Q&A #6 | Ozempic, MAO-Inhibitors, and Dr Mike was WRONG!
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Welcome everybody to another episode of Dr. Matt and Dr. Mike's medical podcast. Today is a special Q&A episode. I'm your host, Dr. Mike Todorovic. I'm joined by my co-host, George Lucas. How are you today, George? Return of the Jedi. Question. No. Joke. Here we go. Yes. What did the pirate say on his 80th birthday? What did he say? Matey.

All right. They are getting worse. Cognitive decline is setting in. I think we might need to do an entire episode on Matt's cognitive decline and what can be done to help treat it. Great job. Great job. Matty, today we're doing Q&A and I think we should just jump straight into it. And listen to me.

Yes. Oh, good point. Listener mail. So we've got some questions about the human body, how it works, and we've got some thank yous or maybe some corrections, possibly correcting you, which is probably most likely. No doubt. And we should just get started. Let's jump into it. I'll get the first one. So just a huge thank you, Dr. Mike.

and Dr. Matt for the incredible videos. I just watched the enteric nervous system neural regulation video. Fascinating. That's a video I've done. That's my video, Matt. No, yours is mine. I did it. That was your endoscopy? That was, yeah. It was simply I just asked my gastroenterologist to send me the footage of my endoscopy and colonoscopy.

Which was done with the same camera. So it was done with the same camera. And he asked me at the beginning, he goes, look, we're running low on costs. We've only got one camera. Which end should I do first? So they've said, this is Anthea, by the way. She said, I love all the videos. Saying all the videos sort of makes it seem like. There's 500 of them. That's true. But that makes it also seem like they're your videos as well. But anyway, she says they're the best out there.

As a nurse, I'm always interested in gaining a greater understanding of the human body and systems. Keep them coming, Anthea. Thanks, Anthea. We've got another message here. This is from Taz. So I don't think it's the state of Australia. I think it's an individual called Taz. I wonder what Taz is short for. What do you think Taz is short for? Talia? Tasmeen. Tasmeen? Tasmanian devil?

First of all, thank you so much for the time and effort you put into your videos. This must be just directed to me because I don't think you've put any effort into your videos. They're a great help. If you wouldn't mind and if you have the time, could you please do one on taking vital signs both for adult and pediatric and add it to your YouTube? Thanks, Taz. Matt, this would have to be something that you do.

I don't do the clinical stuff. I am not a clinician. So I can't do vital signs, particularly not for pediatric. Well, I could take your vital signs and you could pretend to be the pediatrician.

Pediatric patient quite easily. I could feed the baby. As long as you don't try and pick me up like you always do every time you see me. When we greet each other, instead of a regular handshake, he picks me up and rocks me like I'm an 18-month-old. I'm not comfortable with that. Like Andre the Giant in the wrestling ring. That's also true. Yeah. But I don't appreciate it when you then say, are you hungry, little guy? Yeah.

So first question, Matt, first question we have. So thank you, Taz, and thank you, Anthea, for the wonderful, wonderful emails. This is a question from Eugene, and Eugene's asking if we could help explain certain antidepressant medications and how they work. So let me caveat this, Matt, like I do every week, is that we are not your healthcare providers or professionals. We are not qualified to be healthcare

healthcare providers or professionals. We are educators, university educators, and we teach anatomy, physiology, pathophysiology and pharmacology. We help with mechanisms and structures and functions and things like that. So

Just know that we cannot provide any medical advice in any regard. Just educational information. So just wanted to put that out there. So Eugene's curious about monoamine oxidase inhibitors. Sometimes they're written as MAOIs and their role in treating depression.

There's a couple of questions here from Eugene, but let's just preface by letting everyone know what monoamine oxidase inhibitors are. So let me just begin by saying that monoamine oxidase inhibitors, they've been around for quite a while. Since pretty much the 1950s, they were introduced as a medication.

as a class of antidepressants, but they're a separate class of antidepressants. And they're often used to treat certain forms of depression as well as other nervous system disorders, including panic disorders, social phobias, and depression with atypical features, which can include oversleeping and overeating and things like that. Now, we're not psychiatrists, so the specifics and details of how...

How and why monoamine oxidase inhibitors would be prescribed goes beyond our expertise, but we can talk about monoamine oxidase enzymes and how the inhibitors broadly function. So Matt, let's start. What are monoamine oxidase enzymes? Okay, so this would come to the term monoamine, which would be an amino acid.

mono being singular. So my guess here, please correct me if I'm wrong, Michael. I will. Since you're the biochemist. I'm not a biochemist. What are you talking about? Just go with it. You've done a lot of biochemistry videos. Oh, you mean I'm smarter and more well-read in biochemistry. Yes, yes, yes. That's true. Sorry, go on. So the monoamine refers to a single amino acid being tyrosine. Not always. Okay. So the tyrosine...

