Geoff

I'm super excited to welcome Dr. Latt Mansor onto the H.V.M.N Podcast. He's not just expert in metabolism, he's also the new Research Lead at H.V.M.N. So excited to introduce you to the H.V.M.N Podcast community as well as the welcome you on the team.

Latt M.

Thank you very much, Geoff. Glad to be here.

Geoff

Likewise, we're really glad to have you onboard as well. Let's start from the very beginning. What's your background? What are your key interest areas? What led you into getting a Ph.D in physiology at Oxford? What got you interested in metabolism?

Latt M.

Wow, that's a long story. So let's start with, born and bred in Malaysia. Then I did my undergrad and masters in biotechnology. My undergrad was in Nottingham University in the UK and masters was from Columbia University in New York. Then I worked for about a year-and-a-half with a pharmaceutical company, up in New Jersey called The Medicines Company where they really focused on cardiovascular health at that point as well. Then I went back to UK and started a Ph.D in cardiovascular science, cardiovascular metabolism.

So what got me into metabolism as a whole, I think growing up I was kind of overweight all my life pretty much until my second year in undergrad where I started to exercise and I started to learn more about fat metabolism. In fact, my undergrad final year project was in mathematical modeling of a fat adipose tissue metabolism. So then I lost a bunch of weight, I lost about I think 20 kilos. Then when I went to New York, I learned further in terms of working out, I joined the gym and then I also did my masters thesis on sarcopenia, which is muscle loss due to aging and how exercise works as an intervention comparing endurance exercise versus resistance exercise to prevent sarcopenia.

Then because of my background in metabolism and physiology and I started working in the clinical trials for the Medicines Company as a clinical trial coordinator, and then subsequently as an analyst. I learned more about cardiovascular health. My late father, he passed away from stroke and he had a heart attack few years before that, and my mother's side has quite high prevalence of diabetes in the family and obesity as well. Obviously, we all know that having diabetes increase your chance or your risk of having a myocardial infarction or a heart attack.

Exploring the link between diabetes and cardiovascular was of a personal interest to me and that is how I got started in Professor Kieran Clarke's lab in Oxford, where professor Kieran Clarke she led a research group called Cardiac Metabolism Research Group, CMRG. That was where I did my thesis work, looking specifically at the metabolism of the type 2 diabetic heart in hypoxia. So I'm looking at hypoxia as a sub-component of ischemia, which is the lack of blood flow to the heart.

Geoff

I think that touches a couple of interesting paths that we'll walk towards. I think one, you mentioned hypoxia recently that subject won a Nobel prize in medicine. It's just a couple of weeks ago, which is really exciting because I know that one of the investigators that was awarded was an Oxford fellow. Second, you mentioned diabetes and overall metabolism what under Kieran Clarke's group, which obviously is our key partner behind our Ketone Ester work.

It's interesting crossover from hypoxia and Nobel prize-winning work as well as entry point into metabolism through the lens of a disease model, but ultimately it's still kind of tying into why ketones and ketosis are interesting metabolic state. But even before going into more of the scientific topics, I'm just curious in terms of your personal story. So did you grow up wanting to be a scientist? Do you... it sounded like a lot of your focus in physiology and medicine really came while you were a young adult.

Latt M.

From an interest point of view, I have always been interested in science. I've always been curious about how things work. But I think in terms of evolving that into a more personal interest, it definitely started when I started exercising, learning more about metabolism, losing the weight and seeing how people can potentially change their lives, by changing their lifestyle or by changing the diet by including certain things in the diet, excluding certain things in the diet. I think that was developed throughout that undergrad days and then up till now and trying to apply what I know theoretically into practical aspect of my life.

Geoff

That's something that I've just been thinking more about, if you look at just paths of people's lives and in people's careers, there's a couple of critical moments that nudges you in the right direction because you've got a really great physics teacher or an astronomy teacher versus really great biology teacher maybe you'd be here with a cosmology Ph.D talking about black holes.

Latt M.

I very close to doing a Ph.D in biology in space actually in Madrid in university of Autonomous in Madrid. But somehow that fell through and then I ended up doing masters in biotechnology instead in New York.

