Understanding Diabetes and Insulin Resistance

Most people don't die with diabetes as the main cause. It's not that diabetes has killed them. It's typically that the diabetes is aggravating or exacerbating or even outright causing a different situation. And so I've indicated that here, really, I think, helping us appreciate the relevance of diabetes well beyond its narrow, small, little confines of diabetes itself. It touches on so many different disorders, heart disease, cancer. being right there at the top of the most lethal of these diseases. A 2019 study of U.S. adults showed that 88% are metabolically unfit. So only 12% of adults in this survey were okay in all five of these areas. So a narrow enough waist circumference, normal blood pressure, normal blood levels of HDL, cholesterol, triglycerides, and glucose. So... that's how they define metabolic health. What is insulin resistance? If I'm putting it at the middle of that insulin resistance syndrome, let's define it. Let's get to know the villain here in this story. Now, insulin is a hormone that's flowing through all of our blood. It's made from the pancreas, unless we are a type one diabetic, and we have insulin flowing through the blood all the time. Every cell in the body has insulin receptors, and I mean every cell, bones, muscles. From the bottom of our feet to the hair on the top of your head, we've got insulin receptors. Now insulin will bind this receptor. It's essentially a door that only insulin can knock on. Insulin will come and knock on that door. And then just as if we were knocking on the door of someone's house, someone will come and answer the door or something happens inside the home because of that knocking door. So I'm just going to call this action. Really, whatever the action is depends very heavily on the cell. Insulin will do something differently at a liver cell. As opposed to a kidney cell as opposed to a neuron so there are different effects I'm just calling it action so insulin comes and binds the insulin receptor then there is a cellular action now one Prominent action in the body is that glucose that is outside the cell will be Ushered into the cell it will if you will it will walk in the door That a lot that insulin allows to be opened So blood glucose levels will come down when insulin is elevated. Now over time, this action can be diminished. And this is one of the two important points to make about insulin resistance. It's that insulin has a diminished action. Now this is not universal throughout the body, but it happens in a few important cells. So as this diminished action occurs, we have then consequences. One being that glucose starts to climb because the body... This is especially relevant at the muscle. So when the muscle becomes insulin resistant, its ability to pull in glucose in response to insulin is compromised. And then insulin itself begins to elevate. Now there is a part of a vicious cycle here. We've come to this point where if this given amount of insulin was not enough to do the effect, like, for example, lower blood glucose, so the body makes more insulin. Now what was once a polite tap... at the door has become a pounding and this is sufficient to overcome that diminished action in response to a given amount of insulin and the action essentially goes to some degree norm. So there are two important takeaways in defining insulin resistance. One is that some events or actions within the cell are compromised in response to insulin and then second and this is often overlooked but it is an essential part of the definition of insulin resistance and that is the blood insulin levels are actually elevated so a hyperinsulinemia this is the normal situation the healthy scenario where glucose is normal and insulin is normal but in insulin resistance it is importantly the glucose is normal but insulin is not this is insulin resistance essentially more insulin is required to keep glucose at a normal level so these are the five aspects of the metabolic syndrome or as I submit more accurately, the insulin resistance syndrome. Let's just kind of go around them briefly and look at how each of these is relevant or derivative of insulin resistance. Now, glucose, this one's quite obvious. As someone is living a life that is constantly elevating their glucose, chronically elevated hyperglycemia is lethal. And so the body wonderfully has this mechanism to prevent that. So constantly bumping up glucose in the diet, will result in constantly bumping up insulin. As the insulin is chronically elevated, the body will become progressively resistant to that insulin, where the elevated glucose is driving elevated insulin, which is driving insulin resistance, which in turn is pushing up the glucose. So this is often one of the end results of chronic insulin resistance is that the glucose finally starts to climb and then we spill into the realm of type 2 diabetes. Now what about waist circumference? There are two phenomenon that I'd like to refer to. One is how insulin will reduce metabolic rate and of course as metabolic rate goes down the body will be more inclined to store energy. And then second it's the direct effect of insulin on fat cells stimulating the fat cells to grow. So first of all, with metabolic rate, this is a remarkably old finding. In 1912, two of these legendary scientists, so in 1912, they published this report finding that in type 1 diabetes, untreated type 1 diabetes is associated with this significantly elevated metabolic rate. First of all, they used formulas to predict what energy expenditure ought to be based on body mass. Their metabolic rate should have been in the mid-1700s calories per day, but they found that they were actually about 300 calories higher, so sort of 15% to 20% higher than it should have been based on the body size. Now, interestingly, as we shift over to the right, when they began insulin therapy to properly control the diabetes, the metabolic rate slowed down by about 300 calories, putting them right within, you know, remarkably accurate range of what the… what the formula predicted they would be based on their body size. But over on the left of this slide, you'll see that minute by minute, with the beginning of insulin therapy, they could detect this steady drop in metabolic rate. So this is a real phenomenon that happens in real time. Even in type 2 diabetes, with the beginning of insulin therapy, metabolic rate starts to slow. Now, to this other idea, or furthering this idea of insulin and body weight, When we aggressively use insulin to control glucose in type 2 diabetics, whether it's a conventional therapy or a more intensive, so more aggressively increasing the insulin even more, they will gain a significant amount of weight. Another study in type 1 diabetics found that with the beginning of insulin therapy, they gain a significant amount of fat, no significant gain in lean body mass. Interestingly, despite this weight gain, the metabolic rate... which is over here on the right side, started to slow as the insulin therapy was increased. This is a unique phenomenon within human physiology. Typically, as I indicate here, as body weight is going up, so too does metabolic rate. Now, this is in adults that are grown. Of course, it's obvious if you're looking at an adolescent who's going through puberty