What is type 2 diabetes?
Diabetes is a group of diseases that impair the body’s ability to regulate blood glucose and convert it to energy. Type 2 diabetes, the most common form, usually begins as insulin resistance, a disorder in which fat, muscle, and liver cells do not use insulin properly. At first, the pancreas compensates by producing more insulin to meet the body’s needs. Gradually, its capacity to secrete insulin in response to meals falters as does the timing of insulin secretion. When diabetes develops, insulin production continues to decline. Many people with type 2 diabetes can control their blood glucose by following a careful diet and exercise program, losing weight, and taking oral medication. About 30 percent of patients eventually need insulin, either alone or combined with oral drugs, to control their blood glucose.

How common is type 2 diabetes?
In the United States, about 18.2 million people have diabetes. Type 2 diabetes is the most common form of diabetes, accounting for up to 95 percent of diabetes cases. Currently, we have no national data on the prevalence of type 2 diabetes in youth. However, studies from clinics across the country have found that this form of diabetes, once seen only in adults, has risen dramatically in young people. In 1994, type 2 diabetes accounted for less than 5 percent of new childhood diabetes cases. By 1999, however, type 2 diabetes was accounting for 8 to 45 percent of new childhood diabetes cases. Today, some clinics are seeing more new cases of type 2 diabetes in children than type 1, an autoimmune disease that tends to affect children.

To determine diabetes prevalence in children and to help clarify trends in disease development, the Centers for Disease Control and Prevention (CDC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the National Institutes of Health, are sponsoring a study called SEARCH, which will identify all cases of diabetes in children in six regions of the United States: Hawaii; Seattle, WA; southern California; Colorado/Arizona; South Carolina; and Cincinnati, OH.

What are the risk factors for type 2 diabetes in youth?
Type 2 diabetes is increasingly affecting younger people of all ethnic groups. However, most youth who develop type 2 diabetes are overweight, have a family history of diabetes, and are of African American, Hispanic/Latino American, or American Indian descent. Researchers have noted that type 2 diabetes in youth is usually diagnosed in adolescents in mid to late puberty. However, as children become more overweight, diabetes may begin earlier. About 15 percent of U.S. children and adolescents ages 6 to 19 years are overweight, according to the National Health and Nutrition Survey (NHANES) taken from 1999 to 2000. This is 4 percent more than the overweight estimate of 11 percent from the NHANES survey taken from 1988 to 1994. For more information about obesity trends, see CDC’s fact sheet on overweight and obesity.

What are the symptoms of type 2 diabetes in youth?
Some people—adults as well as children—don’t have symptoms. Those with symptoms may have fatigue, nausea, frequent urination, unusual thirst, weight loss, blurred vision, frequent infections, and slow healing of wounds or sores.

A condition called acanthosis nigricans—dark, velvety patches in the skin folds of the neck, groin, or armpits—is also common in children and teens with type 2 diabetes. Polycystic ovarian syndrome (PCOS) may affect girls and women who have insulin resistance or type 2 diabetes. PCOS is marked by infertility with irregular or absent menstrual periods, increased facial or body hair, and high levels of androgen, a male hormone.

How do doctors diagnose type 2 diabetes in youth?
Most children with type 2 diabetes are overweight with a family history of type 2 diabetes. Most are also going through puberty, which spurs the secretion of growth hormone and worsens insulin resistance. In some children who already have insulin resistance, the added stress on pancreatic beta cells causes the development of diabetes. The child’s weight and symptoms, physical exam, family history, and the results of standard diabetes tests such as the fasting blood glucose or the oral glucose tolerance tests may be enough to guide a doctor in making the diagnosis. If there is doubt, several tests help distinguish type 2 diabetes from type 1, such as fasting insulin, C-peptide, and autoantibody tests.

Why is the TODAY trial important?
The longer a person has type 2 diabetes, the greater the chances of developing its painful, debilitating, and even fatal complications. In time, high blood glucose levels as well as high blood pressure and lipid changes—conditions that tend to accompany type 2 diabetes—damage cells, tissues, and organs. Often the result is vision loss, nerve problems, kidney failure, and blood vessel damage leading to heart attack, stroke, and limb amputation. Doctors are already seeing diabetic complications in some teenage patients with type 2 diabetes.