Geoff

I think just from me personally, I think I told you the story where when I was graduating from my undergraduate program at Stanford, I had option to either join Facebook as a software engineer that was in 2011, do a Ph.D at Princeton and computer science was one of my first company and there were all-

Latt M.

Viable options there.

Geoff

... Phenomenally awesome options, right?

Latt M.

Actually.

Geoff

At the time, they all sounded fun, but being your own boss seemed like the most fun. I could probably always maybe do a Ph.D or probably always go work at a big software company. Then took the shot there and that's unfolded like a very interesting path to be here. Having my own podcast, working with Zhill the producer, talking to you, working in... I think a very exciting area of ketosis and metabolic products and research and that would not be where I was if I did a Princeton Ph.D or worked at Facebook. Right?

Latt M.

Yeah, and if I'd done anything else, I wouldn't be here being a research lead either. So from my perspective as well, a few things that changed me in terms of inspiring me to do a Ph.D. Because at the end of my masters, I have concluded that I do not want to do a Ph.D. I do not want to stay in the lab, I do not want to do wet lab work. But then joining the Medicines Company allowed me to meet a lot of individuals who inspired me ultimately to apply for a Ph.D at Oxford. A lot of them have got PhD, but they're also very entrepreneurial and business-minded. That inspired me to apply for a Ph.D and yet also be able to be in the business side of things. So I think that played a big role in me going back to school after one year and a half working in the pharmaceutical industry.

Geoff

Yeah, it's super exciting. I know that our dear friend Brianna Stubbs, our previous research lead was in the lab. So you didn't necessarily work directly with her but she was as part of the overall cardiovascular research group, broader research group. Your advisor's advisor just recently won the Nobel prize so I say tongue in cheek, you're a grand noble prize pedigree researcher. Can you talk about what was it like, how long ago was it?

Latt M.

I started my study in 2011 and I finished it in 2015.

Geoff

So like almost a decade ago when he started like seven, eight years ago.

Latt M.

Yeah, almost. So Brianna and I, we did overlap during our times in the same lab. We did crossover when it comes to changing ideas about some experiments and some protocols and all that. My supervisor is also Lisa Heather, during her first fellowship when she was supervising me, her mentor is Peter Ratcliffe who got the Nobel prize announced last week for his work in hypoxia and hypoxia signaling and how cells sends hypoxia oxygen sensing and the mechanism of HIF, which is Hypoxia-Inducible Factor.

Geoff

So just for clarity and my understanding, when the body, when an animal, when a human is in hypoxia there is an oxygen-sensing pathway that's governed by HIF. I think the way I've come to think about it is that if you have like mTOR, which is a nutrient-sensing pathway, HIF is kind of like the analog for oxygen sensing pathway. So when mTOR is triggered or upregulated or downregulated, a number of things happen, mTOR builds muscle or autophagy and that was like a Nobel prize-winning mechanism discovered I think in 2016 by a Japanese scientist. That's very interesting to see that today you have oxygen-sensing pathway being awarded a Nobel prize. So what are the effects of a HIF response?

Latt M.

HIF is always present in our cytoplasm. In normoxia which is normal oxygen level, HIF is constantly being broken down. So it's constantly being targeted by ubiquitin-proteasome degradation. So with the presence of oxygen, that's what's happening. So that inhibits it from going into the nucleus and start a whole gene expression that reacts to hypoxia.

Geoff

I see.

Latt M.

So when oxygen is absent in hypoxia, for example-

Geoff

The HIF does not get broken down.

Latt M.

... HIF escapes the degradation and therefore translocate into the nucleus and then binds to this region call HRE, HIF response element. That kick-starts the gene expression that leads towards whatever cascade that helps with the adaptation to hypoxia.

Geoff

So what is upregulated then? So you get-

Latt M.

Glycolysis.

Geoff

... glycolysis?

Latt M.

Yeah. So you get probably increase in glutes in taking in more glucose because you can't increase glycolysis without having glucose.

Geoff

For more glucose transporters, more glycolysis.

Latt M.

Yeah. There are quite a few other mechanisms that get upregulated as well, which is a surprisingly quite opposite to diabetes and the pathogenesis of diabetes is almost the opposite direction. That is why we started studying diabetic in hypoxia.

Geoff

Is there implication for longevity?

Latt M.

