We are bombarded with information that reinforces the idea that there has been an enormous increase in the frequency, prevalence, and incidence of type 2 diabetes over the last 10 to 15 years. This parallels an increase in obesity in the country. In 1994, in the majority of states in the country, less than 4% of the people had diabetes. Only in a few states did more than 6% of the population have diabetes, and a relatively low percentage of people were obese by body mass index (BMI) standards (BMI ≥ 30 kg/m²).

If you fast-forward to 2004, only 10 years later, prevalence of diabetes is greater than 6% in the majority of states, and a number of those states have a 25% incidence of obesity.

Note that no state has the same prevalence of diabetes and obesity as it did in 1994. Multiple factors contribute to the increase (ie, people are living longer and diabetes is a condition of aging; more people belong to ethnic subgroups that have a high incidence of diabetes; we have changed the diagnostic criteria for diabetes), but clearly, obesity is the major issue.

When we talk about the kind of obesity that leads to diabetes, insulin resistance, and vascular inflammation, we are talking about visceral adiposity, which refers not to subcutaneous fat around the waist but rather to fat deep within the abdomen, in the abdominal organs such as the liver and the omentum.

We used to think that fat was simply a repository for extra calories, but now we know that there is a very rich organic life to adipose tissue, which is the source, in many people's opinions, of the whole problem of insulin resistance and vascular inflammation. Many chemical factors (cytokines or adipocytokines) are released from fat cells and the macrophages that are embedded within the adipose tissue, which either directly affect inflammation or lead to other processes; in other words, they initiate other processes that will lead to insulin resistance and inflammation.

A very large number of people who have diabetes are overweight or obese. The National Health Interview Survey, an epidemiologic study, looked at over 30,000 people with newly diagnosed diabetes; 30% had BMIs 25 to 30 kg/m² (overweight category) and 60% had BMIs over 30 kg/m² (obese category). This is a well-documented problem.

Another very important issue is the broadening of the metabolic, insulin-resistant, dysglycemic syndrome. We have broadened the categories of dysglycemia, and I think it is a good idea to review them.

Normal fasting plasma glucose is less than 100 mg/dL; in a 2-hour glucose tolerance test, the 2-hour value should be less than 140 mg/dL. We diagnose diabetes if either the fasting blood glucose is above 126 mg/dL on two occasions, or the 2-hour glucose tolerance test is above 200 mg/dL.

Between normal plasma glucose and diabetes are the categories of impaired fasting glucose and impaired glucose tolerance: people whose fasting plasma glucose is between 100 and 126 mg/dL, or whose 2-hour glucose tolerance test is between 140 and 200 mg/dL. These categories have assumed quite a bit of importance because with impaired glucose tolerance, which is synonymous with what we call prediabetes, there is a 40-fold likelihood of developing type 2 diabetes, and a substantial amount of cardiovascular risk is associated with this relatively early state of dysglycemia.

The problem, framed in numbers, is that as of 2005, about 1 of every 10 adults in the United States had type 2 diabetes (about 20 million people), and about a third of those people are undiagnosed and do not know they have diabetes. Approximately 25% of US adults have impaired glucose tolerance. If we consider the whole spectrum of insulin resistance, about 1 out of every 3 adults has either diabetes or prediabetes—an estimated figure of about 70 million people. This is a large number, but the projections are that this number is going to further increase by 50% to 60% over the next 15 to 20 years.

As noted, there is a substantial relationship among impaired glucose tolerance, diabetes, and cardiovascular disease. A 2006 study looked at 180 consecutive patients admitted to a critical-care unit with their first myocardial infarction.

Individuals who were not known to have diabetes were administered glucose tolerance tests. Of the people who said they did not have diabetes, about a third really did; they were undiagnosed patients with diabetes. Another third had prediabetes. So almost 70% of the patients who were admitted with their first myocardial infarction had either prediabetes or diabetes.

In addition, other studies have shown that impaired glucose tolerance increases the mortality rate in the population. This slide looks at the mortality hazard over a 10-year period in about 25,000 people in different categories of glucose tolerance, normal being on the bottom with the least mortality. The worst mortality hazard is in those individuals who have diagnosed diabetes. Between those two categories are the people with impaired glucose tolerance, and their mortality hazard is also substantially increased. Remember, impaired glucose tolerance, by definition, is a condition that defines people by postprandial elevations of glucose. We are going to be discussing the issues related to postprandial hyperglycemia.

