I am Dr. Barry Goldstein, Chief of Endocrinology at Thomas Jefferson University in Philadelphia. In this presentation, I will summarize the important features of insulin resistance and type 2 diabetes. We are on the threshold of dealing with the interface between what is diabetes, meaning hyperglycemia, and the impact that insulin resistance has on cardiovascular disease. Many of the presentations at the American Diabetes Association (ADA) this year have a focus on the causes of cardiovascular disease. Obviously, this is a major epidemiologic problem. We need to address this in our treatment of patients with type 2 diabetes, and in our patients earlier, before the disease is diagnosed. What are we going to be doing over the next few years? I think there is a revolution under way in this field, and we will soon have more data to support earlier interventions by identifying patients with impaired glucose tolerance and what's been called the metabolic syndrome, or the insulin resistancesyndrome, and treating them appropriately even if they do not have significant hyperglycemia. But right now as this evolves, we are really looking at treating diabetes in the context of this background.

When a survey showed that Philadelphia was the fattest city in the country, the mayor put this city on a diet. And this is just such a great picture. "The mayor says we're too fat." And he's right. Obviously this is really the problem. This is the epidemic. And I just took one glimpse of the new guidelines from the National Cholesterol Education Program (NCEP), where it's finally recognizing the metabolic syndrome and the features of insulin resistance syndrome for cardiovascular disease.

What's really astounding, the numbers of patients that have been projected in this country to be targeted for either therapeutic lifestyle change (which means getting off the sofa, watching what you eat, and exercising) is 65 million people. These are just phenomenal numbers. This is part of the epidemic. You're going to hear more about this from Dr. Steve Haffner. Drug therapy, which I think truly we try to avoid if we can, is projected for 36 million people. This is because of the need for lifestyle changes in so many individuals and because of the severity of the metabolic syndrome. So we really need to address both sides of this issue--prevention and adequate treatment.

When we look at this scheme, genetic predisposition and environmental factors lead to insulin resistance. This is the underlying phenomenon that is seen very early before hyperglycemia. There are several points that I'm going to make. That clearly we're trying to prevent complications of diabetes--coronary disease, amputations. The complications that have a vascular basis are prevalent because of all of these risk factors that are running together. The hyperglycemia that you see in diabetes, which defines diabetes, is related to the microvascular complications: retinopathy, renal disease.

There's no question that controlling glucose carefully is important because we can delay or prevent the progression of microvascular complications. But it has been much more problematic to try to figure out what's causing atherosclerosis, primarily because there are so many things going on and we really do not have a full handle on why patients have insulin resistance. What is the role of hyperinsulinemia, changes in lipids, and other factors, such as hypertension? It is very hard to separate these variables. Together, these variables need to be addressed because we are trying to prevent complications, and certainly if we can prevent diabetes altogether, that would be a wonderful thing.

There is some recent data, really not a lot of data, but we know that insulin resistance tends to arise in patients mostly because of this genetic background, but more importantly because of obesity and sedentary lifestyle. You reach a point where you have insulin resistance. This was also looked at in the United Kingdom Prospective Diabetes Study (UKPDS). It doesn't seem to get worse and worse and worse. It is somewhat reversible. There have been patients who could lose some weight, their blood glucose will come down, and their blood pressure will come down. But it tends to be in the background. And to compensate for the insulin resistance, before the glucose goes up, you see in the upper panel here, beta-cell function has to increase. So insulin levels come up to match the resistance. The demands in the body for more insulin need to be met. And if those demands are not met, then you start to see postprandial glucose and fasting glucose goes up, and patients have full-blown diabetes.

There are two processes causing type 2 diabetes. This is the dual impairment--insulin resistance, impaired insulin action, and impaired beta-cell function.

What is insulin resistance? It is resistance in the body to insulin that affects insulin's action on glucose disposal in muscle and fat as well as suppression of liver glucose output. It is a phenomenon that you can show with endogenous insulin, so if the pancreas is able to provide sufficient insulin, levels will be high. Or in many patients that lose their beta-cell responsiveness, you need to give them exogenous insulin, and they take high doses of insulin. In both of those cases, those patients are insulin resistant. There are physiological measurements that you can make in the sense that it takes more insulin to at least do a minimal job, and in some patients you can not have as much of an effect on glucose disposal or suppressing glucose output, as you should be able to do normally.

