Good morning to you all. In a sort of, I’m going to call an audible on the line here a little bit, using a football analogy. I am going to talk about the clinical impact of different therapies, looking at beta cell preservation. However, given the stress that Dr. Juneja has put on weight and weight management, I elected originally not to focus as much upon that, because I have found in my experience that it’s very difficult for as, as providers, to really develop weight-loss therapies. It’s a hard thing to do. Most of us have not had significant training on weight-management techniques. And weight management, historically, requires not only an intensive intervention, but a long, sustained, followed up intervention.

But I’m actually going to talk about that a little bit more than I had planned to do. So, I beg your indulgence on that.

Just so you understand the basis of some of the ad lib comments I’m about to make, it turns out that I was the principal investigator here at Indiana University for the diabetes prevention program, which was the study that looked at a randomized trial in 27 centers that looked at whether or not we could prevent or delay the onset of type 2 diabetes in persons with impaired glucose tolerance, who were already moving up that curve that Rattan was talking about.

And I’ll talk a little bit about that data, but the one thing I’ve learned about that is how incredibly difficult it is to get people to lose weight, particularly when they have a genetic and social predisposition toward it. I mean, Indiana, I’m sure you’re aware of this, we hover around the top five of fat states in the United States. And people laugh when I go to these meetings, investigative meetings with 27 other states represented, you know, they talk about the Hoosier effect.

And the Hoosier effect is, they really believe that gravy is a drink here, okay. They’re honestly convinced that we eat an amazingly high-fat caloric intake. And, in fact, when you look at data that looks at this, the average caloric intake in Indiana has gone up about 700 calories in the last decade. And I have a slide, which I didn’t include in here, and it shows a restaurant that’s over on the East Side. Has anybody ever eaten at Jumbo Everything?

You think I’m kidding. I’m not. There’s Jumbo Everything where you can get a breaded tenderloin that’s literally larger than the plate, okay? And you have to fold it, you know? Now, I’m the first to admit they’re wonderful. They’re a very gratifying foodstuff. But we have a real serious issue here about weight loss. So, as I get into this talk, I’m going to stop at a point and talk a little bit about what I have learned about weight loss and what maybe you can do.

Let’s start just really re-emphasizing the point that Rattan made, that this slide shows the natural history of type 2 diabetes. What I want to emphasize is that once diabetes develops, there’s a progressive decline of beta cell function in individuals with type 2 diabetes. Rattan showed it, I think, quite nicely.

A major focus of diabetes management, then, is to try to prevent the loss of the beta cell or even to regenerate the beta cell to maintain or to restore insulin secretion in persons who have type 2 diabetes. So, you can see, this is similar to what Rattan was showing, but it starts early and it progresses on.

Now, one of the contributors to impaired beta cell function is what I call metabolic toxicity. It’s high glucose and high lipid levels impairing beta cell function. And lipids can impair pancreatic function through increased fatty acids and from intraislet cell triglyceride accumulation. That point was made in the last lecture. Now, metabolic toxicity is both the cause and a consequence of insulin resistance and acts in concert with genetic susceptibility and, as Rattan said, what is genetic susceptibility? We’re still trying to guess at what that is, okay? But it’s there. It’s part of the equation.

And perhaps, intraislet cell amyloid accumulation is in this equation to contribute to the progressive beta cell demise. So, what we’re talking about is that there is beta cell demise in these individuals who have this metabolic-meeting-genetic interface that causes this insulin resistance phenomenon.

Now, when we think about clinical therapies for type 2 diabetes and how they may be able to sustain or improve beta cell function, the short-term methodologies that have been looked at include weight loss and antidiabetic medications. This is mainly the oral insulins, secretagogues, the sulfonylureas, and insulin. And there is some evidence that intensive insulin therapy can have beneficial effects on enhancing insulin secretion in type 2 diabetes.

And by the way, I have to admit, I’m one of the people that is sort of an advocate of the early use of insulin in type 2 diabetes. I find it interesting that when you look at data that shows when do we initiate insulin therapy in type 2 individuals, it’s usually after sustained A1c of 8 percent or greater that’s gone on for about 35 months. That’s what you see when you look at the average data.

