Let’s move straight into the first part of the presentation today. Natural History of Type 2 Diabetes—What Happened to the Islets? I’m just going to try and put an overview to this, and then the other speakers will go into deeper details about this.

The way I tried to structure my presentation—is we’re going to talk epidemiology, normal glucose regulation. And here you see beta cell. And this is going to go back and forth from beta cell to the islet, because it’s a little bit deeper. It’s not just the beta cell within the islets, but all the other cells also that are involved. Hepatic glucose output. And whatever happens to the beta cell. And again, even though I’m saying beta cell over here, you’ll see as the talk progresses, we are really talking about the entire islet, not just the beta cell. And then the treatment. What are the goals of treatment of type 2 diabetes? Is it prevention of failure of the islet or prevention of death due to cardiovascular disease or a combination of the two?

So, epidemiologically, what do we have here? Well, we have metabolic syndrome on wheels. And most importantly, look at this. There’s a baby down there, right in the middle. Baby doesn’t need a helmet, obviously, because it’s protected by all that adiposity.

But this is what’s really causing the problem for us, not only in the United States but all over the world. Why does this occur? Well, why do certain people get more of metabolic syndrome than others? Well, let’s walk ourselves. Let’s take us back maybe to 1000 ad. And let’s look at this gentleman here. Hunters and gatherers. There wasn’t so much food available. And why are Native Americans getting so much diabetes? Why do I get so much diabetes, or at least Indians and African-Americans?

Well, so this person survived during periods of famine because he carried certain genes that allowed for different thermal regulation in him. In that setting, he was allowed to conserve whatever he ate, or his genes helped him conserve whatever he ate as fat. And so, he survived. So, people now are descendents of this person.

Now, you take this person and put him in an environment of plenty. Here he is with his nachos and Diet Coke. No, it’s not Diet Coke, really, it’s regular Coke, right? This leads to obesity and insulin resistance, and, therefore, diabetes. This was called “The Thrifty Genotype Hypothesis.” We really don’t know what the genes are, but there’s a whole series of genes. So, that’s what’s causing his diabetes.

Well, this is me. Believe it or believe it not. This is me, 1991, when I first left India and came to Dublin, Ireland. This was up on Howth Head; beautiful place. Where was I? 130 pounds; 6 feet, 130, maybe 140 pounds, 150 pounds? This was 2000. I didn’t have the same shirt, because it wouldn’t fit me any more. Same pants wouldn’t fit me any more. And I was 20 pounds heavier. And this is me today, another 10 years later. So, you can see, I’m getting really Americanized here.

Let’s move on. So, adipose tissue. In these 15 years or whatever I’ve been out of India, adipose tissue has changed, really. Adipose tissue is considered to be just a static fat storage or fat depot. Fatty acids were coming in; glucose was coming in. And the fatty acids were going out and glycerol was being produced.

Now, however, we know that the adipose tissue is an active, breathing, endocrine organ. It’s producing all these adipokines that have differential effects. And we don’t really have the time to delve deep into this. In the discussion session, we might be able to talk about this. But the adipose tissue is the largest endocrine organ in the body. And that pun is a deliberate one here.

So, what happens with increased adiposity? With increased adiposity, it really is creating a proinflammatory milieu. That’s producing substances called adipokines: MCP1, IL6, TNF-α. You hear about all of these things. These are adipokines. The greater the number of adipokines, the greater the insulin resistance, and the greater is the endothelial dysfunction, and therefore, the predisposition to getting atherosclerosis.

In addition, when this adipose tissue is increasing in size and number, there’s a decrease in another substance called adiponectin. And that also perpetuates this insulin resistance, as well as the endothelial dysfunction. So, adiposity is not good for us. That’s the moral of the story, right?

Well, how bad is it for us? If you look at weight, this is in over 1 million men and women. If you follow the weight, at about a BMI of about 26 in men and 25, and maybe 25.6 in women, you could start seeing that the risk of cardiovascular disease starts to take off. And if you reach over here, then you can see how the risk is way up there. You can see also that if you’re very thin, there’s an increased, or at least slightly increasing risk. But there’s a clear correlation between obesity and increase in cardiovascular risk.

Well, not only that. If you look at the effects of obesity, aging, smoking, drinking on chronic medical conditions and health-related quality of life, so, the color bars that will come up is obese here, 20 years of aging. Current smokers, if you’re overweight, previous drinking, and past smoking. And let’s see what happens with these different conditions. An increase in number of chronic conditions and decline in health-related quality of life.

Now, what this slide is telling us is that being obese is like you’ve aged 20 years. You have that many increases in your chronic conditions, as well as decline in your quality of life as somebody who is 20 years older.

Now, let’s look at the same thing, but at services and medications used. Here are services utilized and medications used. This is obesity; this is obesity. This is 20 years of aging. Again, obesity is like 20 years of aging. And compare that to others.

Every time I show this data, somebody in the audience always says, hey, this means I should start smoking., because that’s what this is showing, that smoking is a little bit better than if you’re obese. But, really, you know, smoking has its own problems.

