146: The Muscle Biology Behind Diabetes Risk

Your muscles might be causing insulin resistance. Most people blame diet, but your muscles play the biggest role, and not all muscle is the same. Slow-twitch fibers are highly insulin sensitive. They pull glucose out of your blood very efficiently. Fast-twitch fibers, they're not as good at this, especially the most glycolytic of those fast-twitch fibers. So if you have more fast-twitch muscle, your body may struggle more with regulating blood sugar levels. And those are the fibers that break down first with a poor diet and aging. That's why two people can eat the same way and get very different results. But here's the upside: you can change your muscle. Simple aerobic movement like just about what you eat, it's about what your muscle is made of. This is Lecture 146 of The Metabolic Classroom. Welcome back to the Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. In today's mini lecture, we are learning about muscle fiber types and how they influence insulin sensitivity, and why this slightly more technical topic has some very interesting and meaningful implications for understanding the, the diabetes risk specifically But as you'll see, this has important implications for why different ethnic groups can develop type 2 diabetes so much more readily than others. I find this topic personally very interesting because it bridges some basic cell biology, as you'll see, but all in the context of a practical clinical pattern that we do see play out across populations and ethnicities globally. When we think about insulin resistance, we tend to focus on the usual suspects like liver and adipose tissue and diet and stress and poor sleep. And those are all, of course, very legitimate, very relevant, but we don't often talk about— well, even when we talk about muscle tissue, we don't talk about the differences in muscle type, as you'll see. And in order to understand what I mean by that, let's start this mini lecture by discussing muscle fiber types. Skeletal muscle is not a heterogeneous tissue. It's not like fat tissue. Fat tissue is fat tissue is fat tissue. You know, depending— assuming we're talking about it from the same locations. But when it comes to muscle, it's a very mixed tissue. It's not made up of a single uniform cell type, but rather it's a bit of a mosaic. Of different fiber types, muscle fiber types. And each within these different fibers are distinct, uh, structural differences and contractile differences and metabolic characteristics, as you'll see. So when you look at a cross-section of, say, leg muscle, that's the most commonly studied muscle. You take a biopsy of someone's leg muscle, their quadriceps, and if you look at that under a microscope, you see that within Even one person's muscle tissue, it really is a mosaic. There are some dark fiber muscle fibers interspersed with some light muscle fibers, and each of those has a different metabolic identity and activity. The classical classification system divides the human muscle fibers into two broad categories, Type 1 and Type 2. Type 1 fibers are commonly called slow-twitch fibers. They contract more slowly. They generate less force and are relatively resistant to fatigue. So they're used to being contracted for longer periods of time. These are the fibers that you use during these sustained, very low-intensity activities, like you're going on a walk or you're standing in the kitchen, or you are cycling at a very steady, low-intensity pace. Uh, the type 1 fibers are very densely packed with mitochondria. They have a rich vascularity to them. So a lot of capillaries and no surprise with these two attributes in mind, they also rely primarily on oxidative metabolism. In other words, the oxygen-dependent production of ATP in the mitochondria. So these are also fibers that will very readily burn fat. They will burn glucose, they'll burn ketones, but always relying on the mitochondria and a high amount of oxygen. So you could think of them as like a diesel engine in, in your musculature. They're not really flashy, they're not going to put out a lot of high rapid power and speed, but they are very efficient over the long haul. Now, Type 2 fibers are fast twitch fibers. They contract quickly, they will produce a lot of force, but they also fatigue fairly quickly. These are your sprint and power fibers, the that fire when you're lifting weights or you are sprinting. If the Type 1 fibers are like the diesel engine, then you could say that the Type 2 fibers are like a high-performance gas engine. This is like a race car. It delivers explosive power, but it burns through the fuel very quickly. Type 2 fibers actually do have some subdivisions where in humans they're often further divided into Type 2a and Type 2x. And just a little bit on that, although through the, through the rest of the mini lecture, I'm not going to really further distinguish them just beyond calling them Type 2, but for the sake of being thorough, I'll be brief in covering them. Type 2a fibers are of course fast twitch, but they also still have a pretty