Well, in this case, being the amino acid that is being made into, being a precursor of three neurotransmitters. But let me caveat that, that monoamines can be any neurotransmitter or chemical substance

signaling molecule that is made from a single amino acid, which yes, does include tyrosine, but can also include tryptophan and phenylalanine. So there are other amino acids that are included in the monoamines. And then there's subcategories like catecholamines, which are predominantly tyrosine, for example. Right. Okay. So in that regard, for this particular class of medications, which you said as their therapeutic indication would be an antidepressant,

When we talk about depression, that would be, I guess, a definition of persistent feeling of sadness, but also a loss of interest in everyday activity. So these medications...

would be working at a root level around three main neurotransmitters, which would be serotonin, noradrenaline and dopamine. They've been derived from tyrosine, correct? But like you said, you can have other monoamines which could work on different neurotransmitters. Yeah, they'll be recognized as the classical monoamines. Yeah, yeah.

So in terms of the oxidase inhibitor part, that just refers to a particular enzyme that would... And let me just also jump in. Did you say that serotonin isn't from tyrosine? That's from tryptophan.

Oh, is it? Okay. Yeah. So that's why other amines. So dopamine and noradrenaline, they're tyrosine, but serotonin is the amino acid that it's made from. Tryptophan. Yeah. Okay. All right. So that's why the catecholamines are noradrenaline and dopamine, and then you've got others like serotonin, for example, which are a separate subclass of the monoamines. Okay. All right.

So in terms of the inhibition, there's an enzyme that would work. So take a step back for a second. So when we're talking in the context of these medications being antidepressants, they would be working on the assumption that there may be some challenges within the brain around neurotransmitter regulation. And a group of neurons being those that use serotonin as their neurotransmitter, so that's like their chemical signaling molecule...

as well as noradrenaline, which I guess you would say are adrenergic neurons, and also dopaminergic neurons. So those are kind of three neurons that we're talking about today in the context of this medication. And these will have a role within the brain in numerous different ways. But these neurotransmitters are kind of the intermediate between communicating between neuron one and neuron two. We would use the term presynaptic and postsynaptic.

Now, when these neurotransmitters are released... ...and communicating between these two neurons... ...they're not going to stay there forever. They're going to be removed out of what we call the synapse or the synaptic cleft. The space between the two. The space between the two, right. And so usually what happens is there's a mechanism that re-uptakes it. So it kind of sucks it back up into the first neuron... ...so it can be repackaged to be used again, essentially. Now, what this enzyme essentially does...

is it would break down those kind of neurotransmitters within the presynaptic neurons. So before it's allowed to be repackaged, some of this oxidase enzyme would kind of break it up and maybe can be used for other parts, maybe somewhere else. But what this class of medication does is inhibits this enzyme.

So essentially what that means is there's going to be more serotonin, more adrenaline, more dopamine in their respective neurons to be repackaged into their vesicles. So when the pre-snaptive neuron is then stimulated again, you would have maybe a little bit more of a powerful response, hence their effect in depression. Now where it gets a bit tricky is because serotonin neurons

Noradrenaline neurons and dopamine neurons have very diverse functions. They're not just doing one thing. For instance, serotonin does anything from mood, well-being, sleep-wake cycle, appetite feeding, pain modulation, cognition, sexual behaviour. Noradrenaline, very much centred around arousal, stress response, mood, emotion, attention, because that sometimes fits with...

Other conditions like, what's the one we're going to talk about soon on our podcast? ADHD. ADHD. So that would be an attention challenge for some individuals. Not enough attention placed, therefore challenges with condition and memory and so forth. Also with pain and sleep. And then when we go to dopamine, probably we've heard a lot about reward pathways, motivation pathways.

mood cognition, awakefulness, mood again. So you can see from that there's a lot of diverseness in what they're actually doing. Or diversity. Diversity. So just changing the presence or the amount of these neurotransmitters doesn't solely focus on the one thing. It has quite wide-ranging functions and outcomes which can be challenges with these medications.

Because, and this particularly goes to, with this particular class of medication, the monoamine inhibitors, why are they used or maybe then why they're not used as the first line therapy in depression is because they have a relatively large or wide side effect profile. And that goes to or speaks to all those diverse functions that I just spoke about in the brain. So to clarify, we've got...

All of these neurotransmitters, noradrenaline, dopamine, serotonin, all made from a single amino acid, they get released in the brain from a neuron into the synapse where it binds to another neuron to have its effect.

And like you just said, the effects are broad, right? Quite broad depending on the neurotransmitter and depending on where it's released and which neuron it speaks to. And that the monoamine oxidase, that the enzyme monoamine oxidase breaks down these neurotransmitters to sort of regulate its levels, maintain homeostasis. So the levels don't get too high, it can help break it down.

But there seems to be over the years or decades, evidence has accumulated that dysregulation of monoamine neurotransmitter systems are implicated in the development of depression. So I think researchers would have thought, well, if the dysregulation of these monoamine neurotransmitters are implicated in depression, then maybe we try and

increase the amount that are available. And so then we can get inhibitors of the monoamine oxidases that stop their breakdown and they remain elevated and accumulated. And like you said, the potential side effects of that could be quite broad because of the broad effects of the individual neurotransmitters. Okay, cool. So let me ask the first question then from Eugene. I think that's a really good question.

background on it because it's hard to really answer any of these questions without understanding the MAOs, monoamine oxidase inhibitors. So why might monoamine oxidase inhibitors be effective for some individuals when other classes of depressants are not? That's a hard question. It is very hard.