I think it's still quite early in the stage to speak of... I think longevity studies are very interesting in the sense that you can't do a fully decisive longevity study without following that study for a long time. Because of that, because the practicality is limited as well.

Geoff

I just bring it up because if I see a parallel between MTOR as a nutrient-sensing pathway, it's not obvious that have an implication to longevity.

Latt M.

You can look at it this way, when a person ages they might have more complications with vascularity and a decrease in oxygen or some form of blockage that causes hypoxia in certain organs. So how adapted someone is to hypoxia may play a role as to whether or not they develop those hypoxic related complications.

Geoff

I see. So-

Latt M.

So hypoxia can play a role in like say cancer, stroke, cardiovascular disease in a lot of these different diseases. That's why I think they're are Nobel-price worthy because that sensing mechanism is so quick to act and it's so useful in so many different applications and so many different disease cases that it becomes a fundamental understanding as to how the disease progress or how can we potentially intervene with these diseases. Lisa Heather, my supervisor has regular meetings with him and a lot of our publications has gone through him in terms of looking at the results, looking at the study design and he has given some feedback on those studies as well. So that's why we have acknowledged him in our papers as well.

Geoff

His original paper discovering or describing the HIF mechanism was rejected by nature, which I think it's like the challenging, interesting part of doing something at the cutting edge of technology understanding. Half people or most people think you're wrong-

Latt M.

Exactly.

Geoff

... then let's see what the data shows.

Latt M.

Most people think that you are not with the norm and therefore you're not doing something right.

Geoff

I think it's like, it would be almost arrogant to say that we know how everything works. If you look at history, every paradigm has been disrupted by a better paradigm. So it would be, I think, overly arrogant to assume that our current understanding of physics, biology, longevity, performance is defined and is true. Nutrition, nutrition is a space that the human system is designed to continue to eat, to allow themselves to survive and procreate.

That's something that our species and thinking about forever and that's... So we do not have a defined answer. What is the best way to eat? So let's not open that can of worms just yet. Let's talk about your thesis work. Let's dive into hypoxia. Why do you think was so interesting? How did your slice of working on hypoxia and your novel contribution to space tie into the overall understanding of hypoxia?

Latt M.

In the conditions of lack of oxygen, which is hypoxia, our body need to adjust and need to switch its metabolism to adapt to hypoxia so that we continue to survive because there are certain organs in the body like the heart or the brain. It cannot survive without oxygen for a long, for an extended period of time. There's no rest for these organs where it's continuously working throughout our lives until we die essentially.

So, but then the understanding of how the certain cells sends oxygen and therefore create a cascade that jumpstart a whole mechanism that adapts to it has not been clearly illustrated or described before. So I think that is why Peter Ratcliffe and Greg Semenza, they got the Nobel prize for it to really illustrate the mechanism at which HIF is being activated or how HIF is responsible for expressing genes and translating proteins that are related to the adaptation of hypoxia.

My thesis project is that I looked at a type 2 diabetic rat models. So if I have to give an overview, the first part is to develop a type 2 diabetic rat model. So that's what I did.

Geoff

So a type two diabetes model for rat that didn't exist before or?

Latt M.

It did. A lot of different models existed before. They've got genetic knockout models. They've got different form of diet models. But we try to improve a model that was done by Srinivasan in 2005 by using a different strain of rat and combining streptozotocin, which is a drug that partially impasse pancreatic beta cells that impair the insulin secretion and combine that with high-fat diet to induce diabetes within about three weeks. So we saw the hallmarks of diabetes, increased blood glucose or hyperinsulinemia or increased fat mass.

Geoff

Interesting. Why do you need to create a new model?

Latt M.

From what we want to look at, which is and the techniques that we're using, which is isolated heart perfusion, a lot of good models are in mice models. We can do heart perfusion with mice models as well but for the sake of... It's much easier to do rat heart perfusion just because it's bigger, and also obviously when it's bigger, you get more tissue and you can run more tests and all that as well. In terms of logistics, a lot of it with regards to the practicality of the model, it was much better if we can use a Wistar rat model.

Geoff

I see. So basically there's a consideration around amount of tissue size between a rat and mice and the better models happen to be mice models or mouse models.

Latt M.