This slide shows another study of 15,000 to 20,000 patients followed over 3 decades. Patients were stratified by their 2-hour oral glucose tolerance test blood glucose level, and that was correlated to their coronary heart disease mortality.

The higher the 2-hour post-glucose value, the more likely patients were to die from coronary heart disease. But notice where the line starts to rapidly increase: at a 2-hour value of 83 mg/dL, which would be considered normal. In an epidemiologic sense, however, the point is that the risk of coronary heart disease mortality increases very early in the natural history of dysglycemia.

Let's examine the natural history of type 2 diabetes in a schematic way, because we are going to have to address these issues earlier in the course of the disease. We are going to have to be more aggressive, which means earlier intervention, earlier identification of patients, and establishing treatment targets and trying to achieve those targets. It is not enough just to treat a patient; we have to treat to some predefined target if we are to be successful.

The first thing to appear in the natural history of type 2 diabetes is insulin resistance, which goes up. It is either near or at a maximum by the time we make a diagnosis of type 2 diabetes, and it stays at that high level unless we intervene. The take-home message is that whenever we treat patients with type 2 diabetes, we have to assume that they have insulin resistance, and some component of our strategic plan must address that insulin resistance.

A patient who has insulin resistance will make more insulin. And if you can make an unlimited amount of insulin, you will keep your blood glucose at normal levels; you will have high insulin levels, but you will have normal blood glucose levels.

If you are in the 25% of people who cannot generate an unlimited supply of insulin, your insulin levels will decrease as beta cells die. Blood glucose levels will go up, and we will establish a diagnosis of diabetes. But it can be late in the course of the overall disease when complications are either overtly present or detectable by currently available testing procedures (microalbumin testing, cardiovascular evaluations) that this diagnosis is made. We need to move all of our timelines to the left, which is one of our major messages.

Insulin resistance is associated not only with abnormalities of blood glucose, but also with a number of other macrovascular risk factors such as high blood pressure and dyslipidemia, which are part of the metabolic or insulin resistance syndrome. We need a strategy that reduces insulin resistance; we could raise insulin levels, theoretically, by giving an insulin secretagogue or insulin itself. But if we have not lowered the insulin resistance, we may not have a complete program.

The insulin resistance syndrome is very important from a cardiovascular point of view. You can see by these data, whether you have normal glucose tolerance, prediabetes (impaired glucose tolerance or impaired fasting glucose), or diabetes, the presence of the cluster of risk factors known as the metabolic syndrome (including hypertension, dyslipidemia of insulin resistance, and central or visceral obesity), as well as blood glucose abnormalities, increases the likelihood of having coronary heart disease by at least a factor of 2.

If insulin resistance is present so early and it is associated with risk of cardiovascular disease, the question is whether people are experiencing coronary artery disease before they develop diabetes. This study examined that question and led to the concept referred to as the "ticking clock" hypothesis.

These are data from the Nurses' Health Study. Over 100,000 women were followed for over 20 years for a variety of reasons; in this particular situation, they analyzed those who went on to develop diabetes. They went back to the patients' histories to determine the incidence of major cardiovascular events (myocardial infarction or stroke) before diabetes developed. They found that before diagnosis, there still was a 3-fold increase in myocardial infarctions or strokes. So these people who had not yet, but would, develop diabetes were having strokes and heart attacks. This is a very strong message for earlier intervention. We have to reshape our concepts of how we diagnose patients who are in this metabolic state, and how we treat them.

The Etiology of Type 2 Diabetes: Glucose and Insulin Responses Over the Course of the Disease

Overall, we have a huge pool of people with insulin resistance, 70 to 80 million or more. This also includes individuals who have insulin resistance and do not have any glucose abnormalities yet. They have insulin resistance partially because of genetic predisposition, represented by the double helix. And they have acquired additional insulin resistance from sedentary lifestyles and obesity, represented by the burger and fries—Western living at its best and worst.