Well, this just speaks to the personalised approach in mental health therapeutics, that this would just come down to the therapist, the psychiatrist, that would work with the individual on a personal basis and figure out their challenges and the medication that best suits. As I said earlier, it's probably not going to be the first line of medication with depression. The first line is usually the SSRIs, which are the...

selective serotonin reuptake inhibitors so that's the kind of transport system of just focusing on serotonin only to bring it back into the presynaptic neuron and with those line of medications i would have a a short no a narrower that's probably the wrong term as well specific less side effects as the monoamine inhibitors

So that would be generally, from a clinical standpoint, the first line of antidepressants that would be used. And if they aren't necessarily effective, then the therapist may go into other options, which this has been one, the monoamine oxidase inhibitors. And that could work for certain individuals. And that's potentially where this question is focused or being aimed at, that these particular...

line of medication might be more suitable for some types of depression. Yeah, yeah, I think that's pretty safe to say, you know, outside of genetic and biological variability that sort of underpins the vast majority of differences in our anatomy and physiologies, you know, that's the baseline that's going to make us all different, our genetics.

and our just broad biological variability. So there's that. And I think you also spoke about some of the reason or some of the specific indications for the monoamine oxidase inhibitors is not only depression but also other things that go with that being feed-in, so more likely to...

want to eat more and more likely to want to sleep more. And as I spoke about with the functions of serotonin, noradrenaline and dopamine, they can have effects on the feeding part of your brain, the hypothalamus, but also the sleep-wake cycle, your depth of sleep, but also your wakefulness. And so that may help with those atypical aspects of depression.

..being the feeding and the arousalness. And so that's where maybe they are more effective for some than the SSRIs. Yeah, so, you know, broadly...

Why might MAOIs be effective for some when other classes of antidepressants may not? You know, genetic, biological variability, the fact that it works through a different mechanism than other drugs, which, like you said, might suit an individual compared to another. So, like you were saying before, with the SSRIs, the selective serotonin reuptake inhibitors, you know, that's one... That's serotonin, which might be the issue for a lot of people. But, you know...

It could be due to, like you were saying before, certain types of depression, such as atypical depression, possibly involves multiple neurotransmitters that go beyond serotonin, so go beyond the SSRIs and might extend out to the dopamine and noradrenaline neurotransmitters. But again, I don't even think the literature is confident as to why, you know, the why difference, because again, it's just...

Many drugs work for some people and not for others. Like you said, personalization of medications are an important thing. That's why you need to have a good relationship with your medical provider. All right. Next question is, why is it necessary to follow a specific diet when taking monoamine oxidase inhibitors? Well, the one part that I came across this in the research that I did was a particular...

What was it? A precursor, would you say? Tyramine? Is that a precursor of tyrosine? Well, no, I would say it's a stimulator and like a sympathomimetic. So it's sort of similar to...

the tyrosine-based neurotransmitters like noradrenaline. And so in a way, if its levels elevate, it can stimulate its release or it can even replace its presence in the neuron.

So the only thing that I came across in terms of diet, following a specific diet with this particular class of medication is around tyramine and specifically tyramine-rich foods. So these would be things like certain cheeses, wines, beer, even...

yeast-based foods and like in Australia where you have Vegemite. Ah, true. But I think in Britain they have Marmite which also has a question around... So when you look at...

the full guide of this medication. So if you wanted to really do a deep dive in understanding all the aspects, as I guess a pharmacist would need to know with medications, if you looked at certain foods that might have high tyramine, Marmite is one, probably not as high as cheese or some of the cheeses or some of the fermented foods.

But what seems to happen is with high-rich tyramine foods, in your gut you have enzymes, the same enzymes, the monoamine oxidase enzymes within the gut wall and these modify tyramine. And so if you're inhibiting it through this medication, so insulin,

In the indication of this particular medication, you're wanting to inhibit the enzymes in your neurons in your brain, but it's also going to non-selectively inhibit other enzymes that are the same. And in this case, it's going to be in the gut wall. And that's going to stop or have an effect in the breakdown of tyramine in your food or from your food. And therefore, you have a higher amount being absorbed into your blood

which then runs the risk of having a side effect that's associated with this medication being a hypertensive crisis, which is a number of things, hypothermia, hypertension, increased heart rate and potential arrhythmias. So that would be a caution that the doctor would be giving patients with this medication is be mindful of these types of foods that you may be ingesting.

I think that's because tyramine, like we said earlier, acts as a sympathomimetic. It mimes or copies that of the sympathetic nervous system, which is like the noradrenaline. Because noradrenaline is a monoamine, tyramine is a monoamine. Like you said, generally speaking, we'd have MAOs breaking it down, regulating its level. But if you've got...

inhibitors of that, it's just going to elevate, act like a sympathomimetic, stimulate the sympathetic nervous system and then you can have that hypertensive crisis. So yeah, avoiding certain types of foods might be recommended for people on this medication. Aged cheeses, cured or smoked meats, alcohols and like you said, fermented products which might contain yeast and so forth. Alright, third and final question for this first question because we're spending a lot of time on this first question.

