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(00:00):
Our first speaker is Dr. Benjamin Bikman. He is a professor in the Department of Cell Biology at Brigham Young University, and he'll start off the day by discussing some of the causes and consequences of type two diabetes, including strategies that can be employed to reverse it. Ben, thank you for joining us.

(00:22):
My pleasure. Thank you so much for the invitation and the introduction. I am going to get my presentation started and I'm delighted to particularly be able to share with you my thoughts on type two diabetes because they're a little unique, but I think it's valuable to have this perspective in mind as we continue to go throughout the day. So I very much appreciate the opportunity that I have to set the stage here. So with regards to type two diabetes, let's view it firstly from the perspective of the conventional definition, which is essentially in some degree of wording a problem of too much glucose. That's going to be the very conventional view. So you can see already that the conventional definition is framing type two diabetes in one particular context, namely a glucose centric paradigm. My definition as a scientist who's devoted his life to understanding the origins of type two diabetes is rather that this is a problem of insulin resistance and there may be an additional problem of the beta cells of the pancreas, and we'll get into all of that of course.

(01:36):
So within my definition of type two diabetes, as we are taking a moment to establish a common understanding, a foundation, there are really two parts to this, then two parts to what we call type two diabetes, namely the insulin resistance and the beta cell failure or temporary failure. We'll get into that. So let's start firstly with insulin resistance itself. Just to help you not feel like I have wasted my life devoting my professional career to understanding insulin resistance. I want just to impress upon you the relevance of the problem, even going beyond the prevalence, which is substantial, being the most common health disorder worldwide, far beyond our national borders indeed, but that insulin resistance is foundational to all of the plagues of prosperity. All of these disorders that are killing us in bankrupting nations around the world, while they all have individual causes that would be unique to them, they all in fact also share a common cause, the noxious stimulus that they all have in common being insulin resistance.

(02:50):
Now, I'm not going to take the time of course to talk about all of these disorders. Let's focus on the matter at hand, namely the diabetes within the realm of diabetes type two diabetes specifically, we really must appreciate that you cannot understand type two diabetes without understanding insulin resistance. Insulin resistance is the trigger, the initiating events. Now, as I mentioned and alluded to a moment ago, the problem with the conventional view of diabetes is that we've taken our eye off of insulin resistance and have a glucose centric paradigm. Now, this is excusable for two different reasons, a historic precedent and the scientific ease. Now, very briefly on each of these, the historic precedent is that the most common manifestation of diabetes classically, historically, was the excessive production of urine. That was the main symptom of the disease. And that symptom is in fact caused by very high glucose levels in the blood.

(03:58):
As glucose levels get so high, they overwhelm the kidney's ability to filter properly. And so a lot of the glucose and a lot of water ends up spilling into the urine, if you will. And so the person's producing a lot of urine. So again, the most common symptom of the disorder was the high urine production, which is again a glucose problem. Scientifically, it's been somewhat excusable to have a glucose centric view because glucose is simply so much easier to measure. We've been able to measure glucose for well over a hundred years, and insulin in contrast is a much more recent and even still much more complicated process now with insulin resistance, then the problem historically being that we look at type two diabetes through only the lens of glucose. You can see that if we acknowledge that type two diabetes is built on a foundation of insulin resistance, then there is another marker that should matter, namely insulin.

(05:01):
And in fact, insulin is the metabolic canary in the coal mine. If we expand our view of type two diabetes to include insulin, then we are able to measure the first signs of type two diabetes potentially decades before the glucose ever changes. Let me just impress upon you how important that is. If the conventional view is merely the glucose is the marker that matters most for type two diabetes, then we are waiting and waiting and waiting for the glucose to climb. But if we rather included had a more inclusive perspective that allowed us to measure insulin, then we would see that over the years before glucose has ever changed, insulin has slowly been getting higher and higher by necessity, as the body's becoming more resistant to insulin's effects, it needs more and more of it in order to control the glucose, but it does control the glucose until we reach a tipping point, which I'll get to in a moment.