So, people, you try one, you try two, you maybe try two or three. You keep telling the patient, you better start taking the stuff and lose some weight, or I’m going to have to put you on the needle. And then finally, it just doesn’t work any more, we pull the trigger, and we start them on insulin as a last stop, as a last option.

I think we need to rethink that strategy through. Insulin is a pretty effective drug and doesn’t have a lot of the side effects that some of the oral agents have. I suggest, as some of my colleagues in Germany are quite advocates of this, that maybe insulin should be looked at more aggressively as a first-line therapy versus a last-line therapy. But we’ll get a little bit more into that.

Now, this slide shows the effect of weight loss on beta cell function in obese patients with type 2 diabetes. This was a study conducted by Bob Henry in San Diego. It was designed to address the effects of weight loss in people with type 2 on pancreatic beta cell function, using a deconvolution analysis of C-peptide levels.

Now, Barry Gumbiner, who used to be a faculty member here at IU, was the person that actually conducted the hyperglycemic clamps, where glucose levels were experimentally increased to about 360 milligrams per deciliter. And they did this for a period of about 3 hours. And during this time, C-peptide levels and insulin secretions were determined.

Now, these studies were conducted before and after weight loss in each patient. And insulin secretion is shown here. Insulin secretion is shown here, and you can see this is before and then after weight loss. You can see there’s a significant improvement in insulin secretion with simple weight loss. And what this suggests is that the improvement in insulin secretion is to the same hypoglycemic stimulus, indicating a significant improvement in the sensitivity of the beta cell to stimulation at prevailing high-glucose rates. So, this data suggests that, in fact, simple weight loss—now, this is not simple, this is a drop in weight loss—but it has a profound effect on the taxing that we put on the beta cell.

Now, I’m going to stop here, because I have to talk a little bit about weight loss, because this is important. One of the things we discovered in the diabetes prevention program was that very small changes in weight loss have a profound effect on insulin secretion, insulin resistance, and insulin sensitivity in the uptake of the insulin in the individual. And what’s important to keep in mind here as providers is, what do you think the percent of weight loss from baseline has to be before you get the prophylaxis protecting you if you have IGT to go on to full-blown diabetes? Anybody know this number? It’s about 5 percent.

Here’s the trick about this. This is what I find interesting. This is the ad lib part of the talk, because I don’t have the slides for this. But the slides are spectacular; I wish I had them.

All right. When you look at studies that ask people what they think their ideal weight loss would be, what would be your dream weight loss? And these are people with BMIs of 30 or greater, because several studies have shown the same thing. Thirty is the definition of obesity. If you asked them, what would be your dream weight loss; what would be an ideal weight loss; what would be a good weight loss; and what would be an unacceptable weight loss, percentage of body weight loss; what do you think the percentage for unacceptable weight loss is across the board?

Yell out a number, come on. Ten percent; I hear 10; I have 30. Anybody want to go in between? Let’s split the difference. It turns out to be 17 percent on average. Guess what their dream weight loss is? Thirty-eight percent. That’s losing a whole person. That’s taking off a third of their body mass.

Here’s the trick. The trick is, when you look at weight loss literature and you look at weight loss therapy, most people do not achieve a 38 percent weight loss. That’s a remarkable weight loss short of bariatric surgery. So, if you’re trying to do it with diet and changing fat consumption and calorie regulation, the history is that most people can drop significant weight initially, but they all regain it back. What you see is this gradual, or sometimes rapid, regain. I don’t care what diet you use. I don’t care if you use the Atkins, the South Beach, the cabbage soup, the Subway, it does not matter. Unless you sustain that diet for a very long period of time, you tend to regain the weight.

And the theory goes that with the Thrifty Gene Hypothesis, what happens to individuals when they start to go to low calorie intakes is, the body gets a signal that says, hey, we’re going back into a starvation cycle. In other words, the thrifty gene idea was that when the game was in town, we beat it to death and ate like pigs, and we were happy, because when the herds migrated out, they were gone. And so, we had to live off the stores.