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Download the Redfin app and start searching today. So what could explain why someone might struggle with sleep while on this type of medication? It goes to the explanation I gave at the start. All three neurotransmitters have a heavy role in sleep cycle regulation. So serotonin does definitely. And serotonin, my understanding, is a precursor to melatonin, which again plays a role in

sleep-wake. Noradrenaline, as we know, is a stress hormone. So it's important for wakefulness. Fight or flight. It's fight or flight. Think about all the things that happen when you get scared, right? Like you're not going to sleep when you know that there's a tiger around the corner. So if your body's flooded with noradrenaline, you think sleeping is going to be on the cards? Correct. And so REM, which is arguably one of the deepest problems

And Stimpy? Portions of your sleep. Not REM. Oh, okay. REM. Yeah, sorry. That's part of your...

Sleep cycle, which is one of the deepest points, that noradrenaline is the lowest it's ever going to be in your body when you're in a REM state. So with this medication, you're actually going to have high levels of noradrenaline. So that deeper sleep that you normally need to have, you're not getting it. And then dopamine also plays a fairly strong role.

strong role in sleep. So all three neurotransmitters have an effect with sleep. The only thing I'll just add there, and you might be able to add to this, Mike, there is two subtypes of monoamine oxidase inhibitors. There is the non-selective and the selectives. The non-selectives will obviously affect all three neurotransmitters, whereas the selectives is more just for dopamine. But they seem to be used more predominantly in Parkinson's disease.

So, did you come across that with your PhD that they would use this medication for Parkinson's disease? I think early on... I know, I put you on the spot there. No, no, that's okay. I think early on, yes, because dopamine and tyramine are metabolized by both monoamine, oxidase A and B. So...

I don't know. I know that it has been used for Parkinson's disease, but I think it's people with Parkinson's disease, but also people with multiple systems atrophy as well. So I think when it involves these neurotransmitters in other disorders or conditions, it might be useful. But I think, again, the...

lack of selectivity of the specific type of neurotransmitter can bring up issues, right? Because we know that with Parkinson's disease, it's a dopamine-specific issue. And so...

Yeah, I think the problem is too low dopamine, which makes sense. Stop the inhibition of dopamine breakdown. Hey, that's great. But I think they realize that they could just pretty much put in a dopamine precursor and that would probably be better because it's not affecting the noradrenaline or serotonin. All right, okay. So thank you, Matt. All right, great. Question one, done. Thank you, Eugene, for the question. Matty, do we have any other listener mail?

Yeah, so this one's from Helen. So Helen says, I just want to say how much your podcast and YouTube videos have helped me. I'm a 55-year-young nurse who in a wisdom decided to do a master's in advanced professional practice. I was struggling to understand a lot of physiology with my menopausal brain. As I'm quite a visual learner, I'm searching the net for videos on anatomy when I stumbled across your YouTube videos. They are so well done and easy to understand. I've learned so much and rather than finding...

Learning a chore, I've really enjoyed it. Thank you again from a grateful learner. How nice. Thank you, Helen. I love these emails. People listening might go, God, you guys love congratulating yourselves. And the answer to, well, it's not really a question, but it's a statement. The answer, my rebuttal to that statement is yes, we do because we put a lot of time and energy into making these videos. We're proud. Matt won't admit that he's proud, but I'm proud. Proud of you? And I'll admit it.

Are you proud of me, Matt? Of course. Thank you, Helen. All right. So here's another one from Bailey. This is just a thank you. Bailey's from South... Bailey's?

Bailey, you put that in your coffee, don't you? Do you want me to put a South Louisiana accent on? I think that would be for the best for everybody. And I think our American listeners would love to hear your, what do you say, South Louisiana accent? All right, here we go. People don't get offended.

I'm currently in anatomy physiology one with a notorious health professor that only 25% of the class passes. I am one of those. Thanks to y'all. I never do this, but you guys really helped me and I know what to do. It's so important to appreciate it. I'm sending my love from South Louisiana, Bailey. There we go. You sound like...

You sound like there's something wrong with George W. Bush is what you sound like. Let me reread in a more sensible voice. I'm currently in anatomy and physiology one with a notoriously hard professor that only 25% of the class passes. Wow. That sounds like your classes. That's brutal. That is brutal. That's one in four.

Four? I'm a biologist, not a mathematician. So one in four, wow. I'm one of them, thanks to y'all. I never do this. You guys really help me just know that what you do is so important and appreciated. Have you been to South Louisiana before? I've been to New Orleans. Ah, that's awesome. I've never been south. I'm not doing geography off the top of my head because I've been reprimanded.

That's true. Thank you, Bailey. Honestly, that is wonderful. And again, if you have any other videos that you'd like us to make, let us know. Let us know.

