Dr Rupy: Today's episode is going to be all about insulin resistance, how it impacts your risk of disease, why insulin resistance could be driving so many chronic diseases of our lifetime, of our generation, and what lifestyle measures you can do right now to improve your metabolic health by increasing your insulin sensitivity and reducing the likelihood of insulin resistance. By the end of this podcast, you should have a good understanding, not just a general understanding, but a good understanding of the importance of sugar balance in the body. You'll also understand what insulin is and how it actually works, and it's a lot more complicated than it just being a hormone that allows sugar to go into cells in and out, all that kind of stuff that you've probably already know about. We're going to go into a lot more depth. We're going to talk about what happens to you when you become insulin resistant, i.e. resistant to that hormone, what the causes or the proposed causes of insulin resistance are, and what we can do today, all the different lifestyle measures to become more insulin sensitive. I've tried putting this into one podcast and it's going to be a lot of information, but we'll do another podcast where I'm going to talk specifically about glucose hacks that you've probably heard about, what the science behind those are, what the evidence behind that is, and supplements and all that kind of stuff. But we're going to do that in a separate podcast because I think that can sometimes cloud the really big wins that you can have from very, very simple things that don't require supplementation and don't require doing anything out of the ordinary. I think there's so much you can learn and and benefit from from just understanding insulin resistance as a concept and then putting into practice all the things that we're going to talk about.
Dr Rupy: Alright, so whilst I'm going to be talking about insulin resistance, I want you to remember the framework that I tend to use when presenting these ideas to you, and that is the science is complex, solutions are simple, the solutions that I'm going to be talking about are really, really simple, implementation is hard. So I don't want to make this sound like this is going to be super easy, all you need to do is these these things. Actually, the implementation and the consistency of eating well, of exercising, of sleeping well, etc. these are things that take most of the time. Understanding the science and and understanding what the solutions are is just part of the problem. The main problem is implementation. Alright. So let's start off with why am I even talking about insulin resistance? There is a growing consensus among the academic community that insulin resistance underpins a lot of the chronic illnesses that we see, particularly in the UK and the US, but it's also spreading to other nations as well as a result of sedentary lifestyles and the explosion of processed foods, convenience foods, and a move away from our traditional lifestyles. This will become clearer as to why this might be driving insulin resistance. And when people talk about poor metabolic health, obesity, type two diabetes or pre-diabetes, or glucose intolerance, it's one of the core features of what drives it. And conversely, being insulin sensitive, which is where we want to get to, becoming more sensitive to this important hormone, that confers many benefits. So what is this relationship between insulin resistance and disease? Well, the metabolic consequences of insulin resistance can manifest in things that we can measure, things like hyperglycaemia, hyper being high, glycaemia being glucose, high glucose in the blood, hypertension, so that's raised blood pressure, dyslipidaemia, this is an imbalance of the lipid profiles that we tend to measure on blood tests, visceral adiposity. Again, fancy words, simply breaking it down, visceral around the organs, adiposity, fat or adipocytes. Hyperuricemia, we've talked about uric acid on the podcast before with Dr David Perlmutter. Uric acid is not just a feature of gout, it actually has a huge relationship with other metabolic issues and being insulin resistant can increase hyper your uric acid, uremia in the blood, elevated inflammatory markers, and endothelial dysfunction. So the endothelium is the single layer of the lining of the blood cells and dysfunction in that layer can lead to cardiovascular disease through the inflammatory process of atherosclerosis. And I hasten to add the word inflammatory because it is an inflammatory process. It's not just a case of how we've usually described it as a plumbing issue, you get stuff plugged into your arteries. It's it's more an inflammatory process that involves the lining of the blood vessels and a prothrombotic state as well. Again, related to insulin resistance, pro being pro and thrombotic, so all the different clotting factors that can render you more at risk of things like strokes. So insulin resistance is related to all those things and as we unpack it, you're going to learn a lot more about why it it does. Hence, with all those collection of different metabolic issues, it's related to obesity, cardiovascular disease, cancers, hormonal disruption, things like PCOS, dementia. We talked about PCOS recently and and its grounding in insulin resistance, which is actually the sort of reason as to why I thought I should do a full pod on insulin resistance because I don't think it's very well appreciated. Dementia, again, dementia has multiple different causes, one of which is metabolic issues and disturbances. Again, can have its relation relationship with insulin resistance. And of course, the big one, type two diabetes. So the one fact that I want you to remember with all these different things, so we've just talked about insulin resistance related to those different factors, related to those end points, those those conditions, is think about it on a spectrum. So you have insulin resistance getting worse and worse and worse, then you have these um factors that you can measure in the blood, so things like impaired fasting glucose where your fasting glucose as measured in your blood is higher than would be deemed normal. Um you have high high uric acid level, high blood pressure, etc. And then the end point is when you get diagnosed with a disease. Insulin resistance is thought to precede the development of all these conditions like type two diabetes by 10 to 15 years. So by the time you actually have a diagnosis at let's say age 45, actually a lot of the issues that have been going array have started up to 15 years ago, probably earlier if I'm honest. I think there's a lot of evidence to say that inflammatory changes, particularly in cardiovascular disease can occur as early as in