high degree of an oxidative capacity, so they do rely on the mitochondria. So they're more of kind of in between the Type 2, uh, and Type 1. They're, you know, they, they're in Type 2, but they're kind of close to Type 1. But then you have the Type 2x fibers, and these are the proto— the, the prototypical fast twitch. They're very glycolytic, so glucose burning, and they rely on a non-oxidative metabolism, so they don't rely on the mitochondria. They're the most powerful, the fastest, but they also fatigue the fastest. So you get a lot of action out of them and then they're done. In a typical healthy adult, muscle fiber composition is roughly half Type 1 and half Type 2, but there is enormous individual variation. The range range of type 1 fiber content reported in human muscle biopsy studies spans from as low as 13% to as high as 98%. That's a pretty staggering biological range within one species— we humans. Genetics accounts for a large portion of this variation, but also some things like training history, age, and metabolic health. Can play some meaningful roles as well. Now let's transition to talk about why the fiber type matters when it comes to this primary metabolic marker of, uh, insulin resistance. That's the heart of the lecture. After all, skeletal muscle is of course the single largest site of insulin-stimulated glucose uptake in the body. When blood sugar rises after a meal and then insulin's released, to help clear that glucose. It primarily is acting on the muscle. About 80% of the glucose clearance after a meal is going into the muscle. And this has been validated with the gold standard studies of euglycemic hyperinsulinemic clamps. These— the gold standard for measuring insulin sensitivity. And that's where that number was identified, the 80% uptake. Of course, the liver matters. It takes up a good, a good portion. Adipose tissue takes up some. When we look at the insulin-stimulated glucose uptake, but the muscle is the— it takes the lion's share. So the metabolic behavior of the muscle matters enormously when we consider whole-body glucose homeostasis. And here is the central observation that motivates the lecture. Type 1 fibers appear to be more responsive to insulin than Type 2 fibers, most especially when compared with the Type 2x, those highly glycolytic fibers, that fast twitch extreme. Now, why is that? Multiple molecular reasons have been identified, and they present a very coherent picture when you look at them together. Compared with type 2 fibers, type 1 fibers carry substantially higher protein levels of the insulin receptor itself, as well as GLUT4, the glucose transporter, and some enzymes like hexokinase 2, glycogen synthase, and pyruvate dehydrogenase. Now, that's a lot to get at the first pass, so we're going to revisit that. But looking through that list that I just mentioned carefully, and you can see that you can almost— you can narrate the entire story of glucose metabolism from the insulin signal to getting into the muscle to be stored or burned. More insulin receptors at the cell surface means that Type 1 fibers are better equipped to detect the insulin signal and respond to it in the first place. More GLUT4 means that more glucose transporters are available to traffic that glucose from the plasma, from the blood into the cell itself. Uh, and that translocation event is of course necessary. You gotta get that glucose in. Now, once the glucose is in, that's where the hexokinase comes in. Hexokinase will then phosphorylate, or you could say locks in that glucose. Um, the moment the glucose comes in, what prevents the glucose from coming in the glute for then right back out through that same glucose transporter? It's hexokinase. It locks the glucose in. That is that first step in glucose burning or glycolysis. And it turns it into a molecule called glucose-6-phosphate. So hexokinase will add that phosphate group, but that essentially locks the glucose in place and determines its fate. Then you have the other enzymes I mentioned, like glycogen synthase, that can take that glucose-6-phosphate molecule and then divert it into glycogen storage. So a way for the type 1 fibers to store that glucose for later use. But then of course, I also mentioned pyruvate dehydrogenase. That is that last enzyme that sits at the gateway of the mitochondria. So when I had mentioned that the type 1 fiber relies more on oxidative or mitochondrial burning. Pyruvate dehydrogenase is that critical enzyme that will take that glucose signal as we're breaking down that glucose molecule, and it will say, I'm going to send you into the mitochondria. It turns it into acetyl-CoA, and then the mitochondria will burn that acetyl-CoA for lots of ATP. Type 1 fibers have more capacity at every single step of that pathway. They're— they appear to be better at responding to the insulin signal, better at importing the glucose, better storing it or burning it. Research has confirmed that insulin-stimulated glucose disposal rates, so the rate at which you can clear the glucose from your blood, it is strongly