Diabetes has reached virtually epidemic levels in the modern world. In 2005 the U.S. Centers for Disease Control and Prevention estimated that about 7 percent of the American population (20.9 million people) had diabetes - and 6.2 million of them were unaware of it. More than 1.5 million people over the age of 20 will be diagnosed with it in the U.S. this year. About 21 percent of those older than 60 have the disease.

Small wonder, then, given the severe complications associated with diabetes, that it continues to be the sixth leading cause of death in the U.S. And although diabetes was often called a “disease of affluence” in the past, it is now one of the fastest-rising health concerns in developing nations as well: the World Health Organization pegs the global total at more than 171 million cases.

An unfortunate catch-22 of diabetes is that although the right diet and exercise can help with its prevention and management, diabetes itself can complicate both eating and physical activity. Patients may need to pay extra attention to taking meals on a regular schedule and to monitoring how exercise dehydrates them or lowers their blood glucose. Some may fail to comply consistently with prescribed regimens that seem inconvenient or unpleasant, thereby raising their risk of complications. But thanks to leaps in science’s understanding of the disease, doctors now wield a diverse and growing arsenal of drugs and management technologies to fight the progression - and even onset - of illness. People with diabetes have more and better options than ever before for enjoying healthy, active, long lives.

Background
Diabetes is a disease in which too much of a sugar called glucose accumulates in the blood because of a breakdown in how the body makes or reacts to the hormone insulin. Insulin enables muscle, fat and other types of cells to take up and process glucose. If cells can’t burn or store glucose normally and the blood levels rise ­chronically, damage accumulates throughout the body - in the worst cases leading to blindness, amputation, kidney failure or death.

Most cases fall into one of two categories:
Type 1 diabetes (formerly known as juvenile diabetes) occurs when the body sabotages its own ability to produce insulin. A disorder of the patient’s immune system causes it to attack the insulin-making beta cells in the pancreas. Consequently, patients with type 1 diabetes need an artificial source of insulin. Although it is the most common form of diabetes in children, only 5 to 10 percent of all cases of diabetes in the U.S. are of this variety.

Type 2 diabetes, which has become increasingly prevalent during the past few decades, arises from “insulin resistance,” which causes cells, for poorly understood reasons, to stop responding properly to the hormone. At first, the pancreas can compensate by producing greater amounts of insulin. But over time, the pancreas reduces its production, making matters worse. Initially this type of diabetes may respond to diet, exercise and weight control, but later medications, and perhaps insulin, may be necessary depending on the severity of the case.

In addition, about 4 percent of all pregnant women develop gestational diabetes, a form that usually resolves itself after delivery. Diabetes can also be a rare consequence of certain genetic conditions or chemical exposures.

Symptoms, Risk Factors and Diagnosis
More than six million Americans have type 2 diabetes and don’t know it because its early symptoms can seem so harmless and vague:

 
•   Frequent urination
 
•   Extreme thirst and hunger
 
•   Irritability
 
•   Fatigue
 
•   Blurred vision

In contrast, type 1 diabetes comes on more quickly and with more prominent symptoms, such as unexplained rapid weight loss, dehydration or a severe illness called ketoacidosis. Medical science has still not yet determined precisely why some people develop diabetes and others do not - the genetic and environmental triggers for the disease are surprisingly complex.

For example, type 1 diabetes is not simply genetic in origin, because even the identical twin of someone with diabetes, who shares the same genes, will develop the condition no more than 50 percent of the time. Some as yet unidentified factor in the environment - perhaps a virus - must therefore trigger the immune systems of genetically susceptible people to attack the beta cells in their pancreas. Other environmental factors also seem to be involved: research finds that type 1 diabetes is less common among those who were breast-fed.

For type 2 diabetes, the genetic component is greater: it tends to run more obviously in families, and the identical twin of a person with diabetes will manifest the disease up to 75 percent of the time. Yet it is also very strongly linked to weight gain and insufficient exercise. As the American Diabetes Association (ADA) notes, “[A] family history of type 2 diabetes is one of the strongest risk factors for getting the disease, but it only seems to matter in people living a Western lifestyle.” In the U.S., type 2 diabetes is also more common among African-Americans, Latinos, Asians and Native Americans.

