in the processing. But I also read that when we look at cancer cells, cancer cells actually amplify this really well. I'm not necessarily saying...

one subtype of glute transporters, but they need to do it really well to become part of their mutation. Being really efficient at getting glucose into their cell because they change part of the mutation in cancer, particularly malignant cells, malignant cancers, is that they...

so efficient at getting glucose in, but differently to what you normally do with glucose to make ATP, they use it all, they change the glucose to make more cellular byproducts to make more cells because their purpose is just to keep growing and producing more cells. So they actually become super efficient at bringing glucose into their cell and

as part of their mutation and tumogenesis. And we know this by doing, say, PET scans because when we do a PET scan and we have like a radio-linked glucose molecule, we can actually see which cells in the body are most efficient at uptake glucose and that's what the tumour cells are. And so part of chemotherapy is to block that because they're so efficient at bringing glucose in. And so I guess you could maybe...

reverse engineer, look at what cancer cells are doing to make their transporting so efficient. So basically have a glut...

A glut inhibitor. So like we had an SGLT2 inhibitor for diabetes, we're not talking about diabetes now. We're saying that because certain types of tumors and cancers rely upon glucose heavily, that having a glut inhibitor might be beneficial as a cancer treatment. That's right. Right. That's right. But at the moment, we don't have one for a glut inhibitor.

agonist or anything like that for diabetes. I don't even think, do we even have glut antagonists or, you know, blockers or inhibitors for cancer? I don't think we even have those yet. They've probably been tested, but... Yeah, I think that's part of some of the chemotherapy agents is looking at doing so. But the two other glute deficiencies, glute 1 and glute 2...

they can cause quite profound changes. Glute one is probably more neurological. Glute two is liver, pancreas, kidney, liver.

They're from gene mutations. And I guess the treatments to look at that down the track, I don't believe it's currently at clinical trial, but that would be looking at using say CRISPR or genetic, because there is a genetic deficiency or abnormality that's at the gene level and autosomal dominant gene.

mutation, which then changes the GLUT1 or GLUT2 transporter. If we can change that mutation, then we can fix the transporter problem. And so that will probably be something we'll do in the future. But currently that's not being employed from my understanding in both GLUT1, which is more neurological and GLUT2, which is liver, pancreas, kidney. Cool. Well,

So the answer is no, there's no glute drugs as far as we're aware on the market. It doesn't mean that there won't be. But do you agree, Matt? As far as I'm aware, there's no glute drugs. Yeah. In my research, I didn't come across the treatments, particularly for glute one deficiency and glute two deficiency,

is more symptom management than rectifying the disordered transporter. Cool. Thank you, Matthew. Now, I don't have any more, well, I've got heaps of thank yous in the mailbag, but that's the thank yous for today's episode. And they are the questions for today's episode. Hopefully people enjoyed the Randall pathway and talking about the fads of these pH-based diets. Yeah, effectively, yeah.

waste of time and the glut drugs which there doesn't seem to be any at the moment but maybe in the near future so Matthew thank you so much for joining me now for the dear listener you probably could tell that we're doing this online at the moment we could not be with each other as we love to be you

You know, my hand over his shoulder, talking like chums, just having a nice chummy chat as we usually do. You probably heard the ice cream truck in the background.

dinging its way around, even though school's still on. So I don't know what the hell's going on there. And it's pouring with rain. So I don't know how successful the ice cream truck is going to be. But anyway, Matthew, thank you. And we will chat soon on our next episode. And thank, can you thank the listeners for us?

Thank you, Mike. Thank you, listeners, and keep the questions coming in and the very nice compliments. And just so they know, they can send emails to admin at drmattdrmike and you can follow us on social media. You can go to drmattdrmike on YouTube and subscribe. You can also go to our social media accounts, which is at drmiketodorovich. Yes, it's just me. And say hi, and we'll speak to you soon. See you, everyone. Bye-bye.

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