Well, I don’t know about you guys, but I haven’t beat my meal to death in a long time. You know what I mean? I don’t have to do that any more. But the body doesn’t know that. That gene has not had the time to reacclimate itself to continuous food availability. So, what happens is, these people start dieting with very low calories. They’re either doing the sustacals; they’re drinking the drinks, you know, out of two meals, they’re eating the third. They actually signal their body to say, any time you have more calories than you need for metabolic efficiency, store it, because, by god, the herd is leaving. That’s the theory.

So, what happens? These people go on these low-calorie diets. They lose all this weight. They’re living off their fat stores. The day that they exceed their metabolic threshold, that is, the amount of food that they need for energy, functioning, guess what happens? You just slam it into fat. The body says, okay, thank you very much, let’s guard against this, all right? So, the trick about this is, if we’re going to advocate weight loss as a therapy for our patients, there’s two messages I want to give you.

Number one, very small changes have a huge impact, huge impact. Five to 7 percent of body-weight loss has an amazing impact. In the diabetes prevention study, it reduced the onset of diabetes in impaired glucose tolerant individuals by almost 60 percent, which is a whopping big percentage. But it doesn’t have to be 18, 20, 30 percent. You don’t have to get back to your prom dress size. You don’t have to get back to Rattan’s picture of getting back to his Dublin pants. But what you do have to get down is 5 percent.

So, we have set unrealistic goals. And my own doctor, when I came in one day, said, Dave, you need to lose 30 pounds. Well, okay, probably I do. But that’s a big target.

Second thing. Most people who are overweight will tell you that they have a huge history of weight loss and failure. They have cycled. They’ve gone up, down, up, down, up, down. Doctor, I’ve lost a thousand pounds. Have you heard it? Doctor, it doesn’t matter what I eat, I still get fat. There’s some truth to that. The truth is that metabolically, they’re hyperefficient when they’re in a starvation mode of low-calorie intake, and they are more efficient at gaining weight.

So, you have to sort of start thinking a little bit about what is a lifestyle modification that can be sustained for long periods of time? In the DPP, the secret to that was controlling fat grams, because fat grams are high-dense calorie sources. And a gram of fat has about three times the calories as a gram of protein. All right. So, if you want to get bulk and volume and feel satiated, you start eating less fat, more carbs, more protein. You’re going to do a little bit better off with that. That’s just a real important thing.

So, advocate a small, modest goal. Advocate a strategy of diet re-regulation that just cuts out hypercaloric, rich foods, which is mostly fat-gram consumption. Does anybody know what the average percentage of the total daily calorie consumption of the average Hoosier is in terms of fat? Anybody want to guess? Yeah, it’s over 40 percent. It’s almost 50 percent. Fifty percent. I mean, we might as well just have them start IVing butter, because it’s getting to that level.

That was my quick diversion off the topic at hand. But weight loss is an important thing. I agree totally with Rattan. It has to be integral to all therapeutic decisions that we make. But we have to adjust the goal. It should be smaller, more modest goals. And the idea is keeping that person in a 5 to 7 percent reduction at their initial presentation of weight is going to have tremendous benefit for risk reduction on many of the factors that Rattan talked about. And those are achievable goals.

In the DPP, we kept 5 to 7 percent off of the weight of people for 4 to 7 years. It can be done, if it’s reinforced, if you have them reconsider the composition of their diet. And what do you think is the secret to understanding how much you eat, how much fat you got? Anybody want to take a shot at this? I must have dietitians out here.

Write it down. The number one predictor of making these changes was having people keep diet logs and get one of those little books that you can get at every CVS in the universe, it shows how many calories does everything have and how many fat grams. And you calculate it out. I have never had a patient yet that believed that they ate as much fat or as many calories that they thought they did. And I’ll give you a fine example of that.

How many people, show of hands, absolutely know for sure how many calories are in a Snickers bar? Oh, come on. Anybody? Anybody want to guess? I’ve heard 600, someone said. I hear 240. Here’s the deal. Now we’re going to play the size game. What do you mean, the little one, the really big one? The point I’m making here is that you think this is a little snack, okay? I’m just going to grab a Snickers on the run; it’s not much. It’s 260 calories; 260 calories.