(06:03):
So if type two diabetes is built on a foundation of insulin resistance, what is insulin resistance? Let me just take a few minutes to define it because in its definition we do see the beginnings of type two diabetes to define insulin resistance. Let's zoom into the level of a cell. Now, this could be any cell of the body because literally every cell of the body has an insulin receptor. Now, I don't use the word literally too liberally like the kids do These days, every cell of the body has a little doorway, if you will, that is designed for insulin to come and knock on, and insulin as it's flowing through, the blood will come and knock on the door of the cell and then the cell will do something. There will be some action, some response. Now, the most famous response is what happens in some cells, namely that doorways open for glucose to come from the blood and into the cell, thereby lowering blood glucose.

(06:59):
Now, I was very deliberate in how I explain that it's insulin's most famous action, but that does not mean it's insulin's most important action. Insulin does many, many and very important things, even vital critical things throughout the body. Its control of glucose is simply one of many. It's just become the most famous. Now, unfortunately, due to various reasons, the ability of insulin to elicit some action within this cell can become compromised. And a consequence of this would be, and indeed the most famous consequence is that now cells of the body have a hard time pulling in glucose. Some of the cells like say muscle cells, and we'll get to that in more in a moment. And thus, if cells are becoming insulin resistant, it's no surprise that glucose levels start to climb at the same time. And this is very important to understanding insulin resistance.

(07:55):
If this given amount of insulin isn't sufficient to control the glucose anymore, what would you think happens to the amount of insulin? It's no surprise that insulin levels go up. This is a fundamental feature of insulin resistance. So what was once a polite molecule of insulin knocking on the door of the cell becomes an angry mob, all in an effort to try to restore the normal degree of response that the body is expecting. So as we finalize or conclude the definition of insulin resistance, there are two parts to this definition. The first part being that some of the cells of the body are not responding very well to insulin.

(08:40):
That is happening at the cellular level, but there is a different phenomenon occurring at the whole body level, namely that if the body is insulin resistant, insulin levels are higher. So you do not have insulin resistance without hyperinsulinemia. Now let's change the paradigm and look at someone who's progressing through the years getting ever closer to type two diabetes, which is again defined purely by its glucose. Tragically I would add. Now again, the conventional view has no appreciation of insulin, but we do here now. So let's superimpose insulin levels on this same progression. As this average individual is moving ever closer to type two diabetes, long before the glucose has started to spike, you'll see that over the life of this person, their insulin levels have had a very, very different dynamic curve to them. Now, it's important to note that in type two diabetes, true type two diabetes, insulin never goes to zero.

(09:41):
So even my insulin curve here is very deliberately created. You'll see that if you compare where it's ending based on where it's started, it's very often going to be multiples higher than it would've been at its ideal insulin sensitive state. But let's create this arbitrary division that separates two time periods in the diabetes life of the person. This first phase on the left side of the vertical hash line that I inserted here is insulin resistance, namely a state where glucose is normal, but insulin is elevated. So this is the early time. This is the opportunity to detect the problem before it gets too severe. If the problem is not detected or not addressed, then the person progresses, they graduate into type two diabetes, which is now a state of still elevated insulin. Even if the insulin has come down a bit, it's still higher than it was before it ever started.

(10:40):
And now most important to the conventionally trained clinician, glucose is elevated as well. It finally moved. Now, let's further superimpose just to help you appreciate what's happening within the body that is distinguishing these time points. I very much have a fat first focus when it comes to the progression of insulin resistance and type two diabetes, namely that the problem begins in the fat cells of the body. And then when the problem progresses to other tissues, that's when we see the inflection type two of the glucose levels. So bringing us into the conventional definition of type two diabetes in those other tissues that become insulin resistant, that flip this switch are a skeletal muscle, the liver, and then the often overlooked alpha cells of the pancreas. Now, this is another view of what I just shared with you, namely that as the fat cells are insulin resistant, we're not seeing any glucose changes yet, but we do have higher levels of insulin.