in teenage years, but let's just say for argument's sake, it's at least 10 to 15 years. That is a phenomenal amount of time where we haven't intervened and we haven't done anything. If you can prevent the development of or the worsening of insulin resistance and we can uh we can anticipate that, then it goes to say you can potentially anticipate and prevent a multitude of diseases down the line, which is why insulin resistance is such an important topic and that's why we're doing a bit of a a dive into it uh today. Okay. So what is it? Uh what is insulin resistance? I think before we get into exactly defining insulin resistance, it's important to understand how sugar regulation works in the body. The body has a remarkable capacity to satisfy the nutritional needs for glucose whilst still maintaining a good stable level of glucose in the blood. It is pretty phenomenal. Um there is a paper that I I will link to all these papers and references in the show notes of course, but there is a paper called just four grams of glucose. Um you can look it up, it's open. Uh it's open source. Um just four grams of glucose circulates in the average 70 kilo person. That is a ludicrously small amount to keep tightly regulated in your bloodstream. It is the equivalent of a teaspoon of sugar that is in my blood right now as a 75-ish kilo person. There is about a teaspoon of sugar, glucose, in my blood right now that is constantly being kept at that level, maybe with a perturbation of another gram or so, but it is so, so small. And considering how important glucose is as a molecule for the production of energy, for the maintenance of consciousness in your brain, it is quite amazing that your body is able to keep that very, very tight uh balance. I would liken it to acid-base balance. So within medicine, you have a very tightly regulated pH of your blood between 7.35 and 7.45. Outside of those areas, you're running to trouble. There could be a metabolic reason as to why, maybe you've ingested a particular toxin, uh or you have a respiratory issue whereby you are breathing really, really heavily, perhaps you've got uh fluid in your lungs or you have a chest infection, and then that will change the acid-base level in your blood. It is really, really tightly regulated and I didn't realize, I don't think I fully appreciated just how tightly regulated uh glucose is in in your in your blood. Putting this into context, too little sugar in your blood can lead to neuroglycopenia, so that is brain, neuro, glyco, glucose, penia, too too little, uh which can lead to seizure and death, which is why glucose is so important. And remember 60% of the glucose used in a person who is like myself right now, sat sedentary, is being utilized by the brain. And then too much glucose is glucose toxicity or hyperglycaemia. And this is where you have a persistent um uh situation where you have hyper high, glycaemia, glucose in the blood. Um and that can lead to all the other things that we just talked about, blood pressure, dyslipidaemia, um uh visceral adiposity, so fat around the organs, um high high uric acid levels and all the rest of it. Now, this is very important because sugar is generally maintained in a strict concentration of 4 to 8 millimoles per litre. I don't have the milligrams per decilitre uh conversion for anyone who's listening from the states, uh but there are many conversions online. 4 to 8 millimoles per litre is the is the general sort of range that we tend to have uh in in the UK. It sounds like a high range, but it's actually very narrow if you compare it to the number of teaspoons that are being kept stable in your blood. Insulin has a central role in maintaining this tight sugar balance in your blood. I'll say it again, it's got a a central role. It suppresses the release of glucose from the liver. Not a lot of people realize that your liver is uh tasked with a number of different things. One of which is maintaining a steady glucose state through gluconeogenesis that we'll come to in a second. Gluco being glucose, sugar, glucose, neo, genesis, this is the generation of glucose from novel um uh components. Um your liver is constantly doing that. So insulin switches that or suppresses it, attenuates it, mutes it, puts it down, and then it stimulates the removal of glucose from the blood into other cells where it can be stored, muscle, liver, and fat are the key cells that you need to be aware of in this story of insulin resistance. And then the ultimate result of that is that insulin is regulating a stable amount that's in your blood. The aim of the game is to keep the glucose levels in your blood the same because you don't want to have too little or too much because there are some very, very uh nasty consequences of that. In addition to insulin, you have these glycogen reservoirs and these are required to maintain a steady state of glucose in the blood. Now, as you can imagine, we are not having teaspoons of glucose in our diet uh all the time. Um we're having a massive amount more than that in anything that you eat is always going to be uh converted into glucose. With that with this in mind, we need to have stores. If you can only have a teaspoon of glucose in your blood, you have to store the the sugar that we are pumping into our bodies through uh at mealtimes in in various plants. Well, the main storage sites are your liver, there's about 100 grams of glycogen, which is the storage molecules that we store sugar in, glycogen. There's a conversion process for that. That's stored in the liver and there's about 400 grams of glycogen that you find in uh the muscle and you tap into these during exercise when you need to, um or when you're fasting, for example. The liver can also create glucose from non-carbohydrate sources. So this is the process of gluconeogenesis that I was talking about and it uses things you don't really need to know about, glycerol, lactate, pyruvate, and glucogenic amino acids. A lot of people don't realize that um proteins can be turned into uh sugar and your liver does this via the process of gluconeogenesis. You don't need to know about the pathways, just know that happens. So, just to recap, you have a fixed amount in your blood that is highly regulated and to maintain that regulation, we have hormones, insulin, glucagon is coming up in a minute for those of you that are trying to jump the gun. Um and then you have these stores that are basically like uh your your savings accounts and you tap into them when you need it if you if you're exercising or you're fasting or you don't find food. These are all very important evolutionary mechanisms that uh would have been critical during periods of famine that undoubtedly we would have been affected by, but in today's environment where we