If you look at different diseases with this, well, here’s diabetes and here are the others: hypertension, asthma, angina, and, of course, lung disease. So, obesity clearly is a disease state. And there was recently a survey done amongst physicians, and they were asked, do you tell your patients that they are obese or that they are fat? What do you think the physicians said? No, they don’t.

So, then they asked pediatricians, would you tell kids that they are fat? Pediatricians said, no. Well, it’s exactly the opposite what should be done. If you don’t tell people that they are fat, they don’t know that they have a problem. Now, what are we protecting them from? So, the survey really showed that you have to do it. You have to tell; you have to confront the patients with this obvious fact that they are obese.

Now, does obesity relate to diabetes? Of course, it does. Well, here’s BMI, men and women, and you can see as the BMI goes up, the risk of diabetes goes up. So, what’s causing type 2 diabetes? Is it obesity, or is it something else?

Well, we know obesity does cause problems. So, what are we trying to treat in type 2 diabetes? That becomes the question. Are we going to just treat the glucose?

So, we start here. We start at the time point you have diabetes. And you say, I’m going to treat the glucose. Action/reaction; action/reaction. Or, you say, this is diabetes. What caused the diabetes? And the analogy I use is, you know, we’re treating the pain of diabetes, not the cause of the pain. So, we have to start thinking upstream and say, what is the cause of the problem? So, let’s try and see how that can be accomplished.

Well, before we go there, what’s happening with obesity? You know, with obesity comes metabolic syndrome. And here is metabolic syndrome: white, black, Hispanics, others. About 25, 30 percent of the patient population in the United States. This is based on 2000 data. So, if you come to 2007, these numbers are about 1 in 3 Americans. One in 3 people in this room have metabolic syndrome. And a diabetes diagnosis. Well, you start with metabolic syndrome over here.

So, metabolic syndrome. This was what it was supposed to be then, 64 million. So, obviously, much more than that now. And diabetes. Every 21 seconds, somebody is being diagnosed with diabetes; 21 seconds.

So, why does a beta cell, therefore, fail in obese people? Not every obese person gets diabetes, right? So, why does a beta cell fail?

Well, let’s, before we go to why does a beta cell fail, let’s start talking about normal glucose regulation. So, how do we regulate glucose in a normal state? Let’s try and see if we can pull it up from this video here, okay? What the video is really going to do is, it’s going to walk us through the disease state, and then I’m going to try and dissect that out a little bit as we go along.

 

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Click below to watch Windows Media Video:

  Normal and Abnormal Glucose Homeostasis.wmv   

Normal glucose homeostasis is a complex process involving nutrient, neural, and hormonal factors. The feedback relationships between insulin, glucagon, and circulating glucose represent a critical homeostatic mechanism. In healthy individuals, in response to shifting dietary intake and changing metabolic demands, the body adjusts glucose production by the liver and uptake by muscle and other tissues.

Insulin and glucagon are key mediators of these adjustments. Insulin promotes tissue uptake of glucose and helps suppress hepatic glucose production. Glucagon stimulates hepatic glucose production. Both hormones originate in the pancreatic islets: insulin from beta cells and glucagon from alpha cells.

The coordinated functioning of these cells is an essential component of a normal glycemic control. Beta and alpha cells modulate their hormone output in response to changing blood glucose concentrations.

In nondiabetic individuals, after a meal insulin levels rise and glucagon levels fall, enhancing tissue glucose uptake and suppressing hepatic glucose production. In the fasting state, glucagon rises to mobilize stored glucose from the liver.

In patients with type 2 diabetes, there is a breakdown in mechanisms that regulate glucose homeostasis. Two key pathophysiologic factors contribute to the development of type 2 diabetes: insulin resistance and beta cell dysfunction have been shown to be core defects in the disease. A secondary abnormality, excess hepatic glucose production, contributes to hyperglycemia.

Muscle, fat, and other tissues become less responsive to insulin. Beta cells produce less insulin than necessary for optimal glucose control. And the secretory patterns are abnormal. Beta cell dysfunction becomes progressively worse over time. By the time type 2 diabetes is diagnosed, at least 50 percent of their function has been lost.

In type 2 diabetes, the liver produces more glucose than the body needs relative to the levels of glucose in the blood. All 3 defects contribute to hyperglycemia, the hallmark abnormality of diabetes.

 

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So, let’s try and break this down now. So, there’s excess glucose production from the liver and beta cells failing. And why is there excess glucose production from the liver? So, let’s go and see how we, therefore, regulate glucose in the body. The regulation of glucose really depends upon the rate of appearance balanced by the rate of disappearance. So, depending on how much glucose is coming in and how it’s being metabolized or used up is going to tell us if the glucose is going to remain normal.

So, glucose coming in; of course, meal-derived glucose. So, if you’re eating too much carbohydrate, you cut down on the carbohydrates or you take a drug, such as Precose, that reduces the preload, so to speak. Hepatic glucose production. And we’ll break that down a little bit more into gluconeogenesis and glycogenolysis. And that has to be balanced by how you’re excreting the glucose.