With unlimited amounts of insulin, blood glucose levels will remain normal, while other elements of the metabolic syndrome may be present. If you are in the 25% who cannot produce enough insulin, you will become a patient who has type 2 diabetes as part of the metabolic syndrome.

If insulin resistance is at a maximum at the beginning, the defining factor for blood glucose may well be beta-cell function. A number of factors can put pressure on the beta cell. One is hyperglycemia itself; the higher your blood glucose, the more glucose toxicity, meaning that when glucose levels are high, the beta cells do not work as well and there is more insulin resistance. When glucose is lowered by any means, there will be some improvement in both of those pathophysiologic factors.

Another factor is lipotoxicity; patients with type 2 diabetes insulin resistance have, as a rule, low high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels. Some of the free fatty acids that will be stored as triglycerides are released from the visceral adipose bed, ending up in the beta cell where they interfere with its structure and function.

We now think that the beta cell itself may be an insulin-sensitive cell; it is a victim of insulin resistance as well, and strategies that reduce insulin resistance will also improve beta-cell function.

We know from studies, such as the United Kingdom Prospective Diabetes Study (UKPDS), that at the time of diagnosis of type 2 diabetes in the average patient, roughly 50% of beta-cell function has been lost. Even when patients are treated with a variety of strategies, they continue to lose beta-cell function. This is another reason for entering early, when we can try new strategies that may preserve beta-cell function. This information has also been used to extrapolate backwards and estimate that the average patient who has type 2 diabetes has had it for approximately 10 years before we diagnose it. That, to me, is an opportunity window for treating patients much earlier in their natural history.

These are data from people with normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes, looking at their glucose and insulin levels.

For people with normal glucose tolerance, the glucose levels are the lowest and the insulin levels the highest after a glucose challenge. If we move along the timeline, people who have prediabetes have rising glucose levels, particularly post-challenge, the equivalent of the postprandial blood glucose. The insulin levels are beginning to slip a little bit. For people who have frank diabetes, we see elevated fasting and postprandial blood glucose, and a clear decrease in insulin production. Their beta cells are dying and as they are dying, the blood glucose is rising.

This is a study in which the first data point after zero is 30 minutes. Let's drill down and see what is happening even earlier.

I would focus on the left side of this graphic, looking at what is going on within the first few minutes after a glucose challenge.

There is a rapid spike of insulin when you administer glucose to a normal individual. But as they move through this natural history of dysglycemia, the first thing lost is this first-phase or acute insulin response.

Something else is also going on in the pancreatic islet cells. There are other cells besides beta cells, and one of them is the alpha cell, which produces glucagon. There is significant alpha-cell dysfunction in people with type 2 diabetes; their alpha cells are putting out more than an average amount of glucagon.

The deficiency of insulin and the increase in glucagon is now going to be manifested in the liver and stimulate glycogenolysis and gluconeogenesis, contributing to elevated blood glucose. Because there is less insulin and less insulin action because of the insulin resistance, the glucose is not being taken up in muscle and fatty tissue, and this, too, is part of the genesis of hyperglycemia.

The glucagon part of this is important, which is something we do not always talk about. In this particular study, the investigators used somatostatin and insulin to induce selective glucagon deficiency; it suppressed the alpha cells.

What is being measured here is hepatic glucose output. Increased hepatic glucose production is a major contributor to hyperglycemia, particularly fasting hyperglycemia, and when there was a reduction in the production of glucagon, there was a 75% decrease in hepatic glucose production. Therapeutic strategies able to suppress abnormal production of glucagon are important.

This is another argument for earlier and aggressive treatment. This slide outlines the relative contributions of postprandial and fasting elevations of blood glucose to mean blood glucose, which is correlated to A1C level.

The longer your diabetes persists, the more the contribution of fasting blood glucose, the less the contribution of postprandial blood glucose. So if we treat early, we have a better chance of being able to attack both of these abnormalities. And again, this is presumed to be a reflection of the death of beta cells.