If you’re having a 1500 calorie-a-day diet, which is probably adequate for metabolic need, that’s a percentage of your total caloric intake. How many calories are in a handful of peanuts, small handful, just enough to cover your palm? Again, the point I’m making here; you’re not sure. How many calories are in a slice of bread? I’m hearing 20, 400. I’m hearing all these different numbers.

The point is, guys, that until you start writing it down and calculating, you don’t have a clue how many calories you’re eating. And I would take a bet with anybody in this room that I could get you all to write down all your food for a week and have you estimate how many calories you’re eating, and you’ll be off. I could win that bet 99 percent of the time. Only the really rigid, controlled diet people that are measuring everything that they eat and goes through their mouth actually have a clue. And most of us don’t.

And when I did the DPP study with 192 of our fellow Hoosiers, and I had them start keeping diet logs, they way underestimated their caloric intake. And this is a common observation. It happened in every DPP site in the country: 3000 people and not one of them guessed their diet correctly. We don’t know. We don’t have a clue.

So, when you’re doing diet regulation in the clinical arena, ask your patients to just write down everything they eat, and at the end of the week calculate it out with the help of a book. And there’re a lot of examples out there to do it. Then look at that caloric intake and say, okay, let’s talk about one or two changes that we can make that would reduce this caloric load, leaving everything else the same.

If they drink fully leaded Coke, start there. By the way, how many calories in a can of Coke? I hear a lot of different variations. Let’s try this one for the guys. How many calories in a standard beer? Ninety-six? That’s a light beer. That’s a really light beer. A real beer, like a Budweiser. Let’s take a can of Budweiser, how many calories? Anybody know for sure, raise your hand. What do you got? Hundred and fifty.

Now, hidden source of calories, alcohol. You don’t need insulin to metabolize it very effectively, and you can get a lot of calories from alcohol. And I’ve had a lot of people who the ah-ha moment was, gosh, Doctor, I’m only eating these three little set meals, and I don’t understand it. What do you drink with the meals? Well, I have a couple of beers. Oh, okay. Now we’re up to 300 calories on top of your 300-calorie meal. Now, we have a 600-calorie load. And if you do that a couple times a day, guess what happened? So, I made the point.

In the same studies that the first slide I showed you about weight loss and insulin secretion, we know that all glucose tolerance tests were also conducted before and after weight loss. And you can see the pronounced changes in the glucose levels on this slide after weight loss in the type 2 diabetic patient. When we focus on corresponding changes of insulin secretion, you can again see marked improvements in the insulin response following oral glucose.

So, from this study and others, weight loss definitely has some short-term benefits on beta cell function. And whether these benefits persist long term, remains to be determined, because very few long-term studies have addressed this possibility. And there’s one in the works right now looking at the effects of modest weight loss in type 2 patients on cardiovascular end points and beta cell functioning. The data is not in yet, but the early data suggest that, in fact, there is pronounced preservation of the beta cell with modest weight loss.

Now, let’s talk about some of the drugs that Rattan put on the big list, see what these do for beta cell functioning here. And let’s look at the effect of glyburide in hyperglycemia and enhanced beta-cell responsiveness.

Even the oral sulfonylurea glyburide has been shown to improve beta cell function. These studies were done by Ken Polansky and his group when he was at the University of Chicago, and they were using a model deconvolution of C-peptide levels. These studies compared insulin secretion in normal individuals and in type 2 diabetic subjects before and after glyburide therapy. These are three meals and a glucose level, breakfast, lunch, and dinner. And you can see a progressive improvement after the glyburide.

In terms of insulin secretion, despite the fact the glucose levels have come down substantially, there is significant improvement in insulin secretion, as well. Thus, treatment with glyburide therapy has also been shown to improve beta cell function, at least in the short term. So, if you’re wondering whether or not there is preservation or function of the beta cell, this seems to be one that works.