have an abundance of food, not really necessary, we don't really need these. Um but we have to manage them because, you know, we haven't evolved. We certainly haven't evolved over the last 50, 60 years when our food environment has completely changed. There are other players in glucose blood regulation like glucagon that I mentioned. Um even things like catecholamines, so these are released from your adrenal glands, um cortisol, growth hormone, but our focus is going to be on insulin today because otherwise we're going to be basically just going into a huge textbook of biochemistry and we don't really need to know that. Our focus is going to be on insulin. Okay. So now you understand about uh the importance of blood sugar regulation, why too much and too little is a bad thing, how on earth we keep uh four grams of sugar in the blood, and the storage mechanisms that we have to maintain that uh that level uh in the blood and the storage that we need to tap into during fasting or exercise. Super important. Crudely, insulin lowers blood glucose by shoving uh glucose into your cells and telling the liver to stop producing it. It's actually a lot more complicated. So, receptors on the cell surface of your target tissues, which are muscle, biggest uh sink for for sugar, fat and liver cells, these passively transport glucose into the cell. Something called muscle glucose uptake is central to glucose metabolism and insulin causes the translocation, this is moving this protein called GLUT4 to the surface of the cell and then it allows glucose to go into the cell. This GLUT4 protein is is very important and you'll hear this or see this, read this in academic journals whenever you uh read about insulin and the receptor. But insulin is not just having an effect on this receptor, this GLUT4 receptor. In fat cells, insulin also works to suppress something called lipolysis or lipolysis. Lipo meaning fat, lysis meaning breakdown. Again, we're using ancient words here to to describe this or Latin words to describe this. Why would insulin suppress lipolysis in fat cells? Well, when you break down fat cells, you increase free fatty acids in the circulation and the breakdown of those those fatty acids are used by the liver to create glucose via gluconeogenesis. So the liver can utilize these different elements that are broken down via lipolysis for gluconeogenesis. So one of the extra actions of insulin is to stop or attenuate or mute that process of fat breakdown. That's really important. So again, you've got insulin stopping the glucose going into cells, you've got insulin stopping gluconeogenesis directly, and you've got insulin stopping gluconeogenesis indirectly by stopping or muting lipolysis. Really important. In the liver, it's reducing hepatic glucose production by also inhibiting the expression of gluconeogenic genes. So insulin is also having an impact on the proteins, the the genes that are switching on and off uh gluconeogenesis. So in addition to all these different things, it's actually having a an impact on on the gene function as well. Again, insulin also suppresses glucagon secretion from the pancreatic alpha cells. So glucagon and insulin are sort of like yin and yang in a very crude manner. And glucagon is responsible for um increasing blood glucose. So it's that's why it's the the yin and yang. We're not going to talk too much about glucagon today. Um but it does that. Uh it it suppresses the release of glucagon from pancreatic alpha cells. Insulin also has an impact on the central nervous system. It suppresses your appetite. So hopefully you're getting this idea that insulin isn't just a case of a lock and key mechanism where you go to a cell, opens up a lock, in goes glucose, thank you very much, and then uh you know, back to the pancreas or broken down or whatever. It's doing a multitude of different things. It's got a suite of different functions at various sites of the body, including fat cells, liver cells, muscle cells, in the central nervous system, that all lead to a nice stable level of glucose in the bloodstream. Alright? So when you're resistant to this hormone, you can understand that a plethora of things can go awry. Let's talk about the biology of insulin resistance now. So we know where insulin is sort of working in in these different target cells of of glucose disposal, liver, muscle, and fat. We know it's changing genes, we know it's changing your appetite, uh we know it's inhibiting another hormone that is responsible for doing the polar opposite, i.e. increasing glucose. But to put it bluntly, we know what happens, but we don't fully understand why it happens. Insulin resistance, uh just the the definition of it is a condition in which the body, the body's cells become less responsive to the hormone insulin. So when cells become insulin resistant, they're less able to take glucose up from the bloodstream, that can lead to high blood sugar levels, and this high amounts of this sugar in the blood over time is not a good thing. I just want to double click on the word over time because since everyone is using continuous glucose monitors or finger finger pricks to measure their glucose responses to foods, which I think overall is a good thing. I think it's um a behaviour change tool. I I've certainly learned a lot of insights from the types of whole grains and and carbohydrates that work best for me. But it's it's really the uh the persistence of high sugar levels over time that is the the feature that we want to avoid rather than the short bursts of uh increases in glucose. Your your glucose level should go up after you have a meal, but it's where it goes too high and for a long period of time, that's where there are issues. And so rather than trying to flatline your glucose the entire time, which is quite abnormal because your body is used to having changes in your blood glucose, but we have these mechanisms to maintain an overall state of balance. That's really what I want you to focus on. It's it's it's more so the um maintenance of these mechanisms that are in place rather than uh a game where you just want to try and flatline as much as possible because that that's just that's not the aim of the game that we're we're trying to play here. Insulin resistance is characterized by impaired insulin signalling and the reduced sensitivity of those target tissues to um to insulin, the hormone itself. So let me make an analogy that makes it uh easier. So caffeine, um if I have a half a cup of coffee and I've never had coffee before and let's say I have a a normal sensitivity to caffeine, I'm going to feel a great buzz, uh I'm going to feel like I can do a million one tasks, I'm going to I'm going to have a a really good productive morning for the next two, three hours or