All right, here's a question from Jeremy. This question is around GLP-1s. What's GLP? Read the question. Okay. This is from Jeremy. Hi, doctors Matt and Mike. Thank you all for your videos. They are incredibly helpful. I'm curious to understand GLP-1 agonists' role in glucohomeostasis. My level of understanding is GLP-1 agonists inhibit glucagon as per stomach emptying symptoms.

and impending nutrients, thus preventing glycogenolysis. If an individual doesn't eat and has reduced glucagon output via Zempik, that's the GLP-1, do they skip into gluconeogenesis and risk ketoacidosis? Are these drugs helpful in hyperosmol situations?

such as in type 2 diabetes, I would like a video and hopefully an answer to this question. Thank you guys so much and I hope to meet you someday. Jeremy.

Hope to meet you too, Jeremy. There's a lot to unpack in this question. Firstly, we need to talk about what GLP-1 is and what GLP-1 agonists are. We need to talk about glucagon and glycogenolysis and ketoacidosis and gluconeogenesis and hyperosmolar situation. So there's a

lot here but to begin let's maybe first talk about GLP-1 and the GLP-1 receptor agonist which he's referred to as ozempic or semaglutide which is probably its additional name. So firstly what is GLP-1 and what are GLP-1 receptor agonists?

Okay, so as you said, there's a lot here, but I'll do my best to break it down. So this class of medication, GLP-1, technically is what we call an incretin, which is a... You say incretin. Incretin. I referred to it the same way I referred to you as a cretin. Sorry, incretin. Sorry, my bad. Incretin.

So what this basically... These are molecules that are released from the gut after food has entered the digestive tract and they are released generally as endocrinal signaling hormones. So some examples here would be CCK, cholecystokinin, which is generally released when you've had more fat and protein in your meal and they are released...

as an endocrinal signaler, but they can also do things like increase gut motility, tell the gallbladder to excrete or secrete. Yeah, I guess secrete its bile, but it will also go in the blood and that plays a role with satiation, as does some other hormones around protein meal. But the one for this one is GLP-1s. So...

What does it stand for? Glucagon-like protein 1. So that's released from L cells, L-cells, and they distal part of your small intestine, proximal part of your colon. They release generally with higher glucose in your meal and they get put into your blood

And they go in the... They obviously go in the blood and they go a lot of places, but they have a profound effect in the hypothalamus, which is specifically the arcuate nucleus, which seems to regulate satiation and...

the feeling of fullness and inhibiting hungriness. So that is a big function. Now, interestingly, it will also go to the pancreas to release insulin. That's going to be its primary function here for this context. So can I just quickly, before you move on, just define again the term incretin? So an incretin hormone specifically...

Released by the gut after eating and it can increase insulin secretion. That's the definition of an incretin hormone. Yep. And to work off that, when we think of insulin release, we would think that the mechanism of insulin release is that glucose is now in your blood. It goes to the beta cells of your pancreas. The beta cells then uptake glucose in a GLUT2 transporter and then essentially depolarizes the pancreas

the beta-2 cell and releases insulin. That's a general mechanism, right? But 60% to 70% of insulin release after a meal actually comes from GLP-1. Yes, it's a strong regulator of insulin release. That's right. So the most profound...

activator of insulin release from your pancreas is in response to glp-1 yes and so these medications and we well the category here would be the semi-glutides which is just a it's a generic name but there are other similar medications that fit here like liraglutide dilloglutide

The glutide part just means GLU, glucagon, and tide is peptide. So the front end, semi, is just kind of the brand name coming from the pharmaceutical company. And let me just take two steps back quickly. What you're referring to is there are drugs available on the market that act like GLP-1.

Correct. That's right. And that's these drugs and these drugs are available for people with type 2 diabetes because they have a problem with insulin. Yes, so they've got a problem with insulin. But I've got a question for you is that if you've got type 2 diabetes... I'll just say that... Okay, you go. Well, I think that this question will help you continue with what you're about to say.

So if you've got type 2 diabetes, you've got an insulin sensitivity issue, right? Yes. So insulin, the final product, that's where the problem is. So why would you take a drug that mimics GLP-1, which is upstream of insulin? Okay, a number of reasons. I also know the answer, but I just thought I'd throw it to you. Okay, so it will...

So when you have type 2 diabetes, in its early stages, you would have a desensitization of insulin or the insulin receptor, particularly on muscle and fat cells. So the muscle and fat cells are less responsive to insulin as they normally would. And so what generally is required from the body is to increase the insulin amount

...that helps you process glucose more effectively...

Now, these medications, the semi-glutides, they probably wouldn't be the first line of medications used in type 1 diabetes. That's usually a metformin, which does a number of different things of glucose metabolism and processing in the body. But semi-glutide seems to be, as I said, a second line, but it can be also used quite effectively with diet and exercise to just help with...

the sensitivity of the insulin and the receptor. But a couple of additional things that it will do is it will tell the brain, the hypothalamus, to be more full, more satiated, so you're less likely to eat and therefore you're also more likely to lose weight. And when you lose weight...

because fat is not only a storage tissue, it's also an endocrinal tissue. And if you're losing weight, you're kind of losing the effect of the hormones that are coming from the fat cells, which can desensitize insulin receptors. So it has a benefit there as well. Did that kind of answer what you thought? Yeah. Well, also, basically, when you...