Now, in contrast to glyburide, metformin has not been shown to improve insulin secretion, despite significant improvements in glucose levels. This slide depicts the glucose levels before meals, after metformin treatment, where there was significant improvement in glucose levels, but it was not associated with any change or augmentation of insulin secretion.

Now, of course, you’re still getting similar insulin secretion of lower-prevailing glucose. So, there is more sensitivity to the glucose, but the absolute amounts of insulin levels were not increased. And I’m curious. How many of you go to metformin as your first oral agent, first choice of drug?

Now, Tim Garvey, who is another former faculty member here at IU, did a study where he looked at intensive insulin therapy in obese type 2 diabetics, many of them with relatively recent onset. So, he was picking people that sort of were fairly new in their diagnosis curve and getting right on intensive insulin. And in fact, he put them on insulin pumps. Which, by the way, when he was doing that study, it was a tough sell to convince people with type 2 who were obese to start using insulin pumps. But he managed to do it.

And he gave them insulin for a prolonged period of time. Now, the daylong glucose levels after meals are shown before and after the intensive insulin therapy here. And what you can see is, there is a marked and almost normalization of daylong glucose levels. But look at insulin secretion, there is also a marked improvement in postprandial insulin secretion following intensive insulin therapy.

And this is starting to address the issue that Rattan brought up about chasing the postprandial. The oral agents that we have, most of them don’t do that very well. Insulin is, in fact, in my mind, the drug of choice for dealing with postprandial excursion. Now, I’m sure some of you will argue that. I’m not an MD. But that’s my read on it.

And it may be, in this case, that removing the metabolic toxicity and reducing the elevated glucose and free fatty acid levels, in fact, improved beta cell function using insulin in the type 2 patients.

Now, how about methods that may lead to long-term improvement in beta cell secretions? So far, we’ve shown you sort of a cute and short-term. There is a great deal of opportunity to see changes in beta cell function or at least limitation of beta cell decline with new therapies that are available to us. One of the antidiabetic medications that we’re talking about is the oral insulin sensitizers. The glitazones have been studied now and clearly appear to have some ability to maintain insulin secretion and, perhaps, to prevent the decline of beta cell function. And I’ll talk about that a little bit more in depth here.

There’s also potential for glucagon-like peptides, or the GLP-1s, analogues, for which I will show you some data, and, of course, the dipeptidyl peptidase-IV, the DPP-IVs, inhibitors—I can never say that one—which also increase GLP-1. And although there’s not a lot of clinical data available to show you, these do have potential, and, like the GLP-1 analogues, to enhance beta cell regrowth and to limit apoptosis of the beta cell. And I’ll show you a little bit on that.

In terms of the glitazones, how might this work? The glitazones have the ability to reduce insulin resistance. And clearly, when insulin resistance is present in people with type 2 diabetes, particularly at the liver and at the skeletal muscle, the insulin resistance can be extremely severe.

When this is reduced by treatment with a glitazone, the pancreas has to work much less hard. It’s that truck thing that Rattan was talking about. You now have a couple more gears to work with to get up that hill. This relieving of the strain on the pancreas may allow the pancreas to perform better and may affect, minimize, or reduce the progressive decline of the beta cell function.

So, I agree with Rattan’s analogy that if you keep continually stressing the beta cells to perform at maximum output by adding more and more weight, more and more resistance to it, at some point, the beta cell says, I’ve had enough of this, and wants to stop. It just fatigues and it tires out.

Now, the glitazones also act through stimulation of peroxisome proliferator-activated receptors, or the PPAR-gamma receptors. And the PPAR-gamma has a number of cellular effects. The PPAR-gamma transcription factor has been found in islet cells of the pancreas. So, we know that it’s operating in there.

So, it also is possible that glitazones could act directly on the pancreas through the PPAR-gamma receptor to enhance insulin secretion long term and, again, prevent the decline in beta cell function over time.

Now, what kind of information do we have about the glitazones? Rattan showed a little bit of this. Here is some data from the pioglitazone on beta cell function. And it’s based on the homeostasis model assessment of the HOMA beta cell function CF model. And in this case, we have change reported from baseline.