Yeah. Other rat models they almost borderline type 1 diabetes, which is too severe for what we want to see because we want to almost look at early-stage type 2 to like mid-stage type 2.

Geoff

It is fairly new to create a new model, so that sounds like exciting part one. Part two.

Latt M.

Yeah. So part two put the rats in hypoxic chamber at about 11 percent oxygen.

Geoff

Sea levels run 20... Is there attitude equivalent to 11 percent? That's pretty... cutting them in half is pretty dramatic for hypoxia.

Latt M.

That's very low. So for the first week, I had to gradually decrease from 21 percent all the way down to 11.

Geoff

Do you know how to off the top of your head? Like what is not being at Mount Everest?

Latt M.

I'm not entirely sure. I have it written down, but not on top of my head. I don't know.

Geoff

So they'll just pull up the number saying that... So at Everest summit, you get around a third of the oxygen availability. So that implies of is 20 percent is sea level, you get around six, seven percent. So you are bringing these rats close to Everest essentially.

Latt M.

Yeah. Then looking at how their cardiac metabolism would react to hypoxia because we know for a fact that in hypoxia the heart would upregulate glycolysis because glycolysis pathway is oxygen-independent. In order to provide continuous energy supply to the heart, it needs to somehow create ATP, which is energy from somewhere, from the field, from the substrates.

Upregulating glycolysis in that hypoxic environment would provide the best option and most efficient option to create ATP independent of oxygen. But we also know that in diabetes there is metabolic inflexibility where diabetic hearts, they can't switch between substrates that easily, so that's the hypothesis. So that was what I was trying to look into.

Geoff

Really fascinating because we talk a lot about metabolic and flexibility through more a nutrition perspective on this program. So it's interesting to hear that you're studying metabolic or looking at metabolic inflexibility that's something to measure with the stress of hypoxia within a diabetic heart, which is, it's like a interesting stacking.

Latt M.

Yeah. Same wordings, but different terms to describe different things. Then the third part was looking at acute hypoxia where during isolated perfusion, I cut off oxygen and then re-oxygenate these hearts and look at the metabolism. So they measure both fatty acid oxidation and glycolysis and see what's the difference there. What we have found is that the diabetic hearts, they are metabolically inflexible therefore normal healthy hearts would upregulate glycolysis in both chronic and acute hypoxia. But the diabetic hearts because of the high-fat content in the system already upregulates the PPAR-alpha in the diabetic hearts. Therefore, they have a sustain elevated fatty acid oxidation compared to normal healthy hearts. So that's why in the final part of my study, we used a CD36 inhibitor called SSO.

Geoff

Can you describe what a CD36 inhibitor...

Latt M.

So CD36 is a fat transporter that transports fat into the mitochondria to be oxidized and produce energy because fats can get past that membrane and it needs a transporter. So CD36 transport fat into the cell and then so that cells can then enter mitochondria to be oxidized to create energy. So what we have that-

Geoff

So this is study acid oxidation or require transporter for fatty acid oxidation?

Latt M.

Yes, because the fatty acids they can penetrate the phospholipid bilayer therefore, it needs a transporter to transport into the cell. So what we have done is using this chemical got SSO to inhibit CD36. We stopped fat from coming into the cells to cardiomyocytes and try to forcibly switch metabolism to glycolysis. Because via Randle cycle, when you up-regulate glycolysis, you get a downregulation of fatty acid oxidation and vice versa. You increase fatty acid oxidation, you would decrease glycolysis. So we're basically forcing fatty acid oxidation to go down via inhibition of CD36 and therefore to see if we can correct the metabolic inflexibility in the diabetic heart.

Geoff

Interesting. So just to step back and give context. So life, they want to maintain homeostasis and there's an entry requirement for the cell. So if you're forcing a shutdown of fatty acid oxidation because there's no fat coming in through CD36 that implies that to that energy deficit there needs to be some other substrate to be used and glycolysis is that alternative energy substrate.

Just to step back...so all these types of substrates have different types of transporters. We talked about CD36, which is necessary for fatty acid oxidation. So this is fatty acids going through the Krebs cycle. You have glycolysis, which is you have glucose transporters that bring glucose into the cell and then feeding the Krebs cycle. Then our favorite metabolic substrate ketones goes through the MCT, monocarboxylate transporter and then that ketone goes through and feeds the Krebs cycle.