Two ways to diagnose diabetes definitively are testing a patient’s blood with either a fasting plasma glucose (FPG) test or an oral glucose tolerance test (OGTT). The FPG measures the concentration of glucose in the blood of a person who has been fasting for 12 hours; if it is above 125 milligrams per deciliter, the patient is diabetic. The OGTT measures the subject’s blood glucose level both after a fast and two hours after consuming a glucose-rich drink; diabetes is the diagnosis if the latter reading is above 200 milligrams per deciliter. (The ADA favors the FPG because it is less expensive, faster and easier for patients.)

Prevention and Prediabetes
People do not become diabetic overnight. Almost all of those who eventually acquire type 2 diabetes move first through a “predia­betes” state in which their blood glucose levels are elevated but not quite high enough to qualify as diabetes. (Predia­betes is also called impaired glucose ­tolerance and impaired fasting glucose, depending on the tests used to diagnose it.) Research suggests even those slightly less than diabetic blood glucose levels may do long-term damage to the body, and patients with prediabetes are at a 50 percent higher risk for heart disease and stroke. In a major clinical trial from 2002 called the Diabetes Prevention Program (DPP), roughly 11 percent of those with prediabetes became type 2 diabetics during the three years of the study.

The good news for the estimated 54 million Americans who have pre­diabetes is that many can prevent their conditions from progressing through moderate exercise and changes to diet. In fact, many of them might even be able to return their blood glucose levels to normal. The DPP found that patients who lowered their body weight by a mere 5 to 10 percent - typically just 10 to 15 pounds - through diet and moderate exercise reduced their risk of developing diabetes by 58 percent. These interventions were even more effective among patients older than 60: their risk fell by 71 percent. And it should go without saying that regular exercise and a healthy diet can help keep people from acquiring prediabetes, too.

Management and Treatment
The main goal in diabetes management is to constantly keep blood glucose levels as normal as possible. Clinical studies have shown that the rate of complications from the disease drops markedly when this standard is maintained over long periods.

But doing so is not just a matter of swallowing a pill or taking a shot. People with the condition need to steadily monitor their blood glucose levels or to anticipate changes in them and respond appropriately. To state the obvious: a sound program of diabetes management and treatment needs to be developed with a qualified health care team.

Monitoring blood glucose. All people with diabetes should periodically have a hemoglobin A1c test, which indicates the patient’s average blood glucose concentration over the preceding three months. This measurement is often the best way to see how well a treatment is going overall. Depending on his or her situation, a patient might also be monitoring daily blood glucose ­levels with a home blood tester. Typically this test involves pricking a finger (or palm or arm) with a trigger-style lancet, applying the drop of blood to a test strip and inserting it into a digital reader.

In a major technical advance, three companies have recently introduced continuous glucose-monitoring systems, which sample blood glucose levels many times over the course of the day with small radio-equipped sensors embedded under the skin [see “Monitoring: An End to Pricked Fingers,” below, and “Docs on Call,” below]. The systems can be programmed to sound an alarm if blood glucose goes too high or too low. Such units could eventually help revolutionize the treatment of type 1 diabetes in particular: linked to pumps for delivering insulin, they could be part of a “mechanical pancreas” that would both sense glucose in the blood and administer insulin accordingly.

Insulin. Until the 1920s, when type 1 was still the dominant form, a diagnosis of diabetes was virtually a death sentence. That all changed with the identification and isolation of insulin, which made it possible to treat the condition for the first time.

But making use of insulin began as a messy process. Running animal pancreases through a meat grinder to obtain insulin yielded a murky liquid with difficult-to-predict efficacy levels, which sometimes provoked allergic reactions. Because digestive enzymes destroy the insulin molecule, it cannot be taken orally: insulin had to be injected under the skin with a syringe. Moreover, delivering insulin in ways that most closely mimicked the body’s natural hormone action was a challenge.

Over the decades, however, every aspect of insulin therapy has improved:
Better insulins. Thanks to recombinant DNA technology, since 1982 the biotechnology industry has been able to mass-produce human insulin proteins by growing them in bacteria. Such insulin behaves more like the body’s own than animal proteins can and is less allergenic. All insulin sold in the U.S. is now of this human type.

Normally a pancreas releases small amounts of insulin into the circulation constantly, with bigger infusions at mealtimes. Most people who take insulin therefore use two types: a long-acting “basal” insulin administered once or twice a day and a rapid-acting “bolus” insulin before meals. In recent years, pharmaceutical companies have further reformulated the human insulins to create faster-, slower- and intermediate-working versions, with different durations of action, all in an attempt to re-create what the human body does.