This is a graphic view of that, what's causing the glucose to go up. Insulin has difficulty disposing of glucose in muscle. The liver is making glucose. There are two insulin resistance points. The pancreas is in the middle of this because clearly if you provide enough insulin, you can prevent the glucose from going up.

There's a failure of this balance system in patients, and that's why the glucose rises.

One of the most important phenomena that needs to be sorted out, and there's a lot of research going on in this area related to type 2 diabetes, is obesity, and in particular, visceral adiposity.

Why do people collect fat in their visceral compartment as they age? That is a very important question that I can not answer for you, unfortunately.

But we know that fat has very important effects on metabolism. The best correlation that has been shown by many researchers -- this is one study by David Carey, showing a decrease in insulin sensitivity associated with central abdominal fat. What is fat doing in this situation? There has been a very important focus on fatty acids and fatty acids' effects on insulin action.

Fatty acids are released from fat tissue, and in particular, it has been shown that the visceral adipose tissue has a high rate of lipolysis. When you expand the visceral adipose tissue mass, this delivers significant amounts of fatty acids into the bloodstream.

There is some very interesting information about lipodystrophy, and patients have syndromes where they retain fat in certain compartments. They retain fat in their face. In most of the very severe cases of lipodystrophy, patients still retain fat that has mechanical properties in joints or around organs. The message is very clear that not all fat is alike, and there are fat depots that are doing specific functions and have metabolic roles or differences in their metabolic rate in the body.

We know there are some differences between the visceral fat and the subcutaneous fat, and in particular, the visceral fat has been associated with fatty acids in insulin resistance.

This is another way to look at that phenomenon, that fat tissue releases free fatty acids; however, the exact mechanisms are being evaluated. There are also changes in signaling that are due to the fatty acids.

In effect, they are preferentially metabolized and have direct effects on insulin action; therefore, they block the promotion of glucose uptake into muscle and they enhance gluconeogenesis in the liver. On both sides, tending to cause hyperglycemia and contributing to hyperinsulinemia.

In addition to some of the metabolic exchanges hypothesized by Professor Randall, Gerry Shulman's group at Yale University has also been studying PKC enzymes that are activated by fatty acids and are shown to phosphorylate specific components in the insulin-signaling cascade and can negatively affect the function of these proteins and their signaling ability to promote glucose transport.

We know fatty acids are a target to try to improve insulin sensitivity. All of this work has been coming around full circle because it is true that the thiazolidinediones (TZDs) were discovered because they lowered glucose in animal models. There has been a tremendous amount of work, and now clinical experience, using the TZDs in patients, and we're trying to figure out the mechanisms.

One of the most significant effects of TZDs, which is shown above with rosiglitazone, using the drug in monotherapy for a year against glyburide, is that there is a drop in free fatty acid levels. This is one of the most significant highly reproducible effects of the TZDs. It's believed that this is fundamental to their mechanism.

Part of the rationale for this effect is if you look at the rate of loss of free fatty acids in the bloodstream, it takes several weeks to months for this to become established. It precedes the drop in blood glucose. You know clinically when these drugs are used, it does take 1 or 2 months before you see a clinical response in lowering glucose levels. That is due to the secondary effects of changes in fat metabolism and the resultant improvement in glucose. You don't see this with glyburide. We are looking now in detail at the differences in the mechanism between different drugs for treating diabetes and also the other aspects of these drugs in approach to treating patients in general.

We know that another aspect of the effect of TZDs is its ability to redistribute fat. What do they do to fat metabolism? It seems as though they affect certain fat depots. They increase the amount of adiposity in the subcutaneous depot, which may be contributing less free fatty acids to the bloodstream. But they also cause more smaller metabolically active fat cells that do not release fatty acids as much as the larger fat cells. They also affect fat cell differentiation. There is a loss of visceral fat, which seems to be redistributed to the subcutaneous compartment. There may also be changes in fat oxidation, as was demonstrated by the group at NIH in patients who have lipodystrophy.

We are looking at this very complicated, but interesting, communication between fat tissue, secreting fatty acids, other factors, cytokines, that have been implicated also in causing increased fatty acids and having effects of their own to block insulin action as the target of drugs like the TZDs, and their effects on liver and muscle, leading to changes to glucose metabolism. This leaves the pancreas in the middle of the picture because the pancreas has to try to secrete enough insulin to keep the glucose under control.