Geoff

Because glucose is a more of available substrate there, it makes sense that you would push metabolism towards glycolysis. But I think the next question if we are putting on the ketosis hat if the ketone's available it probably be an interesting deflection or shunting towards both glycolysis and ketosis. Right?

Latt M.

Yeah. That would be interesting as well because we know from different studies that ketone bodies in the bloodstream or in the system, it does increase the cardiac output and cardiac efficiency. So they measured hydraulic work by the heart over the oxygen consumed and with ketone bodies, they managed to increase the cardiac efficiency similar to insulin.

Geoff

Yeah, the Sito paper in ninety six.

Latt M.

Ninety five.

Geoff

Ninety five.

Latt M.

That's correct.

Geoff

I think just for context for the audience, this is one of the key papers that a lot of researchers and podcast people site as why ketones are metabolically advantageous. You get energetic boost or output with ketones as a substrate. So I want to just make sure that closed-loop on your thesis. So it sounds like you had the model of diabetic rats and then he started looking at hypoxia-

Latt M.

Chronic and acute.

Geoff

... chronic and acute and then you had an inhibitor to see how you can manipulate metabolic inflexibilities, or understand metabolic and flexibility in diabetes. What were some of the key conclusions or results from that? It makes sense from being an observer of the space, seeing that, okay, you found that diabetics are more metabolically inflexible. What was that kind of the key contributions to the field there.

Latt M.

The key findings that we found is that in diabetics, the upregulation of PPAR-alpha due to the high-fat content in the system-

Geoff

So this is final PPAR-alpha. PPAR-alpha is an important-

Latt M.

PPAR-alpha is an important gene that regulates fatty acid oxidation. We often see an up-regulation of PPAR-alpha, especially in the heart. There's different types of PPARs as well. There's PPAR-gamma, PPAR-delta. But in the heart primarily PPAR-alpha is more readily present. We saw an increase in PPAR-alpha activity in the diabetic hearts because of the high-fat diet that we feed the rats.

This essentially overwrites the HIF response to hypoxia compared to normal hearts. For example, what I'm trying to say is in hypoxia, normal hearts would upregulate HIF, hypoxia-inducible factor to upregulate all the enzyme and proteins that is relevant for hypoxic adaptation. But in diabetics, there is a blunted reaction to hypoxia. So we were trying to figure out what is the mechanism and one of the things that was... One of the theory that was proposed is that the upregulation of PPAR-alpha basically overwrites the hypoxic reaction or response.

Geoff

Super interesting. I want to kind of jump in here and this could be a little bit out of order, but I think in the context of a lot of our audience members who think of keto diet, high-fat diets, fasting is potentially beneficial for resolving metabolic and flexibility because you're... The concern is overconsumption of carbohydrates or glycolysis. So what is the difference there? So it sounds like in the model that you created, there was a heavy reliance on fatty acid oxidation and not a lot of glycolysis happening.

Latt M.

Or lowered glycolysis, yeah.

Geoff

So what is the difference when in the human context, we will talk about having too much carbohydrate or sugar as the main driver of metabolic inflexibility?

Latt M.

The high-fat diet we use with 60 percent fat and then about, I think about 20 percent carbs and then the rest is protein and others.

Geoff

So it's not like super Keto like five percent.

Latt M.

No, it wasn't. It wasn't a Keto diet. It was quite high in carbs as well.

Geoff

So if you were not diabetic and you had a high-fat diet or keto diets, would you speculate that, that would inhibit HIF response?

Latt M.

Whether or not you're diabetic, the increase in fat intake, what I would speculate that it will increase the PPAR-alpha expression anyway.

Geoff

If PPAR-alpha expression down-regulates HIF expression.

Latt M.

Yeah, that's one thing that its interesting point from a cardiology point of view or cardiovascular health point of view wherein ketogenetic diet people while they managed to decrease the biomarkers or the hallmarks of diabetes such as glucose or insulin and all that also, they lose weight. But they did see an increase in lipid profile. So it would be interesting to really look more detail into that and look at whether these increase in lipid profile would be detrimental to the cardiac health.