In terms of A1C, the factors that tend to predominantly influence fasting glucose include more overnight hepatic glucose production, which in turn is, at least in part, a reflection of the liver sensitivity to insulin, and the amount of glucagon that is circulating. Postprandial glucose is going to be influenced by preprandial glucose (the higher it is before you eat, the higher it is going to be after you eat); how much insulin secretion you can mount, both in the first phase and the second phase of meeting your postprandial challenge; how much you ate; and how well your tissues respond to insulin—not just whether you make insulin but how effective it is at the tissue level. That is insulin resistance.

Therapeutic Options: The Evolving Treatment Paradigm

There are therapeutic agents that primarily target insulin resistance, those that target postprandial glucose, and many agents that attack both.

I mentioned that cardiovascular disease is the ultimate target. So we have to consider not only blood glucose when treating patients with type 2 diabetes, but also all the risk factors that these individuals are going to have. Let's set up some of the guidelines.

The minimum A1C target for blood glucose control is less than 7%. The American Diabetes Association goal is less than 7% and the American College of Endocrinology goal is less than 6.5%. But normal is the goal if you can attain it without exposing patients to undue risks of hypoglycemia.

The blood pressure target is 130/80 mm Hg, perhaps lower, particularly in patients with renal disease. In terms of lipids, even though the classic lipid abnormality of insulin resistance or diabetes is high triglycerides and low HDL-C, the primary target of lipid treatment is low-density lipoprotein cholesterol (LDL-C), because we know that statins do such a good job in this respect.

The LDL-C target is less than 100 mg/dL, and many would argue it should be less than 70 mg/dL; that is a secondary prevention goal for people who have had heart attacks without diabetes. Many people believe that if you have diabetes the risk of having a heart attack, even if you have never had one, is the same as that of someone who had a heart attack who does not have diabetes. Thus, every patient with type 2 diabetes is a secondary prevention patient, and therefore, 70 mg/dL should be the appropriate target.

How do we accomplish this? For blood pressure, we are usually going to have to use two or three agents. But the first drugs that we should be using are drugs that affect the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors primarily or angiotensin receptor blockers, particularly in people who cannot, for one reason or another, take ACE inhibitors. Statins are the gold standard for treatment of lipids in patients with type 2 diabetes, regardless of what their LDL-C level is to start.

One of the concepts of treating type 2 diabetes patients is that statins are good for reducing heart disease whether those patients have elevated LDL-C levels or not. Likewise, ACE inhibitors are good for reducing cardiovascular disease in patients with type 2 diabetes whether they have hypertension or not, because they do good things for the blood vessels and improve endothelial function.

In addition, we want to get patients on some dose of aspirin. If they cannot take aspirin, then we need some other type of antiplatelet strategy. We would also like patients to stop smoking.

To summarize, we want to get the LDL-C at least down to less than 100 mg/dL. The secondary targets are to raise HDL-C (>40 mg/dL in men; >50 mg/dL in women) and lower triglycerides (<150 mg/dL). But you need to focus on the LDL-C, the primary target, because so many studies have looked at the ability of statins to lower coronary heart disease events; there are over a dozen good studies with any number of statins that have proven this point. These studies have also shown that the lower the LDL-C, the more the protection.

Most of the classic statin studies excluded people with diabetes. However, some were included in the subgroups of big studies such as the Scandinavian Simvastatin Survival Study (4S study) or the Cholesterol and Recurrent Events (CARE) study. Subanalyses for patients with diabetes show as good, if not better, protection than for the group as a whole.

In the 4S study, there was a subgroup of patients with fasting glucose levels between 110 and 125 mg/dL, ie, a group with prediabetes, and you can see what dramatic reductions statins conferred in cardiovascular events. These kinds of data form platforms for more aggressive intervention in these groups.

In terms of blood pressure, ACE inhibitors have a number of beneficial cardiovascular effects. There are cardioprotective effects from a mechanical point of view, in terms of preload and after-load reduction, reducing left ventricular hypertrophy. There are also a number of beneficial endothelial effects, and everything listed here relates to endothelial function. This is why ACE inhibitors are at the top of the list for treating hypertension in people with type 2 diabetes.