If you want to put numbers to this, so, somewhere between 50 to 100 grams of carbohydrates from your diet, but 0.2 grams per minute from the liver. And then you’re peeing out or metabolizing 1.5 grams per minute. Now, in the future, you will start seeing drugs which are under phase III trials at the moment, which decrease this urinary excretion, or rather, increase the urinary excretion of glucose by changing the tubular max. So, you’re going to start peeing out more glucose.

Now, those drugs clearly will not be available or would not be appropriate for elderly patients, because patients would get polyuric. But that’s one other way to take care of the glucose if you’re really just looking at glucose regulation. If you want to start looking upstream, then that’s where we’re going to try and go today. You need to do other things, too.

So, what’s gluconeogenesis? Gluconeogenesis is production of glucose from nonglucose sources. So, when you have insulin resistance, the liver starts kicking out a lot of glucose. Patients go to sleep in the night; they haven’t eaten anything. They’re waking up in the morning; their glucose is high. That’s hepatic gluconeogenesis. Drugs, such as metformin, work beautifully. Therefore, we say, you know, we’re going to give your metformin in the nighttime. That’s why we start the metformin in the evening.

Well, how does this happen? How does this gluconeogenesis come about? Well, the pathway is related to free fatty acids. So, you have adipose tissue insulin resistance on the top. This leads to lipolysis, this leads to mobilization of free fatty acids. These free fatty acids cause a couple of problems. When they go to the muscles, they get oxidized. These oxidization products affect the ability of insulin to work very well. Therefore, it reduces glucose utilization, and you get hyperglycemia.

And they go to the liver. They facilitate through amino acids and through other pathways of production of more glucose. It’s gluconeogenesis. It’s the same free fatty acids, when they go to the liver, also get packaged into VLDL particles, very-low-density lipoprotein cholesterol. That, we know, carries triglycerides. So, what do we see in patients with metabolic syndrome? High triglycerides.

Now, VLDL is very-low-density lipoprotein cholesterol. It says, get me cholesterol. Where’s it going to get its cholesterol from? HDL says, hey, I’ve got lots of cholesterol; I’ll give you some cholesterol. HDL takes this cholesterol, puts it into VLDL, and consequently, what do we see in patients with type 2 diabetes or metabolic syndrome? Low HDL levels.

And that’s where Pfizer was developing a drug to block that conversion or block that transfer. And the drug was raising HDL but it was killing people. Now, that’s usually bad for business, right? Bad for their business, bad for our business. The drug didn’t come to market. But the point is, not all raised HDL is also good for us. So, we don’t know. That’s what’s trying to be dissected out now. What happened over there. But that’s how the whole free fatty acid pathway works.

Now, what about glycogenolysis?

This is the other hormone from the islets that was talked about, glucagon. Somebody has an insulin reaction. They’re losing consciousness. What do we give them? Glucagon. If they don’t have an IV line, we just inject it. Right? That causes glycogenolysis, breakdown of the stored form of glucose. That’s glycogenolysis. It turns out, glucagon levels are elevated in patients with type 2 diabetes. So, they’re producing a lot of glucose from the liver.

So, if you want to summarize normal physiology. In the fasting state, what’s happening? That’s the pancreas over there; your blood glucose is beginning to drop in the fasting state. Pancreas says, I’m going to make more glucagon. Pancreas is going to say, I’m going to shut down insulin production. So, hepatic glucose output is going to increase, and that’s going to increase your blood glucose.

In the fed state, what’s going to happen? Well, fed-state blood glucose goes up from the meal, goes to the pancreas. Pancreas says, hey, I need to break this glucose down, but I don’t need to produce glucagon. So, it shuts down glucagon, increases insulin, and as long as you don’t have insulin resistance, the glucose gets metabolized, and this whole cycle repeats itself. So, this is normal glucose homeostasis.

What about the beta cell? Well, before we go to the beta cell, let’s try and understand what happens within the islets.

 

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Click below to watch Windows Media Video:

  Normal Pancreatic Islet.wmv   

An understanding of the normal physiology of the pancreas is important for any discussion of type 2 diabetes. The pancreas is an organ that has both exocrine and endocrine functions. The endocrine tissue makes up only 1 to 5 percent of the total pancreatic mass in adults. It is randomly distributed throughout the exocrine pancreas, with a greater concentration in the head of the pancreas.

The endocrine cells are arranged into units called islets of Langerhans. Each islet of Langerhans contains several types of cells, namely alpha, beta, gamma, and delta cells. Beta cells predominate and tend to be located in the center of the islet. Beta cells make up approximately 70 to 80 percent of the islet mass. Gamma and delta cells constitute less than 10 percent of the islets.

The alpha and beta cells both play important roles in glucose homeostasis. Beta cells produce insulin and amylin, and alpha cells produce glucagon. Both insulin and glucagon are essential for glucose homeostasis. When blood glucose is elevated after meals, beta cells release insulin into the bloodstream. Alternatively, when blood glucose levels fall, alpha cells release glucagon. These responses help maintain a normal glycemic state.