We will now take a look at the beta-cell function. It's important to consider that insulin resistance is a physiological phenomenon in the population. The number is something like 25% all across the board in the United States have insulin resistance. Some populations have more insulin resistance than others.

This slide is looking at this phenomenon the other way. This is insulin sensitivity. You can see that certain groups, certain ethnic groups, pregnant women, and obese individuals have reduced insulin sensitivity. They are more insulin resistant than normal subjects.

However, this graph is showing people who have normal glucose tolerance. If the range of insulin sensitivity is over a factor of three or four, how do they have normal glucose tolerance? Well, if you have sufficient function of the pancreas, you keep the glucose under control. If you do a glucose tolerance test on these people, you will see they are hyperinsulinemic.

The reason why diabetes develops and progresses is because there is a loss of beta-cell function. This is what has been shown so elegantly in the UKPDS. This graph shows the years from diagnosis in the UKPDS where we get the classic view that at the time of diagnosis, patients have already lost 50% of their beta-cell function. Beta-cell function continued to decline during the UKPDS, which accounted for the progression and worsening of the diabetes. It is important to consider that the treatments that were used in the UKPDS did not help the pancreas survive longer. Insulin and metformin were used, treatments that you would think should have protected the pancreas because they lower endogenous insulin levels. But there is some programmed abnormality or some response to the pancreas that could not be recovered in the UKPDS. There was a progressive decline.

We also know that in type 2 diabetes there is a functional defect that we can demonstrate early on, a loss of first phase insulin secretion. The beta-cells are still there, but they're not able to respond to glucose stimulation.

What is really interesting about this is something that we have known for a while. This is looking at that first phase of insulin secretion. Intravenous glucose has to be used to demonstrate this very rapid, over the first 10 minutes or so, peak in insulin concentration. Patients with very mild elevation of their fasting glucose lose this first phase response.

We also know from this work from Jerry Palmer, which has been known since the 1970s, that even though the cells are blind to glucose infusion, other secretagogues like arginine can stimulate insulin. This is why we have drugs that are targets for insulin secretion modeled after amino acids. Some of the newer drugs, such as, phenylalanine derivatives. Research also is trying to figure out other ways to wake up the beta-cell so that it can sense glucose properly, with agents such as the new secretagogues and incretins.

When you do an oral glucose tolerance test, this works out to show you that there is delayed insulin peaking in which you lose the first phase. Insulin does come out, but it is delayed, and it is not well matched to food, so you get a high postprandial glucose excursion. As diabetes progresses from impaired glucose tolerance to type 2 diabetes, you can see the peak insulin response gets extended farther and farther out.

It is worth coming back to evaluate some of the newer treatments. If you look at the effects of TZDs, not only on insulin resistance, we also know these drugs are insulin sensitizers, improving insulin resistance. These are data taken from one of the clinical trials using the HOMA model which shows that also there is an improvement in beta-cell function. This is another effect of the TZDs that has been known for many years.

There are a lot of data from animal studies, and right now ongoing human trials. As you can see here in a diabetic type 2 mouse model treated with rosiglitazone, the insulin content in the islets is preserved and it is enhanced. This is what helped protect these animals from not only developing diabetes, but as mentioned before, this is how these drugs were discovered, not only as insulin sensitizers, but enhancing endogenous insulin secretion in the animals.

It looks like this phenomenon is also happening in humans, as seen from the little bit of data from human trials. This is a subject of ongoing research right now.

The interest in diabetes is really on complications and especially cardiovascular disease. There is much more of a focus on insulin resistance.

What's happening here? What is the effect of the insulin level that is compensatory for insulin resistance and some of the effects of this metabolic syndrome? Why do we get the metabolic syndrome? This answer is not very clear, but we are certainly trying to put all the pieces together.

Patients who have this metabolic syndrome, clinically, they can be seen when they come into your office. It has been said you can see them walking down the hall. They have central obesity and acanthosis nigricans, which is a very common velvety hyperpigmented change in the skin, the neck, and the axillae. They have other risk factors, such as hypertension or changes in their lipids. Frequently, women with polycystic ovary (PCO) syndrome have insulin resistance. The other phenomena you will hear more about are some of these risk factors from Dr. Steve Haffner, and more about the vascular phenomenon in insulin resistance from Dr. Hsueh.