(11:51):
So insulin is high, glucose is normal, that is the perfect definition of insulin resistance in its pre-diabetes state. And then once the insulin resistance has progressed to these other tissues, the alpha cells, the liver, and the muscle, now we have the scenario of both high insulin and high glucose type two diabetes. Now, where does it come from to understand where type two diabetes comes from? We must understand where insulin resistance comes from and please appreciate my restraint and not taking much, much longer to go into these because I certainly was inclined to, but I have a time limit and I am determined to meet it. So where does insulin resistance originate from? And then again, in understanding this, we understand the beginnings of type two diabetes. For the sake of time, we will simply review briefly the primary causes of insulin resistance. Now, that is my own term.

(12:50):
I invoke the term primary causes to refer to causes of insulin resistance that have been validated in all three biomedical models, individual cells growing on little Petri dishes in laboratories, in laboratory, rodents like mice and rats where you can perfectly control the environment and all of the genetics. And then in the great variety in the pinnacle of all creation, the human body itself. So the causes that I'm about to share with you have been proven to be independently capable of causing insulin resistance in all three of these models. And these causes are in no particular order, stress, inflammation, and hyperinsulinemia a word that you've already seen and rightly so, you're going to see it more because it's so important. Now, very briefly, let's just review these, and this is where I'm exerting some wonderful degree of restraint. One of my great delights at being a professor is I get to teach a graduate class in endocrinology, which is a topic I love.

(13:54):
These are the two prototypical stress hormones, cortisol and epinephrine. Interestingly, these hormones have almost nothing in common. They are very different in their structure chemically, they're very completely unrelated molecules. They're produced from completely different cells from completely different gland, well sections of a gland that may as well be different glands, and they move through the body in different ways. They signal at various target cells throughout the body in different ways. They have nothing in common except they both want to increase blood glucose and do so very, very well. So they will increase glucose rapidly and in a sustained fashion. This of course, puts them at odd with another hormone, namely insulin. If cortisol and epinephrines, one of their main jobs is to increase glucose. Insulin's most famous job is to reduce the glucose. So it's no surprise that if stress hormones are turned on, if you will, and they stay on, it makes it harder and harder for insulin to do its job.

(14:59):
We need more and more insulin and we have fallen into the pattern of insulin resistance. This happens anytime these hormones are up for a sustained period. Now with inflammation, this is a topic that I have held quite dear. It was the focus of my fellowship many years ago, and we've continued to pursue it even to this day. To understand the effective inflammation on insulin resistance, we need to appreciate the cytokines, the cytokines. That's a term for a family of little proteins that mediate inflammatory reactions throughout the body. Anytime the cytokines are going up, which is a sign of increased inflammation, they are making the body less insulin sensitive, so more insulin resistant. Now, these cytokines can have a variety of origins. It not only happens with illness and infection, which it does, someone will find that they have a harder time controlling their glucose levels if they are sick.

(16:01):
But it also happens with more chronic conditions like autoimmune diseases. If there are studies documenting as an autoimmune disease will ebb and flow, so too will the insulin resistance. You can quantify and even track the insulin resistance changing with the disease, air pollution, particles that can be inhaled and activate. These cytokines also contribute to insulin resistance. And then lastly, the one that I believe to be the most relevant in chronic insulin resistance and then eventual type two diabetes is fat cells that get too big, which is itself a fascinating topic. Alright, now let's leave. The most important for last being the hyperinsulinemia. This is the one that at first glance is a little confusing, but it's worth taking a moment to work through the confusion because it is the most important. Too much insulin causes insulin resistance. Now, this is fundamental reflective of a fundamental biological principle, namely that if there's ever too much of something within the organism, within the body, the body's going to want to become resistant to that something. You see this reflected across biology, whether it is various substances, it is various drugs, various hormones. If there's too much of the signal, the body will try to maintain its function by becoming a little deaf to the signal. It doesn't want to continue to listen, lest it start to be harmed.