These are some of the data from the Heart Outcomes Prevention Evaluation (HOPE) study, which used ramipril, and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), a similar study using perindopril. These studies were interesting because the patients were already getting pretty good therapy to reduce cardiovascular events. They still got a 20% additional reduction by using an ACE inhibitor. In these studies, perhaps only half of the patients had hypertension to begin with, but the benefit, because of the endothelial functional improvement, was every bit as good whether patients had hypertension or not.

I mentioned the antiplatelet strategies. The Antiplatelet Trialists' Collaboration and several other studies have shown a modest but significant benefit of aspirin. The dose is arguable as to whether it should be low-dose aspirin, medium-dose aspirin, or full-strength aspirin. That is not settled yet, but certainly at least 81 mg of aspirin should be used unless a patient cannot take aspirin, in which case other antiplatelet drugs should be used.

The ultimate target is the endothelium, the vessel wall. We have multiple agents in each category to be able to address the elements of the insulin resistance/metabolic syndrome.

We are going to focus on diabetes issues. A number of different agents exist as oral therapy choices for type 2 diabetes. We have agents that work at the intestinal level to inhibit carbohydrate breakdown. These are the alpha-glucosidase inhibitors, which have a modest glycemic effect and a fairly robust gastrointestinal side-effect profile. They tend to be lower on the hierarchy of drugs being used to treat type 2 diabetes.

We have drugs that work at the pancreatic level—insulin secretagogues or the incretins—that can affect islet cells in general, but beta cells in particular, to stimulate insulin release.

Metformin is very good at reducing overnight hepatic glucose uptake. Thiazolidinediones (TZDs) work at multiple levels to enhance insulin sensitivity in muscle, where 80% of glucose is taken up, and also in the fat cell. Two TZDs are available to use, rosiglitazone and pioglitazone.

Although we have all of these therapies that work to one degree or another, we are still faced with beta-cell failure. These are data from the UKPDS, which looked at newly diagnosed type 2 diabetes patients given a variety of treatments: conventional therapy, insulin, metformin, and 2 different sulfonylureas, chlorpropamide and glyburide.

Initially, all of the active treatment arms tended to work. There is a reduction in A1C at the beginning of the trial, but over a period of years that initial benefit decayed, primarily due to progressive loss of beta-cell function over time. Glycemic control deteriorated because beta-cell function deteriorated or diminished.

In our overall paradigm for treating type 2 diabetes, as always we emphasize improved compliance with diet and exercise. Yet, that is very often not enough.

We have oral monotherapy, which, in the past, we tended to take to its maximum before moving on to combination therapy. Many people eventually ended up on insulin. More recently, we had the introduction of the incretins, the glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which has added an additional step that could forestall the movement toward insulin usage.

We are starting to try to diagnose a little earlier, trying to start therapy—monotherapy and particularly combination therapy—earlier so that everything in the paradigm is beginning to move to the left.

Defining the Incretin Effect

In terms of incretins, the word comes from the acronym, INtestinal seCRETion of INsulin. They are gut-derived factors that increase insulin secretion.

Schematically, in normal islet cells we all have some alpha cells, which make glucagon, and beta cells, which make insulin. We do not have amyloid plaques. But if you have type 2 diabetes, you do have some amyloid plaques and you have fewer beta cells—not just less beta-cell function but fewer beta cells. In addition, on a functional level, alpha cells dysfunction and secrete too much glucagon.

In the fasting state, if nothing happened to prevent it, blood glucose would start to go down. The normal physiology of the fasting state is to secrete some glucagon and keep hepatic glucose output high enough to keep blood glucose from falling into the hypoglycemic range. Insulin levels then fall to a basal level. As a result, blood glucose tends to stay up.

In the fed state, the glucagon effect is dampened and the insulin effect is amplified so that blood glucose is reduced. This is normal physiology.

If you have type 2 diabetes, you have too much alpha-cell function, meaning too much glucagon moving glucose out of the liver, and you do not have enough insulin activity to stimulate uptake of glucose in muscle and adipose tissue. Keep that in mind when you think about what the incretins are going to do.

The incretin effect is simply this: if you give somebody oral glucose, you will get a rise in glucose and a nice increase in insulin levels.

In a laboratory, you could recreate this glucose profile intravenously. If you were to program an infusion to get exactly the same blood glucose, you would see the same glucose levels. However, with the intravenous infusion you would get much less insulin than if you created this blood glucose level orally. That difference between oral and intravenous administration of glucose nutrient is the incretin effect.