 

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All right. So, it’s not just the beta cell. It’s the dysfunction between the alpha and the beta cells that’s really responsible. And we’ll try to dissect that further as we go along. So, how does this beta cell actually produce insulin? A beta cell produces insulin in two spikes. The first spike is called the first phase of insulin production. This can last up to 30 minutes.

This slide is showing about 10 to 15 minutes. So, every time you eat, there’s a production of insulin to take care of that meal. That’s the first phase of insulin production. This is followed by the second phase of insulin production.

So, let’s look at incretins now, because the first phase of insulin production is correlated with incretins. Now, what are incretins, because there’s going to be further discussion today about GLP-1 and other hormones, incretin hormones. So, let’s look at the role of incretins, how they impact first phase.

So, incretins are intestinal hormones released after meal ingestion. So, this spike that you saw -- the first phase of insulin production—what is causing this spike to occur? Well, intestinal hormones are secreted every time you eat. And they help to physiologically regulate insulin release. But, this is a key phrase: in a glucose-dependent manner. So, the higher the glucose, the more is the production of insulin at first phase of insulin release.

So, this is how this would occur. This is the gut, this is the meal. It’s going to stimulate the intestines, as well as other nerves, as well as send nutrient signals. We saw the nutrient signals earlier. Neural signals are beyond the scope of today’s discussion. But let’s look at the top part of this, the hormonal signals. Through these incretins, which are GLP-1 and GIP, it tells the pancreatic alpha cells, cut down glucagon production. It tells the pancreatic beta cells, increase insulin production. And that’s how you start regulating your glucose.

So, that spike that you saw can be related to the incretins. So, this is how the incretin effect works. If you take nondiabetic individuals, and you give them an intravenous load of glucose: okay, this is the nondiabetic individual, this is the intravenous load of glucose. This is the amount of insulin that they’ll produce. If you take the same individual and an equivalent amount of glucose is given orally, this is the amount of insulin they’ll produce. This is called the incretin effect.

Now, let’s delve deeper into that beta cell. How does this beta cell then make this insulin? Well, the stimulus for the beta cell to make insulin is glucose. So, here’s glucose coming in. This is the wall of the beta cell. There is glucose coming in. Through certain enzymes called GLUTs, or glucose transporters, glucose is pulled into the pancreatic beta cell.

Now, glucose is the primary source of energy in the body. Being the primary source of energy in the body through our famous TCS cycle—remember the Krebs cycle that we learned about; it’s back to haunt us, right?—TCS cycle, glucose is converted to energy. And what’s the primary energy molecule in the body? ATP. So, higher the glucose, the greater is the production of ATP.

All this energy is being collected within the cell. The energy says, I need to do something. It says, okay, I’m going to do something. I’m going to open these things called ATP-sensitive potassium channels right up here. Higher the glucose, higher the ATP production, greater the opening of the ATP-sensitive potassium channel.

Potassium, which is a positive ion, leaves the cell. If you remember physiology, what happens? It creates an action potential. This action potential then results in calcium getting into the cell by opening calcium channels. Triggers the release of insulin. That’s how insulin is secreted.

Now, these incretins, how do they augment this? You saw how incretins augment insulin production. So, these incretins, GLP-1 and GIP, bind to their own receptors on the walls of the pancreatic beta cell. This results in the formation of cyclic AMP. And through the cyclic AMP, there is amplification of this triggering release. So, if the glucose is normal, you can have any amount of GLP-1 and GIP. It’s not going to do much until you eat. And then the glucose comes in. This side of the pathway is set into motion, and then the amplification occurs.

This is the reason, if you use drugs, such as Byetta, which binds to this receptor, or Januvia, which raises both of these, on their own, they’re unlikely to cause hypoglycemia. They’ll only cause it in some production when somebody eats. But if a person is on a sulfonylurea, that sulfonylurea is going to bind over here. It does not matter what your glucose is. It’s going to open this channel, going to trigger the insulin release.

So, that’s why they say, if you’re on Byetta, or you’re on a sulfonylurea and add Byetta, you should reduce the dose of the sulfonylurea, because the hypoglycemia will come from the sulfonylurea. Same thing with Januvia. If you’re on a sulfonylurea, you might need to back off on the dose of the sulfonylurea.

So, normal glucose homeostasis, to summarize, depends on food intake. You can reduce the food intake or give drugs that do block that. Correct the insulin deficiency by giving sulfonylureas, or Byetta, or Januvia, as we saw how that would work. Insulin resistance, you can use a TZD. You can reduce gluconeogenesis that way, too. Gluconeogenesis, we talked about that: metformin. Glycogenolysis, Byetta, Januvia. Both those hormones help to reduce, or both those drugs help to reduce, the excessive glucagon action.

So, let’s try and go, therefore, a little bit deeper now into pathophysiology of type 2 diabetes. We talked about normal physiology.

Here is type 2 diabetes, occurs through genes that cause impairment of insulin secretion, genes that cause insulin resistance. That added onto environmental problems leads to impaired glucose tolerance and diabetes.