correlated, uh, with, and positively correlated with the proportion of type 1 fibers in the muscle. So in plain language, the more slow-twitch muscle you have, the more easily it seems the body can manage the glucose in response to insulin. Now, everything I said is true and accurate, but having said that, there is an important nuance worth understanding here, that when scientists look at the actual insulin signaling response per unit of protein within the muscle, the intrinsic, um, sensitivity of the two fiber types, so type 1 and type 2, actually appears to be closer than we originally expected. It seems that the main advantage of type 1 fibers is largely quantitative. We— they just carry more of the relevant molecular machinery. It's not that they're fundamentally more responsive to the insulin. The benefit really then comes from— it's a matter of abundance, not kind of inherently anything superior with the type 1. This matters because it tells us that the fiber type effect on insulin sensitivity is primarily about the scale of the glucose handling infrastructure, the molecular machinery. It's not something intrinsic about the type 1 fibers being superior to the type 2. Research on people with metabolic syndrome, so insulin resistance, has confirmed this picture in a very compelling way. When sedentary individuals with metabolic syndrome were compared to healthy sedentary controls using the clamp technique I mentioned earlier, those with metabolic syndrome had significantly fewer type 1 fibers and relatively that word is important— relatively more type 2 fibers. Insulin responsiveness correlated tightly with the proportion of type 1 fibers. Critically, this was true in prediabetic individuals before they were ever diagnosed with type 2 diabetes. This is important because it tells us that the fiber composition shift is more than, um, just a downstream consequence of having diabetes. It's present earlier. In fact, it precedes it. So it might be a genuine contributing factor to insulin resistance and not just a consequence of it. Perhaps the most striking data in this field comes from studies that deliberately recruited subjects with extreme differences in fiber type proportions. So comparing individuals with about 60% type 1 fiber, um, against those with about 36% All of them otherwise healthy young adults with normal fasting glucose and normal fasting insulin. Now, despite appearing metabolically normal and the same by the standard markers, the group with lower type 1 fiber proportion showed whole body insulin sensitivity that was decreased by approximately 50% compared to the high type 1 group. That, of course, is not subtle. A 50% reduction in insulin sensitivity is the kind of magnitude that we often associate with and we see with, uh, prediabetes. But remember, this was in young, apparently healthy people whose blood work would not have raised any alarms whatsoever. The cardiometabolic implications do extend beyond glucose handling, which is just further testament to the relevance of insulin resistance. Research examining premenopausal women found that the percentage of type 1 fibers positively correlated not only with insulin sensitivity but also with favorable arterial elasticity and lower blood pressure, while type 2 fibers negatively correlated with insulin sensitivity and this arterial elasticity. So, you know, just touching on the risk of having a higher or lower blood pressure, a fast-twitch dominant muscle fiber profile appeared to link across multiple cardiovascular risk factors simultaneously. Now, there's more nuance than this, and I hate the thought that I might be sounding like I'm vilifying type 2. Remember, The difference between them is probably that people— that type 1 fibers tend to be bigger than type 2 fibers in the average person. That's the critical thing to keep in mind. Now, what happens when you challenge the organism with a diet? Well, there's some animal research that we have to rely on here, some animal studies that use diet-induced obesity models. So they make them fat with high-fat, high-sugar diets. They've shown that this, this diet-induced insulin resistance develops specifically in, in the type 2 fibers with most, with the most glycolytic fibers showing reduced GLUT4 protein expression compared to GLUT1 or compared to the type 1 rather. So this, this compounds the risk in individuals who already carry a fast-twitch dominant fiber profile. So that's what's important. If someone has naturally more fast-twitch, they might be starting from a bit of a disadvantageous position metabolically, that they may, they may be more susceptible to diet-driven metabolic problems. That's what the animal studies suggest. Now, you're wondering what you can do to shift your fiber type, although it should be more a matter of increasing the fibers in general, which I'll come back to in a moment. Now, when it does come to fiber type, genetics is the dominant factor that determines it. Twin studies suggest that about 40 to 60% of fiber type is heritable, but that still does leave, of course, about 40 to 60% that can