Geoff

I see. So basically what sounded good key takeaway that I'm absorbing from this conversation is that you're trading off different responses, in the sense that it probably makes sense to reduce carbohydrate consumption if you're reducing insulin resistance, reducing inflammation, reducing some of these other biomarkers, but that might in return also trade off some of the HIF response, which are also beneficial.

Latt M.

Yeah, definitely. I think it's an, like you said in the earlier in this conversation that nutrition and metabolism and physiology is an ongoing conversation. It's an ongoing evolution. We're still trying to figure out if you take out the carbs and you fit in more fats you get ketogenic diet and then you get some benefits of it. But then what about the other parts of the equation? Your body try to compensate with other things and you might increase-

Geoff

This is a super complicated can of worms because I'm just thinking like, okay, if you have up-regulated PPAR-alpha in a high-fat diet, okay you might reduce the HIF response, but can that reduced HIF response be recovered if you're a ketogenic or you have ketones in the system.

Latt M.

Then there are other layers that may come into play as well if you're exercising and that might increase that insulin sensitivity or that might increase the HIF sensitivity, I'm not sure. Then you want to add exogenous ketones into the play and then that would make things even more interesting.

Geoff

Yes, it is kind of an open question in at the top end of performance. I think hypoxia is like a super interesting model for it because it's oftentimes hard to tease out the differences in performance in a standard perfect environment and hypoxia is like a very viable model.

Latt M.

Also, it has been proven that ketogenic diet does work in terms of helping diabetic patients or overweight patients to reduce weight and reduce all these, reduce medications and all that. So it has been published already. However, if the concern is hypoxia how often will one get into hypoxic condition over a long time? It depends on.

Geoff

Like when you have a heart attack.

Latt M.

Yeah.

Geoff

I don't think people talk about a lot. I think people talk about, it's probably reasonable for reducing carbohydrate intake, being ketogenic to minimize percentage chance of getting a myocardial infarction. But post-heart attack where you are in hypoxic state and fatty acid oxidation is not optimal because you need oxygen for that...

Latt M.

You get reactive oxygen species generation.

Geoff

Then you must rely on glycolysis. But I think the question is if you can have exogenous ketones, can you replace the reliance on glycolysis as with ketones as an adjunct? I think that's just, again, another open area of research.

Latt M.

That's interesting as well because ketones are known to acutely decrease glycolytic rates by the action of using PDK to inhibit that and that reduces lactic production from glycolysis. So that's interesting in that sense. Like would that be beneficial or detrimental in hypoxia?

Geoff

Does the body of benefits outweigh the potential negatives? I think there's another way to think about it.

Latt M.

Exactly.

Geoff

So I think it's like we're teasing into like below limits of human physiology and then we stack on top of hypoxia and different possible substrates. It gets pretty nuanced. But going back to some of your key conclusions with your thesis work. Anything else that our audience would find interesting in terms of takeaways?

Latt M.

Another thing that we found is that by inhibiting CD36, we managed to increase glycolytic rates even in diabetic hearts in hypoxia. So we basically corrected that abnormality that we saw in diabetic hearts in hypoxia. That is a very interesting point in the sense that it may provide a new therapeutic target. However, because the CD36 inhibitor that we used was irreversible, it was more of a proof of concept, if anything. Then a potential therapeutic agent.

Geoff

So primarily blocked fatty acids.

Latt M.

Yes, exactly. So while that is beneficial in hypoxia or in ischemia or in a heart attack, after that you may want to burn some fat in the heart, because in normoxia the fat burns about 60, 75 percent of the energy is being it's as coming from fat, fatty acid oxidation. So the heart does prefer to metabolize fatty acids over other substrates.

Geoff

I think you think of diabetes or I guess traditionally in the... I would say the low carb keto community think of diabetes as a glucose problem, which it is but I think the nuance that I'm gathering from this conversation is that it's, maybe it's a metabolic inflexibility is like the core problem with it. If you can't dispose glucose really, really well, that's not per se bad. But the problem is that if you cannot be flexible, that's-

Latt M.

Then whatever.

Geoff

... you can't burn any, like whether it's fat or glucose. That's where the real problems crop up.

Latt M.