(17:36):
Alright, so how does this then shift? So we've talked about the origins of insulin resistance, which of course is at the origins of diabetes. But then how does this transition, how do we flip the switch? What tips the scales from just insulin resistance, pre-diabetes into diabetes? In other words, what has to happen for the glucose levels to start climbing? And this is when the insulin resistance has progressed to these other tissues. So let's go through what happens with these other tissues. Now, muscle is incredibly important when it comes to glucose metabolism and insulin function. And this is because muscle eats the most glucose. If you eat a load of starch or sugar and you look at what would happen to your glucose levels, they climb up and then they drop back down. 80% of the drop back down is what's being consumed by the muscle.

(18:33):
And that's in part because muscle is such a big part of our mass. Most of what makes us us is our muscle, but it also has a relatively high metabolic demand, very dynamic metabolic demand. So not only is there so much muscle, but the muscle is very hungry. So it's no surprise that it will pull in glucose very readily. Now, one quirk of the muscle is that when it's not working out, it needs insulin. So at rest, the muscle will not eat the glucose, it will not pull in the glucose unless insulin is there to open up the glucose doors. So you can begin to see the problem. If the muscle becomes insulin resistant, now those doors don't open. Now the glucose can't go into the muscle, and thus the glucose is remaining in the bloodstream contributing to ever higher levels of glucose. So if we take this earlier paradigm where the person was at the precipice of moving in towards having a glucose problem, we've nudged them in a fair degree when the muscles have become insulin resistant.

(19:38):
Now at any other time, before or after we may begin to have a problem at the liver. The liver is metabolically muscles opposite, whereas muscle is an exceptionally selfish organ metabolically. In other words, if it takes in a nutrient, it will never give it back and it will only use it for itself. The liver is an exception to this. The liver is the metabolic soccer mom that if there is another demand for nutrients anywhere else in the body, the liver is ready to help it by producing any number of other nutrients or calorie sources. Now, two that are very relevant is what the liver can do with fat and what the liver can do with glucose. So we have these two processes that can be happening among many, many others within the liver. Lipogenesis, which is the production of fat, the liver is very capable of taking any carbons and turning it into fat, but also the liver wants to store glucose for later use.

(20:38):
So we have another ability of the liver called glycogenesis, so it takes in carbons and it will store it as a stored form of glucose for later use. Now insulin is the ultimate signal telling the liver to store energy that's somewhat thematic of insulin's effects throughout the body. Insulin wants the body to store energy. So it's no surprise that insulin will tell the liver to increase lipogenesis to store fat and to increase glycogenesis. But this is just as a brief tangent, one of the reasons why triglycerides are such a good marker of insulin resistance because of the lipogenesis effect, the making of fats. Now as the liver becomes insulin resistant, we have an interesting dichotomy because the insulin's ability to influence lipogenesis is unaffected. That continues to happen. That signal isn't disrupted, it's not broken, if you will. However, insulin's ability to regulate glycogen and glucose is disrupted rather now than activating glycogenesis, which was a way for the liver to store glucose, thereby helping lower blood glucose, the signal having been lost.

(21:52):
Now we have a liver that even though insulin is trying to tell it to take in glucose and store it as glycogen, the liver's not listening anymore. And now it's breaking down the glycogen resulting in the glycogen spilling out as glucose into the bloodstream, increasing glucose levels, resulting again in pushing the patient to higher and higher glucose levels, making them more and more diabetic. Now, I leave the most complicated one for last, and hopefully my cartoony method of lecturing helps really bring the principle home. Within the pancreas, we have various little neighborhoods of cells where you have beta cells producing insulin tucked right next to alpha cells producing glucagon, and they are neighbors that don't get along because whereas insulin's most famous action is to reduce blood glucose, glucagon's most famous action is to increase blood glucose. And again, they're right next to each other and they're right next to each other by design.