One of the areas that we are really unsure about is, how does this syndrome come about? We know that patients are hyperinsulinemic, and if there is a problem with glucose metabolism, the response of the pancreas to try to keep the glucose normal is to secrete more insulin. But I don't believe that insulin is atherogenic and patients need insulin. When you inject insulin, patients don't have more heart attacks. This was shown in the UKPDS as well.

We know that there are changes in signaling pathways. Just like the insulin resistance to glucose disposal, there are abnormalities in the vasculature. There are changes in lipid metabolism. This is one of the ways that you can have insulin resistance leading to cardiovascular changes. There also are pathways that remain sensitive to insulin, so that the high insulin level, although it may not be causing direct effects on atherosclerosis, it also has been implicated in acanthosis nigricans, which is benign, and ovarian androgen production in PCO syndrome, which is perhaps the best example.

When we approach patients in treating them for diabetes, it is very important to consider what the different treatments are doing. The different classes of drugs that are available include TZDs, metformin, secretagogues that increase insulin. However, these do not have any effect specifically on insulin resistance or the metabolic syndrome. Certainly alpha-glucosidase inhibitors do not affect these risk factors. Insulin itself, if it is replacing a need for insulin or it is also contributing to hyperinsulinemia, it is not really helping to reduce the amount of insulin that is circulating, and really does not have effects on insulin resistance. That is why there has been an increasing focus on the TZDs and metformin.

In the subset of overweight patients in the UKPDS, metformin was shown to have dramatic effects on cardiovascular endpoints, specifically, myocardial infarction was significantly reduced. It is these types of outcomes data that really support the use of metformin very strongly.

It is also important to keep in mind that metformin is different than TZDs. Sometimes they are both described as being insulin sensitizers; however, their mechanism of action is very different. Metformin primarily works on the liver, reducing endogenous glucose production.

As shown in this study by Silvio Inzucchi comparing metformin and troglitazone, the effect of the TZDs is on peripheral glucose disposal. These two effects can be matched up very nicely.

These data are taken from one of the rosiglitazone studies when rosiglitazone was added to the regimen of patients who were already on metformin. Metformin had a relatively minor effect on fatty acids; however, when rosiglitazone was added, a much more dramatic drop in fatty acids occurred, adding to the effect of metformin. This effect was sustained. These are data now out to 2 years. Together there are different mechanisms complementing each other and bringing down the fatty acid level, which is a major contributor to this whole syndrome.

There are many ways that the TZDs have been shown now to improve a lot of vascular effects that are the problems in patients with the metabolic syndrome as well as patients with type 2 diabetes. There are clinical trials looking at effects on beta-cells, like the ADOPT Study, hoping that this can show that there is a reduction in the progression of diabetes. Rosiglitazone is being compared to other monotherapies.

The effects of TZDs may be due to the protection of beta-cell function. Other cardiovascular effects have been demonstrated with TZDs, such as changes in lipids that are quite dramatic, the rise in HDL, improvement in LDL density, drop in triglycerides, blood pressure reduction, and, other vascular effects.

If you look at the different drugs and try to size them up for some of their effects, other than their glucose-lowering capacity, it is fair to say that there is very little hope that the sulfonylureas and alpha-glucosidase inhibitors will affect some of these important risk factors. With TZDs, however, the improvement in lipids, reduction in free fatty acids, and decreased insulin resistance are certain. Other risk factors that will be discussed include changes in the thrombolytic system, hypertension, and C-reactive protein (CRP). Metformin has some effects on these variables. TZDs tend to have somewhat more if you look at the available data. Together, you have a robust combination to help address this.

TZDs and metformin are really close to the top of the treatment list in the treatment scheme that we have been using for drug selection in these patients. Later, insulin can be added as needed. Many patients lose their beta-cell insulin secretion. Because metformin and TZDs do not work without an insulin supply, insulin is often needed in these patients. Even after you go to using insulin, we are frequently including the insulin sensitizer drugs in combination.

Just to summarize, we have long-term challenges in managing patients with type 2 diabetes, and with all this talk about cardiovascular disease, which is the focus of our discussion, to not lose sight of glycemic control in patients with diabetes. Research is now looking closer and earlier at patients at high risk for macrovascular disease, even before they get diabetes. Metabolic syndrome has been highlighted now and it is something that people are talking about, both in the cardiology area as well as with endocrinologists and diabetologists. This is where we need to focus our attention, remembering that it is a long-term process. If there is some way we can prevent this long-term deterioration, it will have to be accomplished over time.