however long that caffeine is going to stay in my system for. If I get into the habit of having one, then two, then three, then four cups of coffee over time, my tolerance of the caffeine is going to wane and I'm going to need ever increasing amounts of the same dose of caffeine to have the same desired effects of me being more productive and me uh having the sort of cognitive energy uh to do my task for the same period of time. Um this is an example of how we become tolerant to the effects of a particular substance. And you can imagine in that same example of caffeine, if I'm having lots more caffeine, it's not just having an impact on my brain, it's also having an impact on my digestive system, my catecholamines, my adrenals, I might become jittery, I might become anxious, uh it might have an impact on my sleep. So there are all these other effects that could get array just because I need an ever increasing dose of the same substance, caffeine, to have the same desired effect. That crude analogy is kind of like what's happening in insulin with insulin and blood sugar. You need ever increasing amounts of insulin to to improve your blood sugar balance. However, because insulin has all these other effects, it's an anabolic hormone, it has impacts on your central nervous system, it has impacts on your fats, these are things that can lead to other issues going wrong, which overall leads to metabolic disturbances that we've described at the top of this pod. So that kind of crude analogy is something that I want you to to understand. Um we're going to talk about the the main underlying mechanisms for insulin resistance, but like I said, just hasten to say this is uh this is not fully understood. The the main mechanisms are, like I said, GLUT4, insulin signalling, fat in the liver and muscle, and inflammation, which invariably leads to mitochondrial dysfunction. This is going to get a little bit technical, so uh just a for warning, for the next couple of minutes, don't worry if you don't get everything. Sometimes it just takes a little getting used to and it's hard to imagine if you don't have the diagrams in front of you. So, GLUT4, like we mentioned before, uh is a protein responsible for transporting glucose from the bloodstream into the muscle cells and insulin normally helps move this GLUT4 receptor to the surface of the muscle cells, allowing glucose to enter. But in insulin resistance, this movement of GLUT4 is hindered, so it's not doing the heavy lifting job of moving this to the cell membrane so glucose can enter. Interestingly, there are other ways to stimulate GLUT4 uh the GLUT4 protein coming to the cell membrane, even in the presence of insulin resistance. And this this will come on to something that we're going to talk about later when it comes to the things and the management techniques that we can use to mitigate against insulin resistance. Exercise and conditions of low oxygen, also known as hypoxia, so that's hypo being low, oxy being oxygen, that can activate a protein that we've talked about on the podcast before called AMP-activated protein kinase, also known as AMPK. And this can help with GLUT4 movement to the cell membrane to facilitate glucose transport. And remember this because it's going to be important when we come to talk about treatments and and why exercise is so important, the doses of exercise as well. So even in the presence of insulin resistance, you can move this GLUT4 protein, but insulin resistance leads to uh issues with moving this and hence why more glucose is left swimming in the bloodstream rather than in the cells where it should be. Insulin signalling, that's the other thing that can go wrong in insulin resistance. So in skeletal muscle, there are problems with the signalling pathway itself and this includes issues with activities of specific proteins called IRTK, RS1, PI3K, AKT. You don't need to know about these specific proteins, but studies have shown that these proteins may not work properly in insulin resistant skeletal muscle, leading to reduced insulin effectiveness. The only reason why I mentioned these proteins is because when we talk about the causes of insulin resistance, one of those is genetics. And unfortunately, there are a few single nucleotide polymorphisms that render these proteins slightly less effective than they should be, and that can affect uh certain people from different backgrounds, um and a cluster of these uh genes that can affect those different proteins involved in insulin signalling can lead to uh issues with a lower uh dose of poor lifestyle. So me coming from an Indian background, I have less of a threshold to tolerate insulin resistance, probably a large part due to my genes, and that's just the fact of the matter. So that's the only reason why I mentioned insulin signalling with those different proteins. Those proteins can be slightly less functioning in certain people based on your genetics, um but otherwise you don't really need to know too much about insulin signalling, although that is one of the key reasons why insulin resistance goes awry. Third, fat in the liver and muscle. So what we've learned about the reason why fat essentially, when you think about fat in the in the muscle and the liver, uh I want you to think of two slightly uh odd things. So foie gras, which is um a horrific, inhumane process whereby goose or duck uh are force-fed uh using a gavage, a very high calorie, high fat diet, um to increase uh the production of fat in the liver. So they're they're overfed a very high amount of energy and this causes fat in the liver. They're essentially becoming insulin resistant. And uh steak, uh but not just a lean steak, a marbled steak, so a something like a ribeye. Um that marbling in between the muscle fibres, that's essentially what is going wrong at the very later stages of insulin resistance. And it's this fat in the liver and in the muscle, first it goes in the muscle, or the the general sort of hypothesis is you get uh uh insulin resistant, that leads to fat in the muscle, which leads to fat in the liver, which leads to all these other issues further down the line. It doesn't necessarily need to be in in that order, but that's generally accepted that's uh probably what's going on. Um the reason why we know a lot about this um this issue with fat in the different uh target tissues is from a condition called lipodystrophy. In lipodystrophy, there is a significant reduction in fat cells in the body's fat tissue, which leads to high amounts of triglycerides in the blood, and then what happens is you get fat accumulation in other cells like the liver or other organs, I should say, like the liver and the muscle, and that leads to severe insulin resistance. So because you've got nowhere to put