(22:55):
Because we cannot have these two signals both operating at the same time, it won't work. One must be dominant and insulin will win that battle in a head to head fight. So if insulin is being released from the beta cells, it will go to its neighbors, the alpha cells and tell the alpha cell make less glucagon, which will help lower glucose helping insulin achieve its goal of reducing glucose levels. However, as can happen with muscle cells, as can happen with liver cells, the alpha cells of the pancreas become insulin resistant. So now even though insulin is trying to lower glucose and trying to tell the alpha cells to reduce glucagon production to help it lower glucose levels even more, the alpha cells are no longer contributing. They're no longer getting along with the beta cells and in the insulin signal. And so now we end up having a scenario of high glucagon as well, and glucagon starts pushing up the liver's release of glucose and thus glucose levels go ever higher in the blood.

(24:04):
And so now we take the individual and we really have kicked them all the way into full-blown type two diabetes. Now, I appreciate that. Up until this point, I've only been talking about insulin resistance. So in my remaining few minutes, let's briefly look at what happens with the beta cells. Now, this was the paradigm I'd shown you earlier with insulin resistance being a state of high insulin, but low glucose and then you see the drop, the tendency or the potential rather for insulin production to drop over time. And this is a problem of the beta cells. What's interesting about the beta cells as happens with so many cells of the body, and this is a direct quote from the paper that I'm citing up in the corner, any of the PMID numbers you've seen are the citations that I'm citing as I create these figures.

(24:54):
So we see that islet cell mass, which is where the beta cells are living, it's dynamic and capable of adapting to various situations. So within the pancreas, if we look at this insulin curve over time, we could take the person's pancreas and look at how many beta cells they had, and they would have say this many beta cells in their normal healthy insulin sensitive pre-diabetic state. But then as they were progressing into insulin resistance, you see that the number of beta cells starts to climb substantially. And this is reflective of insulin resistance and hyperinsulinemia. The body says, I need more insulin. And the beta cells begin to reproduce in order to meet that demand. However, in the pancreas or in the beta cells, the pancreas rather of some people with insulin resistance, although this is not universal, the number of beta cells can go down.

(25:51):
Now it doesn't go to zero, but it can go down. And the reduction in beta cell number results in reduced insulin. And of course that accelerates the glucose spiking even more. But why do beta cells die? Well, interestingly, these three same primary causes of insulin resistance also contribute to the synthesis of a highly reactive fgo lipid named after the enigmatic sphinx, because for so many decades we didn't know what it did, but a molecule called ceramides in Ceramides classic function was to induce a process called apoptosis or the programmed death of cells. Now, that does not make ceramides a villain. This is something that must happen. Cells need to live and die and be replaced, but these signals are known to increase ceramides within beta cells, which then kill beta cells. Now my final thoughts here, can this be reversed? Yes, very readily that we can see that even beta cell mass within people with type two diabetes can be restored very rapidly.

(27:01):
The key is remove the death signal. If you can remove the ceramides from being produced and accumulating within the beta cells, you give a break to the beta cells and they are able to recover as needed. You have not only an increased function, but even an increased mass, ultimately leading to, as Nina teed this up, this what we would call a reversal of type two diabetes. So in the time we've had together, we've covered generally three big questions that you should be capable of now going and talking about on your own. Namely, what is type two diabetes? We covered the origins of insulin resistance being so important to maintaining glucose levels as well as the potential for beta cells to begin to suffer. How does it become type two diabetes, which is that the tissues of the muscle and the liver and the alpha cells become insulin resistant? And then finally, can it be reversed? That's going to be the topic for upcoming talks, but the answer is a resounding yes. Otherwise, we simply would not be having this meeting now. Now in conclusion, I really do hope you found some of this valuable and I very much look forward to addressing any questions you may have during the question and answer panel coming up shortly. Thank you so much.

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