So, let’s look at the role of insulin resistance first.

Here’s insulin resistance. This is a nondiabetic individual. All the white that you see on this CAT scan is fat. This is a person with type 2 diabetes. You can see how much fat there is. And that’s where we started moving away from BMI to waist circumference as a way to figure out how much adiposity the person has.

What does this do, this adiposity? Well, let’s look at this from the perspective of insulin sensitivity. This is a normal insulin sensitivity curve. If you are on that side of the curve, you are sensitive to the actions of insulin. If you are on this side of the curve, you are resistant to the actions of insulin. So, what’s happening in people with type 2 diabetes or who have a predisposition to getting type 2 diabetes? They’re climbing up this curve. And why are they climbing up this curve?

Skeletal muscle, fat, and certain other tissues need to interact with insulin to absorb glucose from the blood. In these tissues, insulin binds to cell surface receptors, triggering a cascade of intracellular signals, resulting in the translocation of glucose transporter molecules to the cell surface, and the entry of glucose.

In insulin-resistant tissues, insulin may bind normally to its receptors, but subsequent signaling is disrupted, resulting in insufficient translocation of glucose transport molecules, and extracellular glucose accumulation. In response to insulin resistance, pancreatic beta cells are called upon to secrete additional insulin. This is why insulin-resistant patients are typically hyperinsulinemic.

So, you can see, it’s like…the analogy I use for this is like a truck going up a hill. You’re making this much, this much, this much insulin to keep your blood sugars here in the fasting state. So, what’s going to happen when this truck needs to overtake? That’s why it has a climbing lane. It has no power to overtake. So, the first abnormality you would see in somebody who is predisposed to getting diabetes is a rise in postprandial glucose. But we wait for fasting glucose to go up.

So, this truck keeps going up in first gear, day in, day out, day in, day out. What’s going to happen to the engine? It’s going to wear out. So, the ability to sustain this much insulin production goes down, down, down. It reaches a threshold, different for different people. This much is not enough, fasting glucose goes up. The disease has been there for a long time, even though the fasting glucose is normal.

So, for me, a fasting glucose is an irrelevant entity. But we have to decide to treat people. So, that’s what we’re going to try and discuss today. How can you prevent this beta cell from failing?

All right, so what, therefore, happens to this beta cell in type 2 diabetes? Well, let’s talk about the role of insulin deficiency.

Well, let’s say that we saw that first phase insulin release slide before, right? Look on this side. If you break that down, and you give somebody who doesn’t have diabetes an intravenous load of glucose, right over here, time point zero, they have a nice spike of insulin production. If you take people with type 2 diabetes and do the same experiment, you give them intravenous glucose, they do not make any insulin. So, why are they not making enough insulin?

One possibility we talked about was incretin deficiencies. Second possibility is this truck going up the hill. It’s just insulin resistance. It has no more power to make any insulin. How much contributes from each of these two? We don’t know. But both of them need to be addressed if you want to address postprandial glucose. And postprandial glucose is the first abnormality to go up in terms of patients with developing diabetes.

Similarly, when you’re trying to bring somebody’s glucose to target, it’s the last one that we treat. But we have to address postprandial glucose. So, in an A1C of 7.2 percent, if you want to get them to 6.5 percent, most of the abnormality is coming from postprandial glucose.

So, really what is happening over time is, this was the curve. People are falling off of that curve. Where they fall off, we don’t know. It’s not like they’ve gone to zero. Relatively, they’ve become deficient. And this is what I was trying to say earlier about incretin deficiency. So, part of this first phase of insulin release might be related to deficiencies of incretins.

This is a study looking at GLP-1 levels in response to meal, and impaired glucose tolerance in green and normal glucose tolerance here, and type 2 diabetes here. So, you can see, type 2 diabetes and impaired glucose tolerance don’t make as much GLP-1 in response to a meal. So, that incretin effect is diminished, right?

And that’s seen over here. We saw this earlier study over here. On the left-hand side was nondiabetic individuals. This side is diabetic individuals. This was the incretin effect in nondiabetic individuals. And this is the incretin effect in people with type 2 diabetes. So, you can see that the incretin effect is diminished.

So, is this all that is contributing to the loss of first phase? Probably not. Part of it is related to that insulin resistance, too. So, you’ve got to address both those abnormalities.

What about the second phase, therefore, of insulin secretion?

Well, look on the top here. This is glucose in millimoles on the top, and then this is plasma insulin. This was normal glucose tolerance, nice first phase of insulin release. Second phase is there. Glucoses go up a little bit. If you want to convert this to milligrams per deciliter, multiply by 18.

Impaired glucose tolerance, first phase is gone. Second phase is a little bit high, but it’s delayed. And we’ll talk about this in subsequent slides, how that happens.

And this is type 2 diabetes. First phase is lower than impaired glucose tolerance. And second phase is also lower than in impaired glucose tolerance. Therefore, the glucose remains elevated. But this insulin level is much higher than what you see in nondiabetic individuals. But see how there’s a mismatch in the production of insulin. It’s occurring much later on.