and experiencing explosive growth, but that's not what we're talking about. We're talking about adults. If an adult gains weight, their metabolic rate goes up. If an adult is losing weight, metabolic rate is going down. So typically these two things go together. Now interestingly, based on the data I've shown you, when insulin therapy is thrown into the mix or just bumping insulin up higher than it was before, we separate these two. And now, so essentially we uncouple body weight from energy expenditure. Now with regards to the actual size of fat cells, if you take diabetics who are using exogenous insulin as part of their therapy, at the sites of insulin injection, we have significant increases in the size, roughly three times expansion of the diameter of the fat cell. And you see that here in panel B that I'm kind of circling with my cursor here, the big adipocytes compared to these much smaller, indeed. more vascularized adipocytes in the non, even in the same person at the areas where they aren't injecting insulin. So just two different fat cells. And this is what it can look like when it's done in one spot, insulin therapy, insulin injections in one spot for a long time. Indeed, this insulin-induced adipocyte hypertrophy is one of the reasons why type, in fact, the reason why type 1 diabetics are told to rotate their injection site. It's because all that insulin in just a few fat cells makes those fat cells uniquely big. Now, let's move on then to blood pressure as we continue to circle around insulin resistance. This is all through the actions of a hormone called aldosterone. And when insulin goes up, aldosterone goes up. And aldosterone's main effect is to induce the salt and water retention or resorption at the kidneys. And then as volume goes up, of course, pressure will go up as well. And so we have an increase in blood pressure. Now what about the bottom two, triglycerides and HDL cholesterol, two common lipid markers? Low triglycerides and high HDL is looked at as an indication of insulin sensitivity, and in contrast, if someone has high triglycerides and low HDL, that is an indication of insulin resistance. Hyperinsulinemia and insulin resistance will reduce HDL cholesterol levels in the plasma, and in contrast, they will increase LDL beyond the... Insulin resistance syndrome. Insulin resistance has a hand in many diseases, including these big three, diabetes, heart disease, and cancer, but also several others that you might not expect. I've already touched on body fat, but Alzheimer's disease, the most common form of dementia, stroke, arthritis, migraines, infertility in men and women, and fatty liver disease. Each of these diseases is either caused by or exacerbated. by insulin resistance. So insulin resistance is extraordinarily relevant in these non-infectious chronic diseases that we're all worried about. I think that if we appreciate the role of insulin resistance in type 2 diabetes, we look at type 2 diabetes with a far greater degree of accuracy. So in looking at insulin resistance, commonly the typical marker that we're searching for is looking at glucose. That's what we want to look at and that's what we want to track. And over the life of a person progressing towards type 2 diabetes, the glucose levels are going to look something like this, starting normal and then becoming progressively elevated. Insulin ought to be the metric that we're scrutinizing when we want to understand type 2 diabetes. And if we superimpose insulin over the lifetime of someone progressing towards type 2 diabetes, it would look something like this. It starts low, it elevates significantly, and then it starts to come down, but it is nevertheless higher than it was before. before. That is so important because so commonly this part here where insulin starts to drop and then glucose starts to climb, commonly in the literature we will say insulin is insufficient to keep glucose in control. And that leads some to erroneously conclude that insulin is essentially zero and we use that as justification for insulin therapy. It is misleading to say that insulin is insufficient. We should be clear that it's insufficient to keep. glucose in check but it is still elevated. Anyway, insulin has that progression. I want to note two specific timelines as if we were moving along that x-axis through time, through the life of the person. This first stage is the insulin resistance stage and you'll note that it is defined by elevated insulin but normal glucose. This is where most people fall nowadays. unfortunately, certainly in the U.S. and other countries. And then as this progresses, and not everyone, but many of these people with insulin resistance will progress towards type 2 diabetes, but not all of them. But this is now where insulin is still higher than normal, but it may start to drop, and now glucose levels will start to accelerate and climb. So insulin is elevated and glucose is elevated. But insulin is the key variable here. You can see how it starts to climb so much earlier than glucose does. And this is played out in the literature, this interesting report, finding that in people with type 2 diabetes, if you're looking at insulin and not glucose, we can detect changes a decade, and I would submit more than one decade, earlier than the glucose changes. And if we're looking at insulin resistance, then this study is making the case that it's insulin, not glucose. that should be used as the marker of the disease. Now, unfortunately, and I alluded to this a moment ago, when we focus on glucose, begin treating the patient with insulin therapy, and then that will most certainly push up the insulin, but conventional medicine would say, who cares? We don't care about the insulin. We care about the glucose, and because the glucose is going down, well, then we're doing what we want. The tragedy in this paradigm, one, we not only have a significant increase in body fat, The diabetic who begins insulin therapy can expect to gain up to 10 plus kilos easily of fat. The risk of heart disease will climb by multiples. The risk of cancer, mortality, actually dying from cancer will go up, one particular study, by about 90% with insulin therapy. So this has meaningful consequences. So what is a takeaway then as I'm wrapping this up? If we look at insulin levels, I make the cutoff of around six micro units per mil. This is based on evidence, and I have some studies linked here, where healthy people, based on... people not adhering to a diet that is based on processed foods, they're going to have insulin levels around 4 microunits per mil. And these are people who have extremely low levels, if any, diabetes at all. Importantly, the average American has insulin levels of around 9 microunits per mil. And oddly, that fits within the healthy range of most clinical cutoffs for insulin. I think that is misleading because the average American, of course, based on that study published last year, is metabolically unfit. So six microunits range that's in the middle of these two cutoffs is going to be one that people should shoot for. The dietary strategy that I believe is best is encompassed in the very name of this low-carb Sydney meeting. Now, so in conclusion, these are the aspects of the insulin resistance syndrome, nowadays referred to as the metabolic syndrome.