Now, in terms of HOMA beta-CF, improvements occur with metformin compared with placebo, but just fail to achieve statistical significance. There is a decrease in the HOMA beta-CF with sulfonylureas, but significant improvement is shown with a pioglitazone alone and in combination with sulfonylureas and metformin. Again, this improvement in beta cell function may indicate the stabilization of beta cell function and improved sensitivity at the prevailing reduced glucose levels.

Now, here are long-term data with pioglitazone that Dan Einhorn produced in a large, collaborative study, showing reductions in A1c with pioglitazone and going out to 72 weeks. And this is associated, of course, with the reductions in fasting plasma glucose. The point is really that the stability of the long-term effects to maintaining glycemic control in these individuals, treated with sulfonylureas and even with metformin and insulin, there has been shown to be a progressive decline in glycemic control and insulin secretion over time.

So, really, when you look at 72-week data and you’re looking at sulfonylureas and other drugs, you don’t see this sustained effect occurring as much as you do with the TZDs. So, pioglitazone treatment has been shown to be stable and durable in maintaining beta cell function over a fairly significant amount of time.

Now, similar evidence exists for rosiglitazone, the other glitazone that’s available to us. This is, again, beta cell function using the HOMA beta-CF model, and there are, again, mean changes from baseline. And you can see improvements in the HOMA values with rosiglitazone at 4 milligrams and 8 milligrams compared with placebo.

In combination with sulfonylureas and metformin, you can see significant improvements, as well, that appear to be dose dependent. So, neither sulfonylureas nor metformin was associated with significant improvement in HOMA scores. So, similar to what you saw with pioglitazone, there are improvements in beta cell function with rosiglitazone in these studies.

Now, with rosiglitazone, as you saw with pioglitazone, there’s an indirect evidence of long-term effects of beta cell function. And these are open-label studies, so they’re open to some criticism, because usually people on open-label studies are the ones that get the best responses. And they come back to play longer and more.

However, these data still tell us that people are successful, continue to maintain success over very long prolonged periods of time. And it is evidence that there may be some durability and long-term sustainability of improvements in insulin secretion with the glitazones.

All right. Let’s talk about the prevention of type 2 diabetes, treating high-risk individuals. How about this: We’re taking a step back down, asking ourselves this question: If we address the decline in beta cells that occurs at the time of diagnosis from diabetes, or even earlier by reducing insulin resistance, can we prevent the development of type 2 diabetes and preserve beta cell function?

This is the data from the diabetes prevention program, which was conducted in 27 centers across the United States, including here at IU. It clearly shows that there could be reductions in the development of the incidence of type 2 diabetes compared with placebo. This is the incident rate in cases per 100 person years, and it’s cut almost in half, down to 6.7 with metformin. So, metformin, by itself, was effective in preventing the onset of diabetes in people with impaired glucose tolerance. Average BMI in this population was 34. Big people, huh?

And it’s even greater with short-term troglitazone treatment, because what has not really been talked about much is, there was an arm of the study, it was a four-arm study, that used troglitazone, the Rezulin drug. The problem was, that we had a liver death that occurred in the study. We had somebody whose liver failed and died as a subject in the DPP.

Well, you could imagine, that was about the time when the whole thing came out with Rezulin, and they withdrew it from the market. So, we had to open the identification of the people who were on the active drug versus the placebo, bring them all in for liver function tests, and then unblind them to the study. But we followed them over time.

But what is not known is, of all the conditions—because clearly, lifestyle was almost a 60 percent reduction—but glitazone was actually much more effective at reducing diabetes, at almost 70 percent. And we had 600 people; we had almost a year of exposure to it. So, it was actually quite a potent drug.

Now, you’ve read about a recent trial, the DREAM study, which has come out, that argues a comparable effect to the lifestyle arm, a little bit better improvement, and similar to what we saw with troglitazone.