shift due to lifestyle. Now, before discussing fiber type shifts, it is worth stepping back and asking the more fundamental question, given that type 1 fiber Given that the advantage, as I noted a moment ago, is primarily a matter of quantity— you just have more of these proteins in larger Type 1 fibers— what I think the better strategy is not to necessarily convert fast twitch fibers to slow. I don't think that's relevant at all, but it's really more a matter of just building more muscle. A larger muscle and larger fast twitch fibers will just carry more total metabolic machinery than a smaller one. This, I think, is the most underappreciated argument for resistance training as a metabolic health tool. It, uh, it does not just, of course, influence fiber type. If you resistance train, you end up having more type 2, um, but it's, it's because you have larger type 2. That's the critical thing, that it expands the overall size of the fiber. And so you just have more glucose disposal potential. With that in mind, I strongly maintain that resistance training is essential. Beyond fiber type effects, the more important metabolic benefit is the absolute increase in muscle mass itself. More total sites for insulin-stimulated glucose disposal regardless of fiber type. Importantly, this is something endurance exercise simply doesn't really do. As much as endurance exercise can shift you to have more of a population or a volume of type 1, uh, it will not— you don't look at an endurance athlete and see big muscles. More— remember, more muscle is generally going to be a better thing here. But in this regard, aging does work against us whether we want it to or not. Fast-twitch fibers atrophy the most readily, more than the slow-twitch. We just continue to use slow-twitch fibers more as we age and as we become sedentary. It's the power fibers that we start to lose the most. And so I feel very strongly that we need resistance training to defend muscle mass and keep total glucose disposal capacity as large as possible. Now let's shift into a topic that you might not expect to focus on when we just talk about fiber type, and that is the ethnic differences, because across the different ethnicities globally, we do see very different diabetes risk. And some of this is attributed to muscle fiber type. So let's talk about ethnicity, because I think this gives a very interesting and kind of beautiful nuance as we look globally, because as I noted, type 2 diabetes does not affect all populations equally, and muscle fiber type and its composition is, I think, one of the more underappreciated contributors to these disparities. Now I'm going to talk in very general, broad terms, which is always dangerous. Please appreciate that within each ethnicity, I am painting in very broad strokes, um, where within the ethnicity it's very, very possible to have these individual differences. You know, you are more than just your ethnicity, of course. With that in mind, Black and Hispanic groups tend to have higher rates of diagnosed diabetes. Now, I'm presenting this, of course, from an American, a U.S. perspective here, where most of the research has been done. So Here with, with Black and Hispanic groups, you see rates of diagnosed diabetes of about 11 to 12%. But that's interesting because compared to whites, you see about 7%. So that's quite a bit different. Now, lest the Black and Hispanic groups feel very disappointed in these numbers, unfortunately, it can get much worse. Native Americans face rates as high as 33%. In some communities within the United States. And South Asians show rates that often will rival or exceed those of Blacks, despite having considerably lower rates of clinical obesity. And when we look at the skeletal muscle physiology data, um, we start to see, I think, a picture that is worth noting. All right, so let's just start as I want to go through these different ethnic groups. Of course, I am presenting this primarily from the American perspective, where not only am I located, but where most of the research on this topic has been done. The primary ethnicity in the United States is white Europeans. So white Europeans have served as the reference population in most of the fiber type and insulin sensitivity research. I don't think that has— is anything more than the fact that, um, the research has been conducted in communities, in areas with predominantly white participants. So that became the sort of standard or the reference point. Now, with that context in mind, white Europeans will show a relatively balanced slow twitch to fast twitch ratio. It really is about 50/50 on average. Of course, there's wide individual variation. There always is in every ethnicity. Insulin resistance in this group has been most consistently linked to mitochondrial dysfunction and, um, and intramuscular lipid accumulation within type 1 fibers. So remember, this is the reference point. And then let's move into the other ethnic groups. So let's turn to Blacks first. The— I think the next most dominant group within the United States. The research has found