being right there at the top of the most lethal of these diseases. A 2019 study of U.S. adults showed that 88% are metabolically unfit. So only 12% of adults in this survey were okay in all five of these areas. So a narrow enough waist circumference, normal blood pressure, normal blood levels of HDL, cholesterol, triglycerides, and glucose.

So... that's how they define metabolic health. What is insulin resistance? If I'm putting it at the middle of that insulin resistance syndrome, let's define it. Let's get to know the villain here in this story.

Now, insulin is a hormone that's flowing through all of our blood. It's made from the pancreas, unless we are a type one diabetic, and we have insulin flowing through the blood all the time. Every cell in the body has insulin receptors, and I mean every cell, bones, muscles. From the bottom of our feet to the hair on the top of your head, we've got insulin receptors.

Now insulin will bind this receptor. It's essentially a door that only insulin can knock on. Insulin will come and knock on that door.

And then just as if we were knocking on the door of someone's house, someone will come and answer the door or something happens inside the home because of that knocking door. So I'm just going to call this action. Really, whatever the action is depends very heavily on the cell. Insulin will do something differently at a liver cell. As opposed to a kidney cell as opposed to a neuron so there are different effects I'm just calling it action so insulin comes and binds the insulin receptor then there is a cellular action now one Prominent action in the body is that glucose that is outside the cell will be Ushered into the cell it will if you will it will walk in the door That a lot that insulin allows to be opened So blood glucose levels will come down when insulin is elevated.

Now over time, this action can be diminished. And this is one of the two important points to make about insulin resistance. It's that insulin has a diminished action. Now this is not universal throughout the body, but it happens in a few important cells.

So as this diminished action occurs, we have then consequences. One being that glucose starts to climb because the body... This is especially relevant at the muscle.