A little quickie story, because I like this one. When we found out that there was this problem with troglitazone, the FDA required that we found each patient that was on it, and bring them, within 24 hours, for a liver function test and assessment at our center. One of my subjects was camping in Wyoming and was way up in—a backpacking person, you know—had gotten way up into the mountains. We had to actually send a ranger up to get her out. And to this day, she still gives me grief about how she was in a campsite enjoying nature, and suddenly here’s this guy coming up with a 4-by-4 and says, you’ve got to go to the hospital now; come on, we’re going to take you out of here. And dragged her down off the mountain. And we had to have an LFT done in Wyoming. Rawlins, Wyoming, of all places. I digress.

Now, these are reductions mainly in insulin resistance, suggesting that there may be some long-term benefits in insulin secretion. Studies done in women with polycystic ovary syndrome and treated to glitazone show improvements in beta cell function. This is improved insulin sensitivity, which is over here, before and after treatment with troglitazone. The acute insulin response to intravenous, IV glucose tolerance test, did not improve significantly. But the disposition index, which is a product of the acute insulin response, which is shown here, in fact, and the insulin sensitivity—so, these 2 factors together—and this is a measure of whole-body insulin sensitivity, were also significantly improved.

So, again, we have improvements that are shown with the glitazones with polycystic ovary syndrome, as well with pioglitazone and rosiglitazone in people with type 2 diabetes. It’s a promising drug in a lot of aspects.

Now, the study that probably best characterizes change in the insulin secretion and the insulin resistance with glitazones was the Troglitazone in the Prevention of Diabetes, or the famous TRIPOD study. Hispanic women with a history of gestational diabetes were treated either with placebo or with the drug troglitazone, Rezulin, for about 4 to 5 years. The percentage of people with diabetes is shown on the vertical axis, and the yellow line in this is the placebo data. This line shows the troglitazone therapy. And there was a significant reduction in the development of diabetes, almost a 55 percent relative risk reduction, and a 31 percent absolute risk reduction in this study.

Now, if one looks at the preservation of beta cell function, these are the women who did not have diabetes during that trial. In both the placebo and the troglitazone groups, you see the hyperbolic association between insulin secretion and insulin sensitivity. This is the acute insulin response presented as a function of insulin sensitivity measured by the minimal model, and following the treatment of the placebo group with people who did not develop diabetes. There was, in fact, a significant reduction in the acute insulin response in association with the worsening of insulin resistance.

In the troglitazone group, in fact, this was stable. Insulin secretion and insulin resistance were absolutely stable and did not fall off this curve. There was a difference between the groups that was consistent with diabetes prevention. And that was a reasonably robust finding. That means that those individuals were able to maintain a tight correlation between their acute insulin response and insulin resistance or insulin sensitivity, were able to prevent the development of diabetes in this study. And that occurs right there.

Now, an interesting aspect of this study was that when they took troglitazone, or Rezulin, off the market, the women were offered the opportunity to go onto pioglitazone for a three-year period. This is the composite of these data, and it shows the effect of troglitazone and pioglitazone on these studies.

On the vertical axis is the disposition index. That is the measure of beta cell compensation to prevailing insulin resistance. In the initial studies, we have treatment with  troglitazone in these women with very high risk for developing diabetes compared to placebo. And with placebo shown in white on the white line there, there is a significant reduction in the disposition index that occurs over the four years where they were exposed to the drug, consistent with a change in insulin secretion for the prevailing insulin resistance. This is obviously deterioration in this relationship, deterioration of the beta cell.

In the same type of patients who were randomized to troglitazone, there is a nonsignificant change and a stabilization of the disposition index. And these patients were then taken off of either troglitazone or placebo or put on pioglitazone, in the Pioglitazone in the Prevention of Diabetes, or PIPOD study. I love how he gets TRIPOD, PIPOD. He sort of has a knack for acronyms.

The troglitazone/pioglitazone group was able to again maintain or sustain the improvements in the disposition index, as shown in the slide. And the pioglitazone/placebo group did get some improvement or at least stabilization and no further deterioration in the disposition index. This, again, suggests that both pioglitazone and troglitazone were able to have a stabilizing effect on beta cell deterioration in people with high risk to developing type 2 diabetes.