Yet little is known about how best to treat type 2 diabetes in youth. Most children with type 2 diabetes are treated with either metformin or insulin, the only approved therapies for type 2 diabetes in youth. However, experience with adult patients shows that in time glucose control becomes harder and harder to achieve with single medications alone.

In the TODAY study, participants will be randomly assigned to one of three treatment groups: metformin alone; metformin plus rosiglitazone; or metformin plus intensive lifestyle changes aimed at losing weight and increasing physical activity. Researchers plan to enroll 750 children and teens ages 10 to 17 within 2 years of a diagnosis of type 2 diabetes. The trial is taking place at 12 medical centers and affiliated sites across the country.

The goal of treatment is to bring blood glucose levels into the normal range and to see how long each therapy yields good glucose control. TODAY is the first study to examine the potential benefits of weight loss through lifestyle change in youths with type 2 diabetes. The study will also determine whether the combination of oral medications (metformin and rosiglitazone) more effectively controls blood glucose than treatment with metformin alone.

What is known about the safety and efficacy of metformin and rosiglitazone?
Metformin is an oral drug that has been used to treat type 2 diabetes for about 40 years. In 2001 it was approved by the Food and Drug Administration (FDA) to treat type 2 diabetes in children. The drug improves glucose control by increasing insulin sensitivity in the liver and lowering glucose production by the liver. It usually keeps blood glucose levels in a safe range without promoting weight gain.

The most common side effects of metformin are nausea, loss of appetite, diarrhea, gas, and a metallic taste. These may affect up to 15 to 30 percent of people but usually subside in time. Lactic acidosis, a rare but potentially serious side effect, is more likely to occur in people who have heart, kidney, or liver failure, which are rarely seen in children with diabetes. Metformin should be stopped if the patient develops an illness that causes vomiting or diarrhea or any condition that leads to dehydration. It should also be stopped before a patient undergoes medical tests requiring a dye (contrast agent).

Rosiglitazone belongs to a class of drugs called the thiazolidinediones (TZDs), which improve insulin sensitivity in fat, muscle, and liver tissue. By reducing insulin resistance, the drug addresses one of the key metabolic abnormalities of type 2 diabetes. Some studies suggest that the TZDs also preserve insulin secretion by the pancreas, though this benefit has not been definitively shown yet.

FDA has approved rosiglitazone and the combination of rosiglitazone and metformin to treat type 2 diabetes in adults. A clinical trial, currently under way to determine the safety and efficacy of rosiglitazone in youth, has found no evidence of liver problems or other concerns about the safety of this drug in young people. The most common side effects of rosiglitazone are anemia, weight gain, and fluid retention in the ankles. Congestive heart failure is a rare side effect seen in older patients with heart and kidney problems.

Some participants will be randomly assigned to a group taking metformin and making lifestyle changes. What are the lifestyle changes?
Participants in this group are given a family-oriented, comprehensive weight management program to help them lose 7 to 10 percent of their body weight. The program will focus on improving nutrition, increasing physical activity, and encouraging healthy changes in behavior relating to diet and physical activity. For example, the program will guide participants to lower calories in their diet by decreasing intake of high-calorie foods low in nutritional value.

Will participants be given support in managing their diabetes?
All patients screened for participation in the study will receive standard diabetes education that provides the participant and their parent(s) or guardian(s) with information about type 2 diabetes and the skills and behaviors needed to manage diabetes successfully. In addition, they will receive diabetes supplies and medications free of charge as well as diabetes care from a team of doctors, nurses, nutritionists, and diabetes educators who have expertise in diabetes treatment.

What medical tests will a trial participant receive?
At screening, participants will be given blood tests that help confirm the diagnosis of type 2 diabetes. Throughout the trial, they will receive physical exams, including blood pressure monitoring and blood tests to determine cholesterol and blood glucose levels. The hemoglobin A1c (HbA1c) test, for example, reflects average blood sugar over 2 to 3 months.

How does a youth with type 2 diabetes enroll in the TODAY trial?
To qualify to participate, the young person must

• be 10-17 years old
• have type 2 diabetes diagnosed no more than 2 years before enrollment in the trial
• be overweight or at risk for overweight, based on height and weight
• have a family member or adult who is closely involved in the child’s daily activities and who agrees to participate in the child’s treatment.