that this group has, on average, a greater percentage of Type 2 skeletal muscle fibers and lower maximal aerobic capacity compared to whites. Direct fiber type biopsy studies found that African-American women showed significantly higher proportion of these type 2x, the most glycolytic fibers, and fewer type 1 fibers compared to comparably obese white women. That further correlated with higher rates of obesity, reduced rates of fat oxidation, and greater insulin resistance. This study, in fact, that I'm citing here was actually conducted where I earned my PhD at East Carolina University. So again, just to paint that picture, cuz it was a very compelling study. I remember when the work was being done, they looked at white women, black women of generally equal obesity levels and found that the muscle biopsy in the black gals had much higher rates of these, the most extreme power glycolytic, um, muscle fibers, uh, muscle fiber type. And they tended to have much higher rates of type 2 diabetes. And, or a risk and very, and much lower rates of fat oxidation, fat burning studies of the skeletal muscle enzymatic activity. So how, how well these enzymes are working really reinforces this showing much higher glycolytic activity compared to the oxidative capacity. So that's that kind of a biochemical signature that's very consistent with a muscle that runs more on a glycolytic metabolism at baseline. All right, now let's shift to South Asians. This is people from India, Pakistan, Bangladesh, Sri Lanka, and any other kind of neighboring countries. They present one of the most clinically important and scientifically puzzling cases of ethnic diabetes disparity. They have remarkably high rates of type 2 diabetes relative to their degree of obesity, and lifestyle factors alone can't really account for this. One contributing factor may be actually detectable from birth. South Asian newborns have much lower skeletal muscle mass and higher truncal fat compared to white European newborns. Um, this is sometimes referred to as the thin-fat phenotype. Remember, of course, since skeletal muscle is the primary site of insulin-stimulated glucose disposal, entering life with less of it may be, uh, a metabolic disadvantage, um, that can compound over time. The South Asian picture carries a striking paradox even at the mitochondrial level, where both diabetic and non-diabetic South Asians have higher skeletal muscle, um, mitochondrial oxidative capacity than non-diabetic, um, white Europeans. And yet they are substantially more insulin resistant. So this suggests that it is more complicated than just having more type 1. As much as I earlier presented a general overview that more type 1 tends to be an advantage, this point, now that we see in South Asians, comes back to the idea of quantity. So again, the primary driver here appears to be the quantity of muscle rather than its quality. More type 1, of course, alongside a different sort of fat distribution where South Asians tend to have much more, um, fat cell hypertrophy. But I don't want to get into all that because remember, I wanted this topic to focus just on muscle. But remember, there are additional inputs that go in here in, in the South Asian population. That's very, very relevant. Okay, now let's go from South Asian to East Asians. Um, overall, East Asians have among the lowest obesity rates globally, but their metabolic status is still problematic because they will tend to have higher rates of abdominal and visceral obesity at any given BMI compared to white Europeans. And this is something evident even in childhood. So I'm going to say that again. You can have, say, an East Asian child and a white European descent child of the same overall body fat, and the East Asian will tend to have more of that stored abdominally and viscerally. Um, the evidence also suggests that there's a lower absolute skeletal muscle mass on average in East Asians. The result is a population that does have a metabolic risk that challenges the standard Western BMI thresholds. Once again, this is an issue where a lot of these baseline metrics were identified in white Europeans, including BMI, here where East Asians tend to just have, yes, both less fat mass but also less lean mass. And so you need to have a different BMI threshold for East Asians than you see in other ethnicities. And indeed you do. You start to see more and more revised BMI cutoffs that have been proposed specifically for East Asian populations. Now let's come back to the Native Americans that I mentioned earlier. We do see within the United States the highest diabetes prevalence in this community by far. Well-studied populations such as the Pima Indians have been documented to have muscle fiber profiles with relatively low type 1 proportions, which of course correlates with profoundly elevated insulin resistance measurable in children and young adults. Long before the diabetes is formally diagnosed. But having said that, the earliest recorded instance of fully diagnosed type 2 diabetes that I'm aware of was a 4-year-old Pima Indian. So this is a