So, just to conclude on these particular studies. The thiazolidinediones treatment of impaired glucose tolerance and early diabetes preserves beta cell function and slows the progression of type 2 diabetes. Reducing beta cells’ secretory demands by reducing insulin resistance with the glitazone preserves beta cell function and impaired glucose tolerance and early diabetes. So, these drugs seem to be the real deal. They seem to have the impact that I think we’re looking for, which is to preserve beta cell function in either a high-risk group or an early-stage group.

Let’s talk for a minute here about the preservation or regeneration of beta cells, the GLP-1 analogues and the DPP-IV inhibitors. Because they have the potential to have beneficial effects in beta cells by enhancing beta cell neogenesis and proliferation, and beta cell hypertrophy, and the ability to inhibit apoptosis. So, the GLP-1 analogues and the DPP-IV inhibitors have significant potential not only to maintain beta cell function, but, in fact, to possibly increase beta cell secretion in people prone to developing diabetes or those who have diabetes with loss of beta cell function.

How many of you are using exenatide out there? Any exenatide users? A few of you, okay. Exenatide is an interesting drug. You know, it’s made from the spit of a Gila monster, which, I think, is just amazing. But in cell cultures and in animals, it increases the expression of key beta cell genes. It also increases insulin synthesis and processing. It also increases beta cell mass, and it has increases in neogenesis and proliferation and reductions in apoptosis of the beta cell.

In humans today, exenatide improves the insulin:proinsulin ratio consistent with improved insulin secretion, and it restores first-phase insulin secretion. And I’ll show you a slide on that in just a second. It also augments insulin secretion at lower prevailing glucose concentrations.

Now, these are the effects of exenatide on first-phase insulin secretion. This is the insulin secretion shown on the vertical axis to an IV bolus of glucose, or an IV glucose tolerance test. There are 3 groups of subjects: healthy controls, untreated type 2diabetics, and type 2diabetics treated with exenatide.

What we see is following an IV bolus of glucose. In the nondiabetic subject, there is a normal, first-phase insulin secretion and then a second-phase tail appears. People with type 2 diabetes have lost their first-phase insulin secretion; however, following acute treatment with exenatide, you see a recovery of first phase and second-phase secretion, and a substantial improvement in the ability of the beta cell to respond to a standard, IV glucose load.

In the exenatide-controlled trials that they did for the FDA approval, hemoglobin A1c was reduced by more than 1 percent over 28 weeks. As with the glitazones, the open-label studies demonstrated that sustained and durable glycemic control was consistent with persistent effect of sustaining insulin secretion. And at least in these individuals with type 2 diabetes, we see this long, fairly stable effect occurring after initiation of this therapy.

There is another GLP analogue, liraglutide, which has also been shown to improve insulin secretion in an insulin-dependent manner. The insulin secretion rate is assessed by a graded glucose infusion from five millimoles to about 15 millimoles in nondiabetic controls and type 2 diabetic subjects treated with placebo or the active drug. There was a marked improvement and near normalization of insulin secretion with liraglutide similar to control subjects. Thus, there is a significant improvement in insulin secretion in insulin glucose-dependent manner in individuals with type 2 diabetes in response to this infusion. Holds good promise.

So, to summarize. Increased beta cell function and mass occur in response to increased beta cell demand. We know a gradual decrease in beta cell function and mass may occur in individuals at a high risk of developing type 2 diabetes. And to prevent loss of beta cell function and mass, beta cell work must be decreased or beta cell stabilization or regeneration has to occur. And these are the elements that contribute toward the prevention of type 2 diabetes in high-risk individuals or the progression of the disease in early-stage individuals with diagnosed type 2 diabetes.

Clearly, weight loss is a low-cost option that needs to be examined more critically. We need to do everything we can as providers to stimulate our subjects to do weight loss and to maintain weight loss. I talked to you a little bit about some of the simple things: calorie restriction, fat-gram control, monitoring of dietary intake. These are all important elements. It’s also very important to set very realistic and modest weight-loss goals. You have to choose a goal that can be achieved by the patient and reinforced.