Yeah. I think that's very interesting as well. Because type two diabetes has so many confounding factors as far as BMI is concerned like body weight is concerned as far as insulin resistance is concerned, inflammation is concerned. There's so many confounding factors that may lead towards this disease that we call diabetes. But it may not be just one mechanism that is diabetes if you know what I mean. So it's really hard to tease out, when we do a Ph.D it's most often than not very much pigeonhole into one really specific detail and try to find that answer to the research question that we are asking.

Geoff

I think it's interesting because, with ketone esters with exogenous ketones, we have now this additional substrate, this additional metabolic substrate that once in previous paradigms you'd have to have a high-fat diet to produce ketones. Now we can-

Latt M.

All stuffed.

Geoff

... so we can tease apart ketone separately from just the high fat or starved paradigm into its own substrate. I hope that we as not just like you and I, but hopefully, we as a community of researchers and scientists and practitioners of human performance and longevity can just really understand how to best use which substrate at which time. Because I think the model that you looked at, fatty acid oxidation was kind of in more of like weight-loss paradigms like yes you want to ramp up fatty acid oxidation because that means you're burning fat.

You want to like reduce glycolysis. Because if you're not, if you're using more glucose, you're not burning your fat. So for folks that aren't in weight loss and like a lot of metabolic conditions, that's probably what you want to do. But in the case that you looked at where in hypoxia for survivability in a hypoxic environment, well you don't want... This is I guess more comparable to like a post-heart attack...

Latt M.

You want to be able to switch that substrate equalization.

Geoff

Which I think is a very interesting part of the conversation that isn't really well discussed or well understood, which I think is interesting.

Latt M.

Because I think there's no linear way of seeing metabolism because it's always in a balance as far as substrate utilization goes in our physiology. I think that's what interesting because our body adapt to different environment and different conditions that we put them through. That is why that flexibility is so important and everything comes into play to make sure to ensure that flexibility is tip top, is on point like exercise, diet, nutrition, sleep.

Geoff

You're just triggering me to just like... Maybe someone has a way to find this but I'm just like creating a framework here. Maybe metabolic inflexibility is the root core issue and type 2 diabetes is a subset of this core metabolic inflexibility if you're very metabolically inflexible at glucose. Does that make sense?

Latt M.

Yeah.

Geoff

Because like your glucose pathways are messed up because you have insulin resistance, all of that. But the core root fundamental problem is that your body no longer inflexible to substrates.

Latt M.

It's always the chicken and egg. Does insulin resistance come first or insulin deficiency comes first?

Geoff

But I would make a stronger claim by just observation of what's happening in society today. That the metabolic inflexibility is primarily driven by glucose surplus and therefore causing insulin resistance, therefore causing all the downstream impact of type 2 diabetes and all of that.

Latt M.

Some say inflammation because of the high adipose tissue deposition. Some say it's because genetics some say it's the diet that trigger certain cascades of pathways that cause insulin resistance. Then that triggered the pancreatic beta cells to produce more insulin and over a long time that chronic positive feedback then cost the pancreatic beta cells to shut down and then that cause diabetes. A lot of times as well, what they say is like, by the time you have been diagnosed that you are diabetic or type 2 diabetic, you are pretty much 15 years-

Geoff

Post, like too late.

Latt M.

... is 15 years in the making and that is why it's so hard to pinpoint the exact mechanism that started it altogether.

Geoff

Yeah. So I would directionally agree with you in a sense that yes, it's complicated, there's like multiple effects but if we can make takeaways to simplify for the general population, if you're not like some athlete with some specific genetic baseline with some bespoke goal, probably reducing refined carbohydrates going more towards a low carb Ketogenic diet is sensible. Would you agree with that?

Latt M.

I agree with that. There are organizations or healthcare providers that utilize that method or that approach to deal with diabetes and they have seen quite promising results. So yeah, for sure. I think that's definitely one way to look at solving diabetes.

Geoff

I'm sure our audience will have a lot of interesting follow-up questions because I think we unpacked a lot of different cans there in terms of your thesis work, HIF, hypoxia, diabetes...as well as teasing into some of the future research or active ongoing research pipelines. I'm sure we'll have you back to help us break down some of those studies and hopefully maybe in the upcoming future some of our own studies that you're involved with. So very excited to have you on board. Welcome to H.V.M.N. Really excited to introduce you to our community and audience here.