So, let’s look at this from the perspective of little graphics, the second phase of insulin release. This is normal insulin response. This is a standard carbohydrate load given. This is a large carbohydrate load given. You make more insulin.

Let’s look at insulin response and insulin-resistant subjects. So, we saw the previous one. Standard carbohydrate load; large carbohydrate load. And now, overweight individuals with a standard carbohydrate load. This is how they compensate. They don’t have diabetes yet, right? But they make a lot more insulin. They need a lot more insulin.

Normal prandial glucose excretion. How would that occur? This is how you would see the glucose going up normally. In impaired glucose tolerance, this is how the glucose would go up. And why is that? When we look at insulin responses, these are the three graphics that you saw before: standard carbohydrate, high carbohydrate, overweight individuals.

And let’s see what happens to insulin production in impaired glucose tolerance. And this has deliberately been slowed down, because that’s exactly what happens. It’s a slower release of insulin because the processing of insulin is not very good. And it comes out later on.

By now, the food has been absorbed, because gastric absorption of food is very quick. So, what do we see in patients early on before they get diabetes? They have high-carbohydrate meals, and they present with headaches and insomnolence and dizziness in the postmeal period. You can see how that occurs, because there’s a mismatch.

And this has been taken from following 17 patients with—or 17 Pima Indians who developed type 2 diabetes over time. And you can see. And they went from normal glucose tolerance but with insulin resistance how much insulin they had. Drops, drops.

If you want to put this relationship in a curve, you can have 2 sets of patients: nonprogressers, obese people who just keep compensating. They just keep making more and more and more insulin. And then you have those in whom the beta cells start to fail. And you go from normal glucose to impaired glucose tolerance to type 2 diabetes. They start falling off that curve. But they’re still making a hell –of –a lot of insulin.

If you put that in graphic terms, this is with real data. This is the fifth percentile of that curve that we saw. This is where relatives of patients who have type 2 diabetes would land on. Polycystic ovarian disease women; impaired glucose tolerance, they’re falling off of that curve; far more gestational diabetics, falling off of that curve; type 2 diabetes. All the way down there.

But see what happens in older subjects. We just bunch everybody in the same category of type 2 diabetes. Well, elderly people might not be that insulin resistant. They’re not over there. They’re here, but they’re just falling off of the curve.

The beta cells are just not working very well. So, do they really have type 2 diabetes? Or do they have some other type of diabetes just related to age and dying of the beta cells?

If you take patients with type 2 diabetes and just treat them with diet alone, this was done in Belfast, Northern Ireland. They started about 40 to 50 percent of their insulin production, and they go down over time, because nothing happened about insulin resistance. So, you didn’t change the obesity level. So, 6 years of diet alone, the beta cell just fails. So, diet alone doesn’t work once diabetes has been diagnosed. Diet alone can work before diabetes is diagnosed, when you have more beta cells. Then, diet alone might work. But once diabetes has been diagnosed, it seems like diet alone doesn’t work. It doesn’t mean we don’t do diet. But diet alone doesn’t work.

So, let’s say, let’s—we’re going to intervene. We’re going to intervene with sulfonylureas or metformin. This was the UKPDS. Most of you have probably heard about the UKPDS by now. Long-term study, newly diagnosed type 2 diabetes, put on sulfonylureas and metformin was the conventional treatment. See what happens.

Well, this is what has famously been called a “Nike swoosh.” A1C comes down with intervention, and then starts going back up, because the beta cell continues to fail. And this is shown over here in the next graphic. Again, like the Belfast diet study, this is where patients treated with insulin, sulfonylurea started, about 50 percent of their insulin production at the time of their diagnosis. This is at the time of diagnosis, time zero.

If you extrapolate this before, it’s about 10 years before the occurrence of diabetes that they had enough insulin. Then they became impaired glucose tolerant, postprandial glycemia, type 2 diabetes, and then insulin-requiring diabetes later on.

So, this is the normal pancreatic beta cell. This is what it starts looking like over time. Or, we should call a normal pancreatic islet. This is what it starts looking like. And let’s see what is happening inside this.

 

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Click below to watch Windows Media Video:

  Beta-cell Dysfunction.wmv   

As type 2 diabetes develops, dysfunctional beta cells cannot secrete sufficient insulin to compensate for the demands of insulin-resistant tissues. Although insulin resistance occurs in nearly all patients with type 2 diabetes, it is the defect in insulin secretion that is responsible for the development of hyperglycemia and progression of the disease.

Thus, beta cell dysfunction is required for the progression to type 2 diabetes. Beta cell dysfunction may arise via several proposed mechanisms. One theory posits that chronic insulin overproduction could simply exhaust beta cells over time. However, many individuals readily compensate for insulin resistance for their entire lives with beta cells undergoing both functional and morphologic changes to keep pace.