your fat other than, and you can't keep the fat in the blood, other than the liver and muscles, this is where you get fat accumulation in the muscles and what we know a lot about um insulin resistance comes from studying patients who have this unfortunate condition. Normally what happens is that after a meal when you have an influx of fatty acids from the food that you eat, your fat tissue acts as a buffer to store these fatty acids. But in lipodystrophy, the reduced fat tissue can't handle this influx of fatty acids and as a result, these fatty acids are basically delivered to the metabolic tissues, the metabolic active tissues like liver and skeletal muscle, which impairs insulin signalling and causes that insulin resistance. So this is one of the reasons why we know a lot about insulin resistance being associated with fat in the muscle and fat in the liver. Other studies have shown us that manipulating certain proteins involved in lipid metabolism and fat uh cell function can also lead to uh insulin resistance. So using these studies collectively to demonstrate that where there is excess fat accumulation in the liver and muscle, it can contribute to insulin resistance. Lipodystrophy is a really, really good example and uh important um important condition to to render some insights around that. Okay, from fat to inflammation, although very much linked, right? Researchers are actively trying to look at uh chronic inflammation in obesity, insulin resistant people are basically finding out a lot about how everything is inextricably linked, right? So when a little primer on inflammation, when your body experiences chronic inflammation, and we're not talking about the macro picture of chronic inflammation, we're really talking about it at a cellular level. Um there is a prolonged inflammatory response. So your inflammatory response is is very much part of your immune system. It's how we fight off pathogenic uh bacteria or microbes, viruses. It's happening throughout the body, but where there is a prolonged response for whatever reason, maybe it's obesity related, maybe it's a malfunction of your immune system, whatever it might be, there are changes in the production of certain chemicals uh called cytokines. These are the sort of foot soldiers of your inflammatory response. And what that leads to is activation of signalling pathways related to inflammation as well. So it's almost like a it's a compounding effect. It's like, we're going to we're going to respond to some inflammation, we're going to send these guys out, and those guys are going to shout out some more guys over there and everyone's going to come. So you're going to get a bigger and bigger army. So you have this sort of like chain reaction of inflammation. So when uh we examine obese people, uh so people who are overweight, their uh and we look specifically at uh their fat cells, also called adipocytes, they recruit macrophages, which are other elements of your immune system uh related to your your your total immune response. Um and these macrophages further recruit inflammatory cytokines like TNF alpha. And when that happens and you have all these different cytokines and they're all sort of in the mix, it impairs insulin signalling in the cells, in particular in the liver, and that leads to insulin resistance and and increased expression of these uh cytokines that are happening in in fat cells and other parts of the body. So with this model of inflammation, you can see how it's a compounding effect rather than the direct effect. The direct effect might be related to uh obesity or or uh certain certain genes that are turned on. Interestingly, what researchers have demonstrated is that you can create inflammation in some of the proteins in your fat cells independent of excess body weight as well. So there is an argument to say that uh you you don't have to be overweight to experience the same issues with insulin resistance, and that's certainly something that we see clinically as well. You can be a thin person, healthy looking habitus, and still have insulin resistance. So it's not all obesity related. However, obesity is definitely uh a trigger that can compound the issue and it's more likely to be associated with that as well, which is why one of the um uh the features that we use to diagnose metabolic syndrome that we're going to get into in a second is uh waist to hip uh ratio. Whilst chronic inflammation can worsen insulin resistance, it's not generally accepted to be the primary target for addressing insulin resistance in things like type two diabetes. Although I think if you were to improve inflammation, whether it be through diet or exercise, you you can get to the the root cause of um or you can definitely get to improvements in metabolic health, but I think what people in the research field would argue is that it's via a different uh different mechanism. Who knows? Um you can't really talk about inflammation without mentioning mitochondria. So again, another one of these reasons, the biology of insulin resistance is mitochondrial malfunction and oxidative stress. They're inextricably linked to inflammation. Just a quick primer on mitochondria, these organelles that live in your cells, they're essential for homeostasis, uh and fancy word for balance, uh energy production, signalling, and dysfunction of your mitochondria can lead to things like type two diabetes, aging, degeneration of your brain cells, uh and what's very interesting about mitochondria is that their their genetic makeup is actually uh separate to those of humans. They're they're literally living bacteria inside of us that provide metabolites and and energy. Studies show that reduced mitochondrial function in healthy, young, lean, insulin resistant people is accompanied by increasing intramyocellular lipid concentration. What does that mean? It's basically when you have dysfunction in mitochondria, what this leads to is an increase in the fat accumulation in the muscle cells or in the liver cells, wherever you find mitochondria. Um and this is problematic, as we know, because fat in the skeletal muscle and the muscle cells and liver cells can further exacerbate insulin resistance. The reason why is because mitochondria use fat for energy production and reduced mitochondrial function is associated with that fat going elsewhere and into the the cells themselves. So overall, the big takeaway is mitochondrial function and inflammation reduces the functionality of insulin in fat cells, muscle cells, and ultimately can lead to impaired glucose delivery to cells. So this is a a very broad overview of the biology of insulin resistance. It's related to signalling, it's related to GLUT4 protein um uh malfunctioning, uh obesity, inflammation, fat in the liver and