In a more quantitative sense, this shows the beta-cell effect in terms of absolute insulin response and relative insulin responses. You can see that the incretin effect predominates. Incretin hormones account for most of the insulin production.

So the incretin hormones are released by the gut in response to incoming nutrients. The one that has clinical relevance at this point is glucagon-like peptide-1 (GLP-1), because there are therapies focused on GLP-1.

Incretin Therapy in Type 2 Diabetes

GLP-1 is elaborated by the intestinal cells, secreted with the ingestion of food. In some animals, just looking at food stimulates GLP-1 production.

What does GLP-1 do? When acting at the islet cell, GLP-1 enhances insulin secretion from the beta cells and dampens glucagon secretion to keep blood glucose in line. Because glucagon secretion is lower, the liver releases less glucose.

In the stomach, GLP-1 slows gastric emptying. Food stays in the stomach and produces a greater sense of satiety, which may contribute to better weight and appetite control. There are even some central nervous system receptors for GLP-1 that may have an effect on appetite and satiety.

Overall metabolism is as follows. We release GLP-1 in response to a mixed meal. A minority of it will get cleared in the urine, but the majority, 80%, is going to be inactivated within a couple of minutes by the enzyme dipeptidyl peptidase-4 (DPP-4).

In type 2 diabetes, GLP-1 production is impaired. In this graph measuring GLP-1 production, the top line represents subjects with normal glucose tolerance, patients with diabetes are at the bottom, and prediabetic patients are in the middle. What the graph shows is a stepwise reduction in the ability to elaborate GLP-1.

GLP-1 has a number of effects on the beta cell, including insulin secretion and insulin synthesis. Experiments that look at islet-cell integrity and apoptosis suggest that GLP-1 may also preserve some beta-cell mass.

Apoptosis is a term that refers to the programmed death of cells, in this case, the islet cells. Shown here is the difference between the control and the GLP-1-treated islet cells. Even after several days, there is much less dissolution of cell tissue in the GLP-1-treated islet cells.

This graph shows that same experiment quantitatively. When GLP-1 is given, there is less death of beta cells.

Another interesting thing about GLP-1 is that it reduces glucose. But when the glucose falls into the normal range, the insulin that you stimulated will not be stimulated any more; the insulin response will be shut off. Likewise, the reduction in glucagon will also cease.

In other words, built-in feedback stops the GLP-1 effect, which prevents you from getting hypoglycemic.

Clinically, that means when you use GLP-1 analogs or a DPP-4 inhibitor, you are not going to see hypoglycemia because internally the effect will be dampened; it will shut off.

In terms of drugs, you have to use a GLP-1 analog because GLP-1 itself will be dissipated in 1 to 2 minutes. Or, you could use an agent that inhibits the degradation of GLP-1 by inhibiting the DPP-4 enzyme.

The analog we have available resembles a substance in Gila monster saliva. That drug is exenatide. It is more resistant to degradation than GLP-1 and can last for 10 to 12 hours.

Exenatide can improve first-phase insulin response. This slide shows that when you use GLP-1 in patients with diabetes, you get a restoration of the first-phase insulin response.

Exenatide and GLP-1 are very similar to each other in all of these aspects: insulin secretion, hepatic glucose uptake, etc. The only difference is that exenatide is resistant to degradation, so it lasts longer.

Another way of increasing GLP-1 action is to use something that will block the DPP-4 enzyme. We only have one of those—sitagliptin—to use orally so far.

This is a comparison of DPP-4 inhibitors and GLP-1 analogs. One is oral, one is only available by injection, and because the GLP-1 analogs have higher levels of GLP-1, they also may have a higher incidence of side effects.

There is some evidence that oral DPP-4 inhibitors have some beta-cell-preserving effect. Comparing islets from diabetic mice with those from nondiabetic mice and diabetic mice treated with sitagliptin, you can see that the sitagliptin-treated mice look more like the nondiabetic mice.

Let me conclude by showing an algorithm for treating diabetes from the American Diabetes Association that will be discussed in the next section.