So when the muscle becomes insulin resistant, its ability to pull in glucose in response to insulin is compromised. And then insulin itself begins to elevate. Now there is a part of a vicious cycle here. We've come to this point where if this given amount of insulin was not enough to do the effect, like, for example, lower blood glucose, so the body makes more insulin. Now what was once a polite tap...

at the door has become a pounding and this is sufficient to overcome that diminished action in response to a given amount of insulin and the action essentially goes to some degree norm. So there are two important takeaways in defining insulin resistance. One is that some events or actions within the cell are compromised in response to insulin and then second and this is often overlooked but it is an essential part of the definition of insulin resistance and that is the blood insulin levels are actually elevated so a hyperinsulinemia this is the normal situation the healthy scenario where glucose is normal and insulin is normal but in insulin resistance it is importantly the glucose is normal but insulin is not this is insulin resistance essentially more insulin is required to keep glucose at a normal level so these are the five aspects of the metabolic syndrome or as I submit more accurately, the insulin resistance syndrome.

Let's just kind of go around them briefly and look at how each of these is relevant or derivative of insulin resistance. Now, glucose, this one's quite obvious. As someone is living a life that is constantly elevating their glucose, chronically elevated hyperglycemia is lethal. And so the body wonderfully has this mechanism to prevent that.

So constantly bumping up glucose in the diet, will result in constantly bumping up insulin. As the insulin is chronically elevated, the body will become progressively resistant to that insulin, where the elevated glucose is driving elevated insulin, which is driving insulin resistance, which in turn is pushing up the glucose. So this is often one of the end results of chronic insulin resistance is that the glucose finally starts to climb and then we spill into the realm of type 2 diabetes.

Now what about waist circumference? There are two phenomenon that I'd like to refer to. One is how insulin will reduce metabolic rate and of course as metabolic rate goes down the body will be more inclined to store energy.

And then second it's the direct effect of insulin on fat cells stimulating the fat cells to grow. So first of all, with metabolic rate, this is a remarkably old finding. In 1912, two of these legendary scientists, so in 1912, they published this report finding that in type 1 diabetes, untreated type 1 diabetes is associated with this significantly elevated metabolic rate.

First of all, they used formulas to predict what energy expenditure ought to be based on body mass. Their metabolic rate should have been in the mid-1700s calories per day, but they found that they were actually about 300 calories higher, so sort of 15% to 20% higher than it should have been based on the body size. Now, interestingly, as we shift over to the right, when they began insulin therapy to properly control the diabetes, the metabolic rate slowed down by about 300 calories, putting them right within, you know, remarkably accurate range of what the… what the formula predicted they would be based on their body size.

But over on the left of this slide, you'll see that minute by minute, with the beginning of insulin therapy, they could detect this steady drop in metabolic rate. So this is a real phenomenon that happens in real time. Even in type 2 diabetes, with the beginning of insulin therapy, metabolic rate starts to slow. Now, to this other idea, or furthering this idea of insulin and body weight, When we aggressively use insulin to control glucose in type 2 diabetics, whether it's a conventional therapy or a more intensive, so more aggressively increasing the insulin even more, they will gain a significant amount of weight. Another study in type 1 diabetics found that with the beginning of insulin therapy, they gain a significant amount of fat, no significant gain in lean body mass.

Interestingly, despite this weight gain, the metabolic rate... which is over here on the right side, started to slow as the insulin therapy was increased. This is a unique phenomenon within human physiology. Typically, as I indicate here, as body weight is going up, so too does metabolic rate. Now, this is in adults that are grown.

Of course, it's obvious if you're looking at an adolescent who's going through puberty and experiencing explosive growth, but that's not what we're talking about. We're talking about adults. If an adult gains weight, their metabolic rate goes up.

If an adult is losing weight, metabolic rate is going down. So typically these two things go together. Now interestingly, based on the data I've shown you, when insulin therapy is thrown into the mix or just bumping insulin up higher than it was before, we separate these two. And now, so essentially we uncouple body weight from energy expenditure.

Now with regards to the actual size of fat cells, if you take diabetics who are using exogenous insulin as part of their therapy, at the sites of insulin injection, we have significant increases in the size, roughly three times expansion of the diameter of the fat cell. And you see that here in panel B that I'm kind of circling with my cursor here, the big adipocytes compared to these much smaller, indeed. more vascularized adipocytes in the non, even in the same person at the areas where they aren't injecting insulin. So just two different fat cells.

And this is what it can look like when it's done in one spot, insulin therapy, insulin injections in one spot for a long time. Indeed, this insulin-induced adipocyte hypertrophy is one of the reasons why type, in fact, the reason why type 1 diabetics are told to rotate their injection site. It's because all that insulin in just a few fat cells makes those fat cells uniquely big. Now, let's move on then to blood pressure as we continue to circle around insulin resistance.

This is all through the actions of a hormone called aldosterone. And when insulin goes up, aldosterone goes up. And aldosterone's main effect is to induce the salt and water retention or resorption at the kidneys.