and muscle cells and and potentially mitochondrial dysfunction as well. Okay, so now we know what insulin does, the context of insulin in overall sugar balance, the biology of insulin resistance, what might be going wrong. How do we measure it? How do you figure out whether you have mild insulin resistance, a lot of insulin resistance, if you're at risk of insulin resistance? This is actually part of the problem. There isn't a generally accepted and accessible test for insulin resistance. Clinically, we use metabolic consequences uh as a markers as markers to see whether you are likely to have insulin resistance. Um so when we diagnose metabolic syndrome, we're looking at impaired glucose uh tolerance tests, we're looking at uh obesity that we measure through various means. We used to use BMI, we're moving more towards a a very quick uh tool called waist-to-hip ratio that you can do at home. Um we look at your lipid profile and in particular uh the ratio of HDL to triglycerides. Um which are which you can uh get on a most uh lipid panels. Um and the presence of uh high blood pressure as well and and the presence of elevated triglycerides. So in the UK, we're looking at uh a waist circumference of over 102 cm for men or over 88 cm for women, or if you want to look specifically at the waist-to-hip ratio, you want it to be 0.85 or less for women and 0.9 or less for men. Um to do your waist-to-hip ratio, it's very simple. I would go on YouTube and look at the methodology because you want to do it in between the bottom of your rib and the top of the iliac crest, the midpoint between there is where you do one measurement, and then you do the other measurement at the largest point around your buttocks essentially. So, and you want to make sure that the waist-to-hip ratio is uh sub those levels. Very, very simple test to do, but again, full of inaccuracies and that alone is not enough to tell whether you are insulin resistant or insulin sensitive or not. It's all a combination of all these different markers, all these different investigations that we have that would enable a clinician to essentially pull up a red flag or an amber flag as to whether you are heading in the wrong metabolic direction. But it is definitely part of the problem because as we're going to the actual gold standard of uh measuring insulin resistance, it's um it's very difficult. Um raised triglycerides, so over 1.7 millimoles per litre, those are things that we want to be careful of. Uh reduced uh HDL cholesterol. So HDL is high density lipoprotein. These are taxis that ferry cholesterol around your body. Nothing, it's not a new type of cholesterol, it's not a different type of cholesterol. HDL cholesterol is the type of protein that ferries the same cholesterol that everyone has around the body um back to the liver where it can be reprocessed. Um so we want to make sure that we've got uh higher amounts of this HDL cholesterol in the context of uh uh low triglycerides as well. Um raised blood pressure, so we want to be looking at no more than 130 over 85. Those are the cutoffs for the UK, although there is a trend towards uh less is better, obviously not too low. And then fasting uh plasma glucose. This, I think, even though in the context of all those different um tests is important, it's it's quite a late stage indicator of insulin resistance. So you really want to be uh looking at other markers of insulin resistance rather than just an oral glucose tolerance test or just a fasting plasma glucose because as we know, insulin resistance precedes any issues with diabetes by up to 10 to 15 years. So this this is why we want to we want to get on on top of um insulin resistance. In research, the gold standard is something called the euglycemic clamp, also known as the hyperinsulinemic clamp. It's a research technique with limited clinical ability, applicability. Uh euglycemic being eu, normal or good, glycemic, as you know now, glucose in the blood, or hyperinsulinemic. This points to it's also known as this. This points to the the method used uh in in the technique where you basically pump a high amount of uh exogenous, so outside of the body, insulin into the body to switch off the glucose glucose production in the liver. So you're just relying on the glucose that one is uh delivering to the body. I'll explain the uh the technique. So picture uh insulin being infused into one vein uh in in a person who's who's lying on a couch. Um and the idea is to reach a constant level of uh insulin in the blood. And since insulin is being pumped into this person, what's going to happen? It's going to plummet your glucose. So in the at the same time, you also have to have another infusion of glucose and you vary the rate of that glucose infusion to reach euglycemia. Euglycemia being a normal level of glucose in the blood. And the the way we measure that is in another uh uh cannula that we put into the back of the hand, we'll be taking measurements of the blood glucose level to make sure that we're getting it to a stable level. At the point whereby you are simultaneously giving glucose infused at a varying rate until it stabilizes the sugar level to a normal level because you've got a constant level of insulin also going in, at that point, that equals the amount that is being taken up by the body's tissues, which is a a direct measure of how sensitive those tissues are to insulin. The more glucose that needs to be infused to keep that steady state of euglycemia, the more is being taken up by the body, which means that the tissue is more sensitive to insulin. So, how do I explain this? The more insulin is driving glucose into your target cells, the lower your blood glucose is going to be. So if you have to infuse more glucose to maintain a steady state, that means that your insulin is doing the insulin is doing a good job and you're sensitive to the insulin that is being pumped into your body at a steady state. It is a research technique, it is not something that we use in uh clinical um uh environments. Um but it is very useful when it comes to uh the the research side of things. There are a bunch of issues with this technique, however. Takes a few hours to do, it's relatively expensive even for research standards, and across the literature, there are varying rates of the insulin infusions that we use. So some people use 40 mils, uh some people use 120 mils per per hour. Glucose infusions are different. They're varying uh ways in which you can measure the sensitivity of uh insulin sensitivity as well. They use something called glucose disposal rate and that's often expressed as a function of body weight, which makes it very hard to compare across individual studies if you're just doing it by weight, then, you know, how do you categorize