When impaired beta cells are unable to keep pace with insulin demands, chronic hyperglycemia follows. This may also prove toxic to beta cells, a phenomenon termed glucotoxicity. Similarly, chronic exposure to excess free fatty acids may damage beta cells. This is commonly referred to as lipotoxicity. Both glucotoxicity and lipotoxicity may activate intracellular signaling pathways promoting beta cell apoptosis or programmed cell death. Apoptosis may account for much of the progressive loss in islet mass seen in type 2 diabetes.

Additionally, abnormal amyloid deposition has been observed in islets of patients with type 2 diabetes. The significance of the role of amyloid in contributing to beta cell dysfunction remains unclear.

 

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So, when I first saw these videos, the first topic that came to my mind was, boy, these things look like lifesavers. And that’s a real analogy or pun there or irony over there that they are lifesavers.

So, what else could go wrong, whether that’s bad enough, right? Well, this glucagon, like I said, goes up, too. So, beta cells are failing and the alpha cells are revved up. So, it’s not just the beta cell failure, but the alpha cell excess that’s causing the problem. Alpha cells, as we know, produce glucagon. So, see, this is impaired glucose tolerance, glucagon levels, type 2 diabetes glucagon levels. The time when you don’t need more glucose, the body is kicking out glucose even in the postprandial stages. So, unless you suppress the glucagon and increase the functionality of the beta cell, you’re really going to have a hard time controlling the hyperglycemia.

So, let’s, therefore, summarize this in the same cartoon that we saw before. Islet cell dysfunction in type 2 diabetes. Now, see how that’s shifted from beta cell dysfunction to islet cell dysfunction. It’s both beta cells and alpha cells. So, islet cell dysfunction, increase in glucagon, which is through alpha cells. This causes increased hepatic glucose output through glycogenolysis. Decrease in insulin production, this also contributes to the liver, all adding up to hyperglycemia.

When you compound this with insulin resistance, insulin, which is a key that unlocks the door as you saw in the muscle to allow glucose to be taken out through those glucose transporters, that doesn’t work, and the glucose levels remain elevated. So, to treat somebody, what are you going to have to do? You’re going to have to suppress the glucagon, increase the insulin, and correct the insulin resistance. Perhaps that is what is required to prevent the beta cell from failing.

We don’t know that for a fact. You’re going find, to set that out in the next two talks, to see, you know, if you can just do one of those things in the prediabetic, Dr. Marrero will talk to us about. And then Dr. D’Alessio will talk to us about what happens with the beta cell itself with, with these new incretins.

So, this is how you feel right now, correct? After I presented all of this, you thought you knew everything. Say, wow. But if you feel this way, this is what the patient is feeling, okay? Here’s the patient with diabetes. He says, all right, what is the problem? Here? We haven’t even talked about that. Liver we talked about. GLUTs, we haven’t even talked about those today. That’s maybe next year’s diabetes update. Is it the muscle? Is it GLUT-2? Remember the GLUT-2 that took the glucose into the pancreatic beta cell? Maybe there’s a defect over there. These are the MODYs, maturity onset diabetes of the young.

So, all of this is going on. What’s the patient thinking? Well, this is what the patient is thinking, right? So, how do we treat diabetes? I’m going to end by just putting up two or three slides as to what can we do. What is the goal of treatment for somebody with diabetes? Do you want to prevent the death of the beta cell? Or do you want to prevent him from dying from cardiovascular disease?

Interesting. ADA and the EASD. EASD are the Europeans. So, they both, for one time across the pond, they said, we’re going to come up with the same conclusions. Diagnosis, lifestyle intervention plus metformin. You see what has changed here? Lifestyle alone doesn’t work after diabetes has been diagnosed. You have to throw in a medication. They said metformin. No arguments with that.

The second change that came about was, see when they started pulling the trigger? It said, pull the trigger at an A1C of 7 percent. That means you, you have somebody who walks in the door. You go to your clinics tomorrow. You see somebody tomorrow who has diabetes newly diagnosed. You put them on lifestyle. Plus you say, hey, it’s now lifestyle plus metformin. And I’ll put you on 5 milligrams of metformin every day for week, and then on a weekly basis, I’m going to up-titrate till I reach 2 grams. So, at the end of 1 month, I’m on 2 grams of metformin. Then you come back to see me in 3 months’ time. If your A1C is over 7 percent, or if you’re a believer of AACE, if the A1C is over 6.5 percent, you have to pull the trigger.

And this is where the problem arose, at least for me. Because the trigger that they suggested was basal insulin or sulfonylureas, or a TZD. Well, TZD makes sense to me. Sulfonylurea doesn’t make sense to me. It’s going to cause hypoglycemia at an A1C of 6.5, 7 percent. Insulin basal will control the glucose. But as we’ve seen, is that the primary abnormality at that point in time? And then, of course, this goes on. And the reference is in there, I think, so you guys can pull it out and read it.

So, this did cause some angst for us. And this is the way I look at it. I mean, what’s the problem? Again, we are in that action/reaction mode. They’re trying to treat the glucose. At an A1C of 7 percent, are you really trying to treat the glucose, or should you be treating the cause of that glucose? You have to treat the cause of the problem. So, what’s the cause of the problem here? One’s a man, and the second is herself, right?