And then as volume goes up, of course, pressure will go up as well. And so we have an increase in blood pressure. Now what about the bottom two, triglycerides and HDL cholesterol, two common lipid markers?

Low triglycerides and high HDL is looked at as an indication of insulin sensitivity, and in contrast, if someone has high triglycerides and low HDL, that is an indication of insulin resistance. Hyperinsulinemia and insulin resistance will reduce HDL cholesterol levels in the plasma, and in contrast, they will increase LDL beyond the... Insulin resistance syndrome.

Insulin resistance has a hand in many diseases, including these big three, diabetes, heart disease, and cancer, but also several others that you might not expect. I've already touched on body fat, but Alzheimer's disease, the most common form of dementia, stroke, arthritis, migraines, infertility in men and women, and fatty liver disease. Each of these diseases is either caused by or exacerbated.

by insulin resistance. So insulin resistance is extraordinarily relevant in these non-infectious chronic diseases that we're all worried about. I think that if we appreciate the role of insulin resistance in type 2 diabetes, we look at type 2 diabetes with a far greater degree of accuracy.

So in looking at insulin resistance, commonly the typical marker that we're searching for is looking at glucose. That's what we want to look at and that's what we want to track. And over the life of a person progressing towards type 2 diabetes, the glucose levels are going to look something like this, starting normal and then becoming progressively elevated.

Insulin ought to be the metric that we're scrutinizing when we want to understand type 2 diabetes. And if we superimpose insulin over the lifetime of someone progressing towards type 2 diabetes, it would look something like this. It starts low, it elevates significantly, and then it starts to come down, but it is nevertheless higher than it was before.

before. That is so important because so commonly this part here where insulin starts to drop and then glucose starts to climb, commonly in the literature we will say insulin is insufficient to keep glucose in control. And that leads some to erroneously conclude that insulin is essentially zero and we use that as justification for insulin therapy.

It is misleading to say that insulin is insufficient. We should be clear that it's insufficient to keep. glucose in check but it is still elevated. Anyway, insulin has that progression.

I want to note two specific timelines as if we were moving along that x-axis through time, through the life of the person. This first stage is the insulin resistance stage and you'll note that it is defined by elevated insulin but normal glucose. This is where most people fall nowadays. unfortunately, certainly in the U.S. and other countries. And then as this progresses, and not everyone, but many of these people with insulin resistance will progress towards type 2 diabetes, but not all of them.

But this is now where insulin is still higher than normal, but it may start to drop, and now glucose levels will start to accelerate and climb. So insulin is elevated and glucose is elevated. But insulin is the key variable here.

You can see how it starts to climb so much earlier than glucose does. And this is played out in the literature, this interesting report, finding that in people with type 2 diabetes, if you're looking at insulin and not glucose, we can detect changes a decade, and I would submit more than one decade, earlier than the glucose changes. And if we're looking at insulin resistance, then this study is making the case that it's insulin, not glucose. that should be used as the marker of the disease. Now, unfortunately, and I alluded to this a moment ago, when we focus on glucose, begin treating the patient with insulin therapy, and then that will most certainly push up the insulin, but conventional medicine would say, who cares?

We don't care about the insulin. We care about the glucose, and because the glucose is going down, well, then we're doing what we want. The tragedy in this paradigm, one, we not only have a significant increase in body fat, The diabetic who begins insulin therapy can expect to gain up to 10 plus kilos easily of fat.

The risk of heart disease will climb by multiples. The risk of cancer, mortality, actually dying from cancer will go up, one particular study, by about 90% with insulin therapy. So this has meaningful consequences.

So what is a takeaway then as I'm wrapping this up? If we look at insulin levels, I make the cutoff of around six micro units per mil. This is based on evidence, and I have some studies linked here, where healthy people, based on...

people not adhering to a diet that is based on processed foods, they're going to have insulin levels around 4 microunits per mil. And these are people who have extremely low levels, if any, diabetes at all. Importantly, the average American has insulin levels of around 9 microunits per mil. And oddly, that fits within the healthy range of most clinical cutoffs for insulin. I think that is misleading because the average American, of course, based on that study published last year, is metabolically unfit.

So six microunits range that's in the middle of these two cutoffs is going to be one that people should shoot for. The dietary strategy that I believe is best is encompassed in the very name of this low-carb Sydney meeting. Now, so in conclusion, these are the aspects of the insulin resistance syndrome, nowadays referred to as the metabolic syndrome.

Transcript for:Understanding Diabetes and Insulin Resistance

Transcript for:
Understanding Diabetes and Insulin Resistance