one group of patients that are obese versus lean? It's it it can get very, very complicated. I don't think anyone's going to be doing a euglycemic clamp anytime soon uh in clinic. So, there are some surrogate markers of insulin resistance that you can do in clinic. Only requires a single blood draw, relatively inexpensive to do, not 100% accurate, but they are useful. So, something called the HOMA-IR, that's homeostatic model assessment of insulin resistance, HOMA-IR. It's a mathematical calculation used to estimate, and I hasten to use the word estimate, insulin resistance based on fasting glucose and fasting insulin levels that you can have measured. It's a simple formula, you times those two together over 22.5. Um values greater than 2.5 are suggestive of insulin resistance, over 5.5 or over 6 is very sensitive to insulin resistance. Um but you'd have to really be pushing the uh those values to to get to that number. And by that time, it's more than likely that you have all the symptoms or all the diagnosis that are related to insulin resistance. So the value of HOMA-IR, I don't think is uh proven out. There are a few others, there's QUICKI, these are all uh mathematical equations that um use single blood draws to estimate the the sensitivity, sorry, to estimate insulin resistance. There are a couple of studies that have compared these surrogate markers of insulin resistance to euglycemic clamps um with okay sensitivity and specificity. Um I think overall, there are going to be other uh markers that we should be looking at to estimate insulin resistance. There are also things called uh insulin resistance indexes, uh like Matsuda, the gut index, uh the Macaulay index. These are beyond the scope of today's discussion. We're not really going to go into the pros and cons of those, but they there are some markers that can point you in the direction of whether you are insulin resistant or not. I honestly go for the metabolic markers that we discussed earlier, so things like blood pressure, triglycerides, uh the triglyceride HDL-C ratio, blood pressure, uh fasting glucose. The more accessible tests that I believe most people would be able to uh get a hold of would be a fasting glucose, although like I explained, it's quite a late measure. Um we want to be looking at no more than um uh or 3.9 to 5.5 millimoles per litre. Uh for the Americans, you can use a calculator to uh to change that. I believe it's 70 to around 99 milligrams per decilitre. Um those can those can indicate impaired insulin function and insulin resistance, but again, it's not it's a very late stage in my opinion. Uh there is a blood test uh called fasting insulin where you actually measure fasting insulin levels. So it's typically done overnight. Um uh you fast overnight and then you do it first thing in the morning. Um but this is very hard to interpret. The range of it is very wide and we usually reserve this kind of test for diagnosing uh things like insulinomas, which are tumours uh of the pancreatic glands where you have very, very high amounts of insulin. Um and you're really looking for a a cause as to why someone is presenting with very, very low levels of glucose, um and other endocrine disorders. So that's the clinical application of that test. I personally don't think it has much um uh use in in clinical medicine apart from perhaps uh being used to calculate HOMA-IR. Um it's HbA1c, which again, I think is a very late stage. So by the time you see changes in uh haemoglobin HbA1c, it's quite late. Uh we haven't anticipated that insulin resistant journey until you're you're literally seeing changes in your in your blood glucose levels over time. Um but that is a general sort of marker that we use to to uh average out your uh insulin your uh glucose control over the preceding three months. Glucose tolerance test, many people have probably already done them. This is where you ingest uh a certain amount of glucose in the form of a drink, um something around 75 grams, and then you at regular intervals test your glucose levels to uh look at the response. Um abnormal results that indicate high blood glucose high blood glucose levels after two hours uh suggest delayed clearance can indicate insulin resistance, but again, I think that's quite a late sign. Um and C-peptide. This is a a byproduct of insulin production. Um measuring C-peptide levels can maybe help you evaluate your insulin uh resistance by looking at it as a surrogate marker of how much insulin you are producing and therefore breaking down. Um but again, I don't think any of these are uh particularly useful for the individual. So you're getting a picture hopefully that it is really hard to figure out your level or your degree of insulin resistance and it's more a case of, well, let's do all the things that we can do today to ensure that we are as insulin sensitive as possible. Do glucose monitors have an impact on changing one's behaviours to maintain insulin sensitivity? I don't think we have long enough studies to to demonstrate that, but my anecdotal opinion is that probably probably would be uh useful as a tool for certain people who love learning a bit more about their analytics. Um I I I personally think it's useful, but hey, what do I know? Um the other thing I want to make really clear is if all of those tests are negative, so let's say you do your oral glucose tolerance test, you do your HbA1c, you do your triglycerides, you do your HDL-C, you do all these all these different tests and they're all negative, that does not mean you have a clean bill of health. And I think this is something that we get very, very wrong in medicine. We assume, incorrectly, that if the tests are negative, if everything is within range, that's fine. You carry on, do what you do, you're you're fine. And then we intervene very, very late. And along that journey of 10 to 15 years where someone is insulin resistant and their body is so adaptable. Our bodies are so adaptable. If you think about it from the perspective of smoking, someone has to smoke for decades, daily, before they get a chronic pulmonary disorder or they have cardiovascular disease or they uh have a stroke. That isn't to say that up to that point, those first 20 years when they were smoking or however long it was, that they were healthy. No, it's it's it's exactly what we're doing with things like insulin resistance. We are intervening only at a very, very late stage whereby you have the the uh investigations that demonstrate changes in glucose uh maintenance. And that that for me is is right at the end because your body is so, so adaptable and has this wonderful mechanism of of maintaining balance. So that's definitely something I want to make really, really clear. You get your investigations great, but