Nicer needles. Insulin-dependent patients used to depend on large-bore needles that were relatively expensive and quickly went dull. Today’s syringes have extremely small gauge needles that can be surprisingly painless. Some insulins are packaged inside pen-shaped injectors, eliminating the need for drawing fluid out of a vial with a syringe. The pen contains many doses of insulin; new disposable needles are attached for each dosage. It makes injecting in public far more discreet.

Alternatives to injection. To most people, needle sticks are fundamentally unpleasant. So researchers have been trying to figure out easier ways to get insulin into the system. One step in that direction is the insulin pump, a pagerlike device that is worn continually and can be programmed to deliver both basal and bolus infusions through a catheter inserted under the skin. For some patients, this system is more discreet and effective than syringe injections can be. Still, pump supplies are more expensive, and care must be taken during exercise that the pump is not dislodged or damaged.

Another alternative is inhalable insulin. Pfizer introduced a version (Exubera) in 2006, but withdrew it from the market last fall, perhaps because of a somewhat unwieldy apparatus (the “insulin bong,” as some have dubbed it), the additional training required to use the device and lingering questions about long-term pulmonary effects. Other delivery methods are still under investigation, including a nasal spray, a self-contained implantable pump and a transdermal patch that uses electric current to move insulin across the skin barrier.

The ideal would be an effective oral version of insulin that could avoid destruction in the digestive tract. A number of companies are working on developing oral insulins, and Generex Biotechnology has an oral insulin spray approved for sale in Ecuador; however, similar products may be years away from proving safe and effective enough to satisfy the U.S. Food and Drug Administration.

Other Medications
Most people with diabetes do not need to take insulin, because their bodies still make some. Instead they take medications that can help them produce more insulin or use it better. Until recently, these oral meds fell into five categories: alpha glucosidase inhibitors (Precose, Glycet), metformin, meglitinides (Starlix, Prandin), sulfonylureas, and thiazolidinediones (Avandia and Actos, which have been in the headlines because of persistent concerns over their cardiovascular effects). A newer class is the DPP-4 inhibitors (Januvia is the only drug of this type available so far), which help to maintain levels of GLP-1, an intestinal hormone that promotes insulin production.

Excitement also surrounds two other new classes of drugs: incretin mimetic agents (Byetta, derived from the saliva of the Gila monster, is the only one currently on the market) and amylin analogues (Symlin is the first to be approved). Incretins are hormones that the digestive tract releases in response to carbohydrates and fats and that tell the pancreas to secrete extra insulin. Amylin is another hormone produced by the pancreas, and it helps to depress blood glucose.

Like insulin, both incretin mimetics and amylin analogues must be injected. They both have a beneficial side effect, however: they slow the emptying of the stomach. As a result, people feel full sooner, eat less and often lose weight on these drugs, which in itself can improve their diabetes.

Extreme Techniques
For some patients, dramatic measures may be called for. Gastric bypass or reduction surgery, which shrinks the space in the stomach for food, can sometimes almost eliminate type 2 diabetes in morbidly obese patients (the surgery carries its own risks, however). For a few people with type 1 diabetes, one option might be a pancreas transplant, to replace the insulin-making beta cells they have lost. But this surgery, too, can be hazardous, and few pancreases are available for transplantation. Moreover, to prevent the patient’s immune system from rejecting the new pancreas, he or she would need to take immunosuppressive drugs for life, which can also be dangerous.

A potentially safer (and less expensive) choice could someday be the experimental procedure of transplanting just the pancreatic islet clusters that contain the beta cells. Such implants would involve less trauma than replacing an entire pancreas, and it might be possible to encase the grafted cells in packaging that would protect them from the immune system. Researchers are also working on using highly versatile stem cells, which can give rise to new tissues, to replace lost beta cells. The early results are guardedly positive, but it will be years, if ever, before such a technique becomes widely available.

By Sara Sklaroff and John Rennie
Contributors to this special report include Sara Sklaroff, a science writer and editorial director for the American Diabetes Association magazine Diabetes Forecast; Justin Ewers, a science writer based in San Francisco; and John Rennie, editor in chief of Scientific American.