Think about when GLP-1 is released, right? It's basically released in response to high glucose, so postprandial, so after a meal. So it's good because it allows for you to release GLP when you need to release GLP. When there's other medications that can make you hypoglycemic because it increases insulin production,

throughout a range of times, right? And so GLP-1 can be useful because of its release immediately after a meal. And so by increasing insulin precisely when it's needed, it enhances the agonistic effect or enhances the insulin supply to meet the demand. It can also be another... But you're totally right because it has other effects. And it will also reduce...

glucagon release and so that then doesn't tell the liver to do gluconeogenesis or glycogenolysis so yeah so let's just talk about that just quickly during fasting so the

Between a meal, let's say any time after four hours post-prandial after a meal, your glucagon levels will begin to rise. Glucagon is a potent stimulator of glycogenolysis, which is the breakdown of stored glucose.

to release into the bloodstream, but also a stimulator of gluconeogenesis. So taking other products like amino acids and fats and breaking them down to produce glucose. But GLP-1 receptor agonists, the drugs like semaglutide or a Zempic, they suppress glucagon release when blood sugar levels are high. And this is important because people with type 2 diabetes...

their glucagon levels tend to be quite high because glucagon levels go up when the glucose availability changes, right? Because the negative regulator of glucagon is often insulin, right? And if you don't have much insulin in the body, your glucagon... So people with type 2 diabetes...

They can have high glucagon and high glucose, which is generally paradoxical in a normal... in a person without diabetes, right? They... Usually isn't the case, but it's because insulin is a suppressant. So, of glucagon usually. But in this case, people with diabetes, glucagon can be high.

and stimulate the release of more glucose in the bloodstream, which is not what a diabetic necessarily wants, right? So GLP can also be an inhibitory regulator of glucagon. So this helps reduce hepatic glucose production, so that's gluconeogenesis, but also glycogenolysis, the breakdown of stored glucose, if that helps.

Yeah. So to answer the first question, let's do this systematically, the first part of the question. He says, how do GLP-1 receptor agonists, like a Zepic, regulate glucose homeostasis and what role does glucagon play? So it stimulates insulin secretion. We said that. It promotes satiation or satiety, right, at the hypothalamus. Decreases gastric emptying. Perfect. And decreases...

and decreases glucagon release. Perfect. Which in turn, that last one, decreases the amount of glycogenolysis, breakdown of stored glucose into free glucose, and gluconeogenesis, the production of glucose from fats and amino acids. Brilliant. And the one thing I'll say here is when we're talking about semi-glutide, how it is different to the other GLP-1

agonists is it's got a very long, very long half-life. Yeah, like they take one injection a week basically, right? One a week, whereas the others are usually daily. And so what that then means is this is staying around. So it's changing GLP-1 as a short-term glucose regulator to a long-term glucose regulator. Good point. Almost more like leptin, which is a different –

that's released from fat cells to give you a longer-term satiation. Yeah. Now, the next part of the question from Jeremy is, can GLP-1 agonists cause a shift to gluconeogenesis or increase the risk of ketoacidosis? And we sort of partly answered this. Do you have anything specific you'd like to say here? From my understanding of ketoacidosis, the prime...

The agent here that would lead to a person going into a state of ketoacidosis is a very low level of insulin or if not zero insulin being present and that's why it's such a problem in type 1 diabetics because they are deficient in insulin. At the same time, having a... Well, at least in type 1 diabetics, they have a kind of a very stressful event. This could come about from after surgery...

drinking excessively alcohol excessively the night before or something and not eating or exercising on an empty stomach and then you essentially you are going to gluconeogenesis and lipolysis so your liver is being bombarded with other molecules but you have got no insulin so it's diverting the molecules particularly the fats into ketones and because this particular medication isn't

resulting in zero insulin. If anything, it's probably stabilizing insulin secretion. It's less likely to put a person into ketoacidosis, working from first principles. Yeah. Effectively, if you've got any insulin...

It's a potent negative regulator of ketoacidosis or ketogenesis. And it's also a potent negative regulator of gluconeogenesis as well. And so the GLP-1s would likely not result in people having

getting ketoacidosis because one, helps maintain the glucagon levels and two, the insulin also helps maintain a balance between utilising the available glucose but also undergoing glucogenolysis and so forth, if that makes sense. Yeah, and when you look at the side effects, the most common side effects with the semiglutides or the Zempix or Wagovi, which is the same, it's a brand name of the semiglutides,

