So let's start with high-intensity interval training. So as I mentioned, this is a very time-efficient way to get your heart rate up and exercise. So it involves very short bouts of intense exercise. We’re talking about a heart rate up at least 75% max heart rate, followed by periods of recovery. There's a lot of different protocols we're going to discuss. But there have been lots of studies talking and showing that high-intensity interval training can improve glucose homeostasis and insulin sensitivity. It also decreases fat mass, improves body composition, and enhances mitochondrial function. So a meta-analysis of 50 different randomized controlled trials compared high-intensity interval training to moderate-intensity continuous exercise.

So this would be exercise that's at a lower intensity, the kind of intensity where you can have a conversation, but you're maybe still breathy. Sometimes called zone 2. And this is a longer duration type of exercise. So high-intensity interval training outperforms moderate-intensity continuous exercise at decreasing insulin resistance. It also improves HbA1c levels, so the long-term biomarker for elevated blood glucose levels. It leads to a decrease in body weight and also significantly lowers fasting blood glucose levels. Again, this is 50 different randomized controlled trials.

And another systematic review of many different randomized controlled trials has found that, again, high-intensity interval training outperforms moderate-intensity continuous exercise at improving cardiorespiratory fitness, improving diastolic and systolic blood pressure, improving HDL, triglycerides, and fasting glucose, lowering oxidative stress, improving adiponectin and insulin sensitivity, as well as beta-cell function to produce insulin. It increases PGC-1α, which is a biomarker for mitochondrial biogenesis, which we'll be discussing in a little bit. And it also improves cardiac function. And this is all better than moderate-intensity continuous exercise. So it really provides an opportunity for people to have a time-efficient way of improving metabolic health.

And part of that is because when you get your heart rate up high, when you are putting in the effort, you're putting a strong stress on your mitochondria in your muscle. And your mitochondria are unable to produce energy quick enough to keep up with the demand. And so your muscle cells shift to using glucose as a source of energy through glycolysis. And that ends up producing lactate, which was thought to be a byproduct, a metabolic byproduct. Well, decades—a couple of decades ago, Dr. George Brooks at UC Berkeley was one of the pioneers to find that lactate generated from exercise is anything but a byproduct. So steady-state lactate levels are less than 1 millimolar. When you crank up the intensity of exercise, you can go anywhere up to— 15, 17 millimolar.

And that lactate, it gets in circulation, and it's consumed by other organs. It goes into the brain. It goes into the heart. It goes back into the muscle. It goes to the kidneys. It goes to the liver. And it's serving a very utilizable source of energy. So lactate can be used and converted into acetyl-CoA and used as energy by the mitochondria. But probably one of its most important roles is as a signaling molecule. It's a way for your muscle to communicate with other organs and other tissues. And one of its signaling roles is back in the muscle. It's increasing the translocation of GLUT4 transporters to the cell surface of the muscle, GLUT4 transporters. And so lactate gets back into the muscle.

It's basically telling the muscle, hey, we're using a lot of glucose here for energy, so we need to bring more glucose in. And the way it does it is by increasing GLUT4 transporters at the muscle. And I mentioned lactate levels go up during this intense exercise. That's very transient. So after about 20 minutes, when exercise stops, your lactate levels go back to baseline because all these other organs, including the muscle, are consuming it so quickly. However, the increase in GLUT4 transporters stays elevated for up to 48 hours, with the first 24 hours being the most robust. So you're getting a long-term effect from that signaling from lactate back to the muscle to increase GLUT4 transporters.

And that is why high-intensity interval training is so potent and powerful at improving glucose homeostasis. So there was another meta-analysis of 36 randomized controlled trials that were looking at optimal conditions of high-intensity interval training for improving body composition. And so it's been identified that the duration of the HIIT workout— high-intensity interval training workout— eight weeks is optimal for improving body composition. The frequency is at least 3 sessions a week. And the intervals are 60 seconds or less of the robust, intense interval, followed by about 90 seconds of recovery. And this leads to improvements in reducing fat mass. Cycling and running was best for that. Also improving percent body fat, so body fat reduction. And that was the best with running.

And then increasing fat-free mass, which includes muscle. And the best at that was actually cycling. Okay. So these are some of the optimal conditions for improving body composition with respect to high-intensity interval training protocols. We're going to talk about how high-intensity interval training can regulate mitochondrial function. But before we talk about that, I think it's important to recognize that people with metabolic syndrome, insulin resistance, obesity, and type 2 diabetes have been identified to have pretty profound dysregulated mitochondria.