population that is very susceptible to insulin resistance and its consequences. This population is the origin of the Thrifty Genotype, um, theory or hypothesis, the idea that ancestral populations, um, in different regions adapted to feast-famine cycles, in that this adaptation resulted in a metabolic phenotype that wants to store energy more efficiently. That, that idea does have some merit, but that same phenotype, of course, that body type becomes very pathological under our modern conditions of constant caloric abundance and, I would say, overconsumption of carbohydrates. The hypothesis does have its critics, and they are The criticisms are very valid. So this is a very kind of general theory that sounds good, but has people— they've poked some holes in it. But just so you're aware of it, that's the origin of that viewpoint that you might have heard of. Now, the last group I want to mention is Pacific Islanders, in part because of where I am in recording this in the state of Utah. We have a high Pacific Islander population, which I love. This group will include Polynesian, Micronesian, and, and other just Pacific Island populations. Of course, this is a group that has within itself a lot of variations. So please, once again, remember I'm not trying to create, um, these siloed populations, that within each ethnicity you do continue to have individual variations. But this group deserves some mention here because they carry some of the highest rates of obesity and type 2 diabetes in the world, with some Pacific Island nations reporting diabetes prevalence well above 40%. Indeed, the most diabetic countries on the planet are the Pacific— are countries within the Pacific Islands. What makes this population particularly interesting from a body composition standpoint is that they tend to have greater muscle mass and bone density than white Europeans at the same BMI. So once again, we have a group here where the standard BMI thresholds tend to underestimate the metabolic risk rather than overestimate it. So it's kind of opposite of the East Asians. East Asians need BMIs that are lower, but Pacific Islanders need, um, BMIs that are generally higher. Now, despite the relatively higher muscle mass, insulin resistance and diabetes remain strikingly high, which points to something— it's a combination of factors, of course, very heavily related to diet. And dietary changes, but also more central fat, but also possibly, possibly more type 2 fibers. Now, why am I saying possibly? Because of all the populations that I mentioned, this is the group with the least amount of muscle biopsy data. We just— there are just huge gaps, um, here. So a very limited amount of data here that my hope is that this important gap will be, um, closed soon. Um, but as much as I'm bringing in the Pacific Island population in this lecture on muscle fiber type, oddly enough, um, we don't have a lot of data when it comes to muscle fiber. In fact, I'm unaware of any, um, looking in Pacific Islanders. I strongly speculate that there's going to be much more Type 2, that this is going to be a muscle fiber profile that will be more similar to what I described in the black populations earlier. All right, now let's wrap this up. Let me bring it all together. The fiber type composition of your skeletal muscle is a biological input that will and does appear to affect your baseline insulin sensitivity. The general overview is that having a higher proportion of the slow-twitch Type 1 fiber appears to be metabolically advantageous because those fibers express more of all of the enzymatic machinery at almost every step to respond to the insulin and to clear that glucose. And a shift toward, or someone having more fast-twitch glycolytic fibers, um, will— it tends to correlate with a muscle that is less responsive. But remember, the difference is in the amount that we have. That's the critical thing to keep in mind here. And, and as I elaborated the differences across ethnicity, which are very real. We see very real differences in risk of these metabolic diseases associated with very real differences in muscle fiber type. It is not the complete story. As I've alluded to, there's differences in fat cell size, there's differences in visceral adiposity, beta cell function in, in Blacks and East Asians, for example. And of course, um, at the end of it all, I would say it's the dietary patterns that will matter most. So regardless of how you go into this with what you think your muscle fiber type may be, genetics is not your destiny here, that it's going to be your lifestyle variable that matters most. That to me, I think, I hope is the most important message. But within the midst of these important messages, I hope you appreciate that fiber type is not necessarily fixed, that with more aerobic exercise you can push a little more type 1, with more resistance you can push more type 2. Regardless of ethnicity. And remember, it's the volume or the amount of the fibers that matters most, less so its type. That's it. Class dismissed. Until next time, more knowledge, better health.