So, this is what happens. We’re looking at cardiovascular disease. With this is hypertension, smoking, and high cholesterol risk for cardiovascular disease. It’s been going down. This is what’s going on. So, just by treating glucose alone, are you going to impact this? Perhaps a little bit. We all know from the UKPDS that it did not reach statistical significance, because there are other factors that go into this. You’ve got to start addressing the other causes of the problem.

That ADA/EASD guideline will only address glucose. Because risk factors in metabolic syndrome, they tend to cluster. And if you just put them together, this is how they are clustering. This is how we’ve been taught to deal with conditions. Well, this is, manage the risk factors intensively today. We can deal with the LDL. We can deal with thrombosis risk. We can deal with elevated blood pressure. We can deal with lifestyle modification and dietary modifications.

Now, there’s nothing about glucose here, right? How many drugs have we thrown in already? All of this is to do what? To keep this heart beating, right? So, then we say, okay, what are we trying to achieve? Cardiovascular disease risk reduction? Stroke reduction? Hypertension? Renal failure? Heart failure? Diabetic renal disease? End-stage renal disease? What’s causing all of this? What’s the cause of the problem?

We are still in that mode. This is the problem; this is the fix. This is the problem; this is the fix. We have to go upstream. This is what we are doing. There is medication here. Medication here. Medication here. Medication here. Medication here. Is this really the way to treat this condition? That’s what we have to ask ourselves. I mean, you need these things. We are talking early on in the disease state.

You can do metabolic syndrome changes by doing diet and exercise. This was a diabetes prevention program. Placebo, metformin, lifestyle. “LS” is lifestyle. This is the change, weight change, and see the reduction in the occurrence of diabetes. What about metabolic syndrome? This was a reduction in development of metabolic syndrome.

Then there was another way. We said, okay, let’s correct the insulin resistance. This is the DREAM trial. The DREAM trial said, let’s use a TZD. Remember that, climbing the hill all the time for the truck? So, use a TZD, such as rosiglitazone, and see if you can correct the insulin resistance, will that beta cell not fail?

Well, yes, it did work; primary outcome. Rosiglitazone did work. But people did gain weight, about 6 kilos of weight gain. So, that’s the issue that we have to grapple with. The weight goes from the abdomen into the subcu tissue. But that’s an issue we have to grapple with. What do we do?

They said, okay, that was before you had diabetes. You can do rosiglitazone. What about after diabetes is diagnosed? Can you do rosiglitazone?

Sure you can, compared to metformin or sulfonylurea, rosiglitazone turned out to be better in terms of preserving beta cell function, at least preventing the failure, 63 percent risk reduction. So, that also works.

But then there was controversy about TZDs that came about. Perhaps in the discussion session, we can discuss the controversies. But this is what the side-effect profile was: nonfatal myocardial infarction, congestive heart failure, and bone fractures in women. And we take this up in the discussion session. What are the issues with TZDs? So, there are some issues with TZDs. Again, there was weight gain. Up to 6 kilos of weight gain in 3.5 years.

So, another way to treat obesity on Halloween is this, right?

Or if you want to be scientific, you say, we’re going to follow the NIH guidelines. Well, NIH guidelines, these are BMI categories. One, this category, this category, this category, this category, this category, this category, and diet and physical activity every way. Pharmacotherapy. Look at the second one. You’ve got to begin pharmacotherapy here.

So, if you have diabetes or if you have hypertension or obesity, you should begin pharmacotherapy. What pharmacotherapy? Meridia? Phen-Fen? I mean, you’ve got to start thinking, you know? We don’t do that. We have issues with those drugs, right? So, which drugs can cause glucose to go down; which can impact weight? I mean, that’s how you’ve got to start thinking.

How do you cause weight loss—weight-loss surgery. When should we start thinking about pulling the trigger for weight-loss surgery? Wow, BMI of 35 because people are going to die. You saw what happens. It’s like you aged 20 years. So, we’re very slow to pull the trigger, because we are not even telling them that they are fat. So, we don’t tell them that they’re fat. We have a problem. It’s a disease.

Imagine somebody walks in the door and you say, you don’t have diabetes. You putz around. You know, five years later some lawyer is going to chew you up. You didn’t tell my patient that he had diabetes. So, if we don’t think that, how can we start thinking this way?

So, what about hyperglycemia? Well, look at all the defects that we’ve talked about. There is no drug that hits all of these defects. So, where does that leave us?

Well, this is the natural progression of diabetes type 1. Beta cells fail rapidly. This is type 2 diabetes. And this is how we try to treat patients. As the beta cells are failing, we are adding more and more drugs.

So, discussing each drug is beyond the scope of today’s talk. That’s for you guys to go back and think about it. But where do you start adding drugs, and what are the effects of the drugs? Because then you have your other problem with the HMOs. They’re not going to give you the new drugs, right? So, what do you do?

Well, go back to thinking about this: glucose intake, insulin deficiency, insulin resistance, gluconeogenesis, glycogenolysis; that’s the disease state.

And always remember; keep your eyes on the road, because that’s the bottom line, right?