So the mitochondria in skeletal muscle from people with type 2 diabetes and obesity have been found in multiple studies to respire about 40% less than skeletal muscle cells from people that do not have type 2 diabetes or people that are lean. So their mitochondria are dysfunctional. And subsequent studies have also identified structural defects in the mitochondria. So mitochondria from people with type 2 diabetes are fragmented. So mitochondria are typically— they form a very connected network. This sort of looks like vermicelli spaghetti. And that's a really beautiful network of mitochondria that are able to undergo respiration and do their functions quite robustly. When mitochondria become really fragmented, they are dysfunctional. They can't utilize or even produce energy very well.

And they're on their way to basically dying and causing cells to die. So there's a very intricate connection between structure of mitochondria and the function of mitochondria. And that's important because vigorous exercise, high-intensity exercise has been shown to increase this repair process in mitochondria known as mitophagy. So when exercise is intense enough, it increases the nutrient-sensing protein AMP kinase, AMPK. It activates it. And this causes the mitochondria to send the signal that they need to repair themselves. And so mitochondria can be— sort of dysfunctional or they can be really dysfunctional. So mitophagy can clear away an entire dysfunctional mitochondrion to be used and recycled, or it can clear away pieces of a dysfunctional mitochondrion.

So when you're doing that acute exercise, your mitochondria, if you have a dysfunctional one, the mitophagy pathway gets activated and the mitochondrion fissions off. It kind of goes through this mitochondrial fission process. And that damaged part of the mitochondria then goes and is recycled through the lysosome. And then what you have is a long-term effect after doing routine high-intensity exercise, you then have more healthy, functional mitochondria because you're just getting rid of the damaged part of the mitochondria. If the mitochondria is dysfunctional enough, you're going to get rid of the whole mitochondria. And by the way, the AMP kinase pathway, many of you are probably thinking, oh, well, that's a nutrient sensing pathway. It's activated during periods of fasting.

And that is true. AMP kinase is activated during periods of fasting. And fasting is a powerful signal for inducing autophagy and mitophagy. However, in this particular study, people that did this high-intensity vigorous exercise for 30 minutes— 30 minutes. It did not matter if they had fasted for 16 hours or not. There was no difference in the mitophagy. So in other words, the exercise itself was such a strong signal for activating mitophagy that it didn't matter if they had not fasted for 16 hours because it was so powerful. On top of the repair process, high-intensity interval training is one of the most robust exercise modalities that can increase mitochondrial biogenesis, so the growth of new mitochondria, increasing mitochondrial volume.

So you're having this double whammy effect where you're getting repairing the mitochondria, getting rid of the unhealthy parts, and then you're increasing the growth of new mitochondria. So one of the reasons high-intensity interval training is very good at increasing mitochondrial biogenesis compared to, let's say, moderate continuous exercise is because Lactate that's generated from that vigorous exercise is a signaling molecule to activate the protein that very much regulates mitochondrial biogenesis in skeletal muscle, PGC-1α. So again, lactate is playing that signaling role. It's generated by the muscle. It's taken back up by the muscle. And then it's communicating with the muscle. It's saying, hey, we can't make energy fast enough because this exercise is so intense.

We need more mitochondria to be able to do that. So it's an adaptation to the vigorous intensity exercise. And that adaptation is making more mitochondria, which is obviously very beneficial for not only people with type 2 diabetes, metabolic syndrome, obesity, but also everybody. So mitochondrial biogenesis improves energy efficiency in mitochondria and also is associated with other benefits like decreased atrophy and improved exercise endurance as well. So there's a whole host of benefits with increasing mitochondrial biogenesis. So a lot of the high-intensity interval training protocols that were used in these systematic analyses and meta-analyses were evidence-based HIIT protocols. So Tabata is one that's used.

That's a 20-second on, 10-second off interval, 20 seconds at the highest intensity you can do. You're going all out. And then you're resting for 10 seconds. And that's repeated 8 times for a total of a 4-minute workout. In some cases, the Tabata protocol was repeated twice. The Wingate HIIT protocol is another very commonly used one. And that is a 30-second all-out sprint followed by 4 minutes of active recovery, where you're low intensity. And then you do that 4 to 6 times. That's about a 20-minute or so workout. And then there's the conventional workout. It's the 1 minute on, 1 minute off. So you're going as intense as you can for 1 minute. And then you have 1 minute of very light active recovery. And then you repeat that 10 times. So that's a 20-minute workout.

It is hard, but it's very, very effective at improving a variety of metabolic parameters. And then there's the clinical workout, also known as the Norwegian 4×4, which I like to call it because the Norwegian ski team often uses this HIIT protocol for their training. It's a 4-minute interval where you're going as intense as you can for 4 minutes. And then you have light recovery for 3 minutes. So you're going very, very light, getting your heart rate down. And that's repeated 4 times. So it's about a 25-minute workout.