it doesn't mean that you have a clean bill of health. There are some imaging studies that I think could be useful for people. Where and how how early they can demonstrate uh insulin resistance is still up for question, I would say. Um so the the ones that I'm always asked about include uh MRIs uh or CT scans looking at visceral adipose tissue. Ideally, you want that you want that to be as low as possible. Higher amounts of visceral fat are commonly associated with insulin resistance. So you want to make sure that's very low. Um abdominal obesity, uh so larger waist circumference, but you can very easily do that with a waist-to-hip uh ratio. Um but you can also do it on imaging as well if you prefer to have it on imaging. So you can have before, afters. Um that's definitely something that could be again a behaviour behavioural change tool. It give you a sort of a range of as to where you are. Uh and then DEXAs as well. So DEXAs are relatively cheap and accessible. I think you can get one for about 150 pounds now, relatively often as well. It will give you an indication of your total body uh fat percentage, um particularly in the central region as well that can be linked to insulin resistance. So those are two things that you could do or a simple waist-to-hip ratio that you keep an eye on. I think is um uh is useful. So a combination of all these different investigations, you've got clinical evaluation that you can get done by your doctor. You can uh have all these different blood tests. You can have the imaging, I think that's a nice to have. These will give you some sort of uh inkling as to where you are on the range of insulin resistance. As you can tell, you know, it it it this I think is one of the problems that we have with insulin resistance that we don't really know how to measure it. Um and I think once we find a reliable test that's easy, quick, sensitive, and specific, I think it would be a real game changer for a lot of people. So, let's let's recap before we go into uh some of the causes and what we can do. We know what insulin is, we know about sugar balance in the body, we know about uh the mechanisms of insulin resistance, we know the issues around measuring it and what the ideal scenario is with measuring it in the research lab. Um what are the what are the causes? What are the sort of driving factors behind insulin resistance? So, I've alluded to a couple of them already. Uh but it's going to be a combination of genes, a high sugar diet, environmental pollutants, not enough lean muscle or poor muscle health, I should say, excess fats in the blood, and also poor sleep as well. Um these all will lead to fat in the muscle, fat in the liver, inflammation, mitochondrial dysfunction, also insulin resistance can be independent of inflammation if there's fats in the liver and cell. But all those things, those catalogue of errors, those catalogue of calamities, these all coalesce to uh create metabolic disturbances, the driving factor being insulin resistance. I'm going to summarize these those causes very quickly and then we'll go into some of them in a bit more depth. So, some people may be more genetically predisposed to insulin resistance, which can be passed down through generations. Genes, big issue, can't really do much about it. So I'm going to talk a little bit about the genes, but we're going to move swiftly on to the things that you can do. Poor muscle health, a surrogate for uh lack of exercise, big, big topic. We're going to talk about that. I think that's going to be the focus um of what one can do with with um mitigating against insulin resistance. There's lifestyle factors, things like diet and stress uh that can contribute to insulin resistance, um things like high processed foods, sugar, saturated fats, um those can all lead to inflammation, oxidative stress, impaired insulin signalling, fat in the muscle and liver. Um gut microbiome, emerging research looking at the gut microbiome. Our good friend, the gut microbiome is involved in everything. Um as you know, it's the collection of microorganisms that live mainly in the large intestine. They may play a role in insulin resistance. There's certain types of bacteria, firmicutes and bacteroidetes, these are associated with insulin resistance. These bacteria can produce different types of endotoxins. We'll talk a little bit about that and why that might be causing or driving insulin resistance. Similarly, there are some other bacteria um that could be beneficial uh and prevent uh via maybe indirect mechanisms uh insulin resistance. Environmental toxins, difficult topic to talk about, but very important. There's exposure to certain environmental pollutants, uh persistent organic pollutants that can render us more insulin resistant. And I think that's why we've seen the um the changes in in what's allowed in our in our uh cookware, in our uh reusable plastics. Um BPA being the one that's been taken out. Um but there are other types of similar materials, even ones that are labelled as BPA-free that are just as damaging. And then poor sleep. Poor sleep, poor sleep quality and quantity can disrupt your body's uh hormone balance including insulin, and studies have shown that sleep deprivation can reduce insulin sensitivity. So, look, today we've talked about a lot of things. We've talked about the impact of pollutants, uh exercise, diet, we know a lot more about metabolic health, what that means, why insulin is so important to sugar regulation, the biology of insulin resistance, what the causes of that insulin resistance could be, how to mitigate it using the biggest tools that you have at your disposal, at your disposal, exercise, diet, and all the other things that we talked about with regard to improving gut health, sleep, removing pollutants, and stress. Next time, we're going to be talking about the sort of hacky things that I didn't really want to talk about on this episode because I think that can detract from the real big tools that we have. If you focus on the big tools, the hacks and the supplements, those are nice to have, but they're not the mainstay of treatment. I would say, let's focus on the big tools. Um and then we'll also be talking about um uh a little bit about uh supplements and um the the drugs that are available for insulin resistance as well in a little bit of detail. I hope you enjoyed watching, listening to that. Um I'm going to be doing a few more of these solo episodes. So if you do want me to do a deep dive into another subject, whatever that might be, leave a comment on Twitter or YouTube, uh or sign up to the listen and read newsletter and we we always have a feedback form there that we we always dive into and we we look for any themes. So uh I'll look forward to seeing you there.