The most common nausea, so in a number of clinical trials, the most common side effects in about 17 to 20% of patients who take it, about nausea is the most common side effect. Fomalting is about 6 to 8% of patients. Diarrhoea, 12 to 13%. And then a reduction in appetite, the 6 to 7%. Now, when speaking to a Zempik, as we said at the start, this has been

the primary indication is type 2 diabetes as a hypoglycemic agent. What they found is that it's a significant appetite suppressant. And so this has become a, therefore, moving into the possibility of weight loss medication. And this has become a, as you can see there, that's a side effect, but now it's become a

off-label of use, so for weight loss and so for satiation benefits. So these medications, Zempik particularly, has been used for individuals wanting to lose weight. Now part of the reason for how that works is it having a role in the brain, the hypothalamus, that regulates the feeling of fullness and

but also the stimulus of hunger. And if you are inhibiting that, probably also with the reward pathway feedback loops because another side effect that's common with this medication is the change in food preference. So particularly fatty foods, they lose that desire of wanting to eat it on this medication and that has changed. And I listened to the podcast recently on this and they spoke about the people who are on a Zempik

no longer kind of crave the foods that they once did previous to that. Now, a lot of those foods would be the ultra-processed foods that have been kind of designed to work at our dopamine level or our dopamine pathway, which is very salty, very sugary, very fatty foods. And a Zempix seems to be inhibiting that. And the podcast, which was

Interesting but scary is some of the big food companies are now trying to develop foods that will get around this feedback to stop people's preferencing. So they are still desiring certain processed foods that a Zempik won't inhibit. Because, you know, like probably something like 10% of Americans are on a Zempik now. So it is becoming a very...

popular medication and so if all of a sudden I don't know 10 to 15 percent of our population no longer is buying these foods it's a big money loss yeah

Oh my gosh. We need to do a whole episode on a Z-Pick, I think. We're going to do a whole episode on GLP-1 because otherwise we could be here all day talking about it. Now, Jeremy also has another part to his question, which is about are GLP-1 agonists helpful in hyperosmolar situations? Now, like hyperosmolar, hypoglycemic state, right? So, I think there's a quick way to answer this question and correct me if I'm wrong, Matt, but

GLP-1 receptor agonists, they're a long-term...

treatment for type 2 diabetes. Hyperosmolar hypoglycemic events, they're acute life-threatening complications of type 2 diabetes. This is characterized by extreme hyperglycemia, so really quite high blood glucose levels, dehydration, high serum osmolality without significant ketosis.

So you wouldn't use a GLP-1 receptor agonist typically for the acute management of this because it's not how it's treated, right? It's not fast acting enough to be of effect in this setting. You know, there's other treatments for this. The question might be, well, what about, is it useful as a long-term preventative? Well, in the sense that it is a medication for type 2 diabetes, you know, it helps prevent

and improve long-term glycemic control. So in that sense, yes, it could be a helpful medication. Does that make sense, Matt? Am I...? Yeah, yeah, yeah, yeah. I think it's a bit like DKA in type 1 diabetes. This is a medication... Oh, sorry, this is an acute state that you're trying to prevent...

And that's just through good glucose management. And the same goes with this type 2 version, which is the... What's the actual term that they use for it? Hyperosmolic hypoglycemic... Hyperosmolar hypoglycemic state.

Yeah, yeah. So this is even higher than DKA or diabetes ketoacidosis in terms of glucose levels. So this is hugely high, which is then changing the way water moves through compartments in the body, which is, as you said, a medical emergency, and that would probably have to be...

treated accordingly in an emergency setting and a medication like this is probably not going to be the way to go in that regard but like you said a prevention is better than cure.

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Yep.

Brilliant. Thank you. Thank you, Jeremy. Thank you for the wonderful, wonderful question. We have some listener mail here as well. It says,

approaching the end of my pre-registration qualification period. Myself and all of my fellow students love your YouTube channel. Thank you very much. And found it fantastic for our learning. Cranial nerves, yeah, that's a good one. Endocrine system, that was a good one as well. And it was brilliant. Myself and a fellow student have set up a podcast called

to help fellow UK student optometrists make the transition from campus to clinic. And we'd love it if you'd be willing to be a guest on the podcast for an episode. Please, please, please, Stuart. Now, first, Stuart, you should have told us the name of the podcast so that we could have plugged it for you. And secondly, yes, send us an email. Happy to jump on the podcast. Matt's put his hand up. I can see it now. Happy to do it. Or I'm happy to do it, or both of us.

Absolutely happy. Now, thank you, Stuart. We've got a question, Matt. This is our last question. This question is from Hossein. Hossein, again, I hope I'm pronouncing your name properly, Hossein. Hi, Dr. Mike and Dr. Matt. Thank you for putting my name first. First of all, I want to thank you so much for your great podcast videos and other resources you are publishing and helping people to gain knowledge in very efficient ways. I'm addicted to your podcasts. Thank you. Uh, uh,

I saw one of, or a few of your podcasts regarding blood pressure and blockage, and you have an analogy of a water hose and how we can push water out by restricting the nozzle. Now, I have an argument here. I think if we restrict the water hose with a thumb, we reduce the... Okay, so let me just quickly say what my analogy is. I've said before, you know, if you put your thumb on the end of a hose, you increase the pressure further.

because it squirts out harder through that nozzle, right? By reducing the area that the water comes out. I said it's like your blood vessels. When you narrow the blood vessel, you increase your systemic vascular resistance or it's sometimes called the total peripheral resistance. Effectively increasing your blood pressure by narrowing the blood vessel. So I use the hose as an analogy to indicate that.

And Hossein is saying that there's an argument against using this as an accurate analogy, right? He says that when you put your thumb on the end of the hose, you reduce the cross-sectional area. And as a result, due to something called continuity principle, velocity of order increases, not the pressure increases.

And based on the Bernoulli rule, the water pressure will decrease due to exchange of tap pressure to kinetic energy and velocity. So it's a trade-off between the pressure and the velocity speed. Okay, let me explain that part quickly because I think it's an important point. So yes, when I spoke... Okay, so firstly, he's absolutely right. My analogy isn't...

entirely correct, right? Perfect. So when you... It's not perfect, but I think it's good enough to be able to get the point across. But let me just explain. When you bring up the principles of fluid dynamics, like something called the continuity principle and Bernoulli's principle, right? Bernoulli's principle and how they apply to this topic, you're totally right. So...

When I talked about blood pressure and blockages using the water hose analogy, the idea was to give a simplified way to visualize how resistance in that blood vessel might affect flow and pressure.

But as you rightly pointed out, when you restrict the nozzle of a hose, what's really happening is that the velocity of the water increases because the cross-sectional area is reduced. Now, that continuity principle that he was talking about basically states that, okay, you've got X amount of water going through an opening, right?

So, X amount of water over time going through that opening. If I narrow the cross sectional area, I still need to maintain the same amount of fluid going through that area, but it's narrow now. So, how do I get the same amount of fluid making it through that hole when it's now narrowed? You need to increase the velocity of that fluid.

And Bernoulli's principle states that when you increase the velocity or the speed of the fluid, you're going to decrease, something has to give way, right? So you decrease the pressure. So I said, well, I put my thumb on the end of the nozzle, the cross-sectional area decreases, the pressure increases in response. Well, accurately it doesn't. The pressure decreases, the velocity increases, right? That's true. But that's true in a closed system.

This is where it gets a little bit different.

Unlike a water hose, our vascular system isn't static. It's not a closed system. It's dynamic. It's heavily regulated by the body. So at the point of a blocked blood vessel, not a hose, yes, the velocity of blood increases and the pressure directly downstream of the blockage drops. Very true. Similar to what happens in the water hose analogy. However, the body has built-in compensatory mechanisms to deal with these kind of issues, right? So unlike a hose,

We've got a brain, a heart, kidneys. When they detect a drop in blood pressure, so a drop downstream of the blockage, they respond by increasing our systemic blood pressure. And they do this by increasing the heart's cardiac output, by narrowing, tightening up, constricting the blood vessels, and even adjusting the blood volume through hormones like the renin-angiotensin-aldosterone system.

So while the blockage itself doesn't directly increase the pressure like I alluded to in the analogy, the body's reaction to maintain blood flow is what causes the overall rise in blood pressure and is associated with the increase in vascular resistance. So yes, to point out you're absolutely correct.

But I think my analogy is still useful and accurate enough to get the point across that when you narrow the diameter of a blood vessel, you increase the systemic vascular resistance, which is part of the blood pressure equation. Matt, how did I go? Did I address it well enough?

Yes, well, I think you could have just said bad analogy. Thank you, Hussain. I would never acknowledge fault, Matt. As you know, it is not part of who I am to say, Hussain, I'm an idiot. OK, in actual fact, I am an idiot. We know that. I think this is why the podcast works so well, because it's two idiots trying to make sense of the world in an understandable way. And while Hussain might be correct...

I think if we were to describe it in the way that Haseen described it, which is accurate to the textbook, people would turn off. They wouldn't be paying attention because it's complex to talk about velocity and pressure and so forth. All right, Matt, we are at the end of the episode. We're at the end. Do you have anything final you'd like to say, Matt? No, I don't think we covered it all.

Keep sending your questions in in your listener mail and we'll try to address it as best we can. We'll probably do these sessions more frequently now. Maybe, what do we reckon? Once a month. Yep. Yep.

So do send the questions in. Probably at this point in time, the best way to send them in is through our email, gubiosciences at gmail.com. Or now we're sort of shifting towards admin at drmattdrmike.com.au. You can send it there as well, but either one, that's fine. You can try the website, but it's been a bit meh, hasn't been doing too well. Otherwise, you can contact us on social media.

TikTok, unless you're in the States, my bad. You can go on Instagram. You can go on X, the artist formerly known as Twitter. You can go on Threads. I'm not on Blue Sky yet. There's too many of these platforms, Matt. Mike's now heavily on Meta because he's not getting fat checked. So he's really happy about that.

No, but the great thing is we get emails from our listeners that do fact check us, which we love. So again, if we're wrong, if we're inaccurate, even if we overstate something, I think you're all aware that Matt and I want to do the best we possibly can and give you the best evidence.

And we're not experts in everything. We are educators. We do teach anatomy and physiology and pathophysiology and pharmacology, but it doesn't mean we are the world best experts in these areas. We try our best to give you sensible, evidence-based, understandable content. So please help us in that process. Matty, thank you so much, mate. Thank you all. Don't do it again. See ya.

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