WASHINGTON — A preliminary look at the children referred for participation in a large treatment trial of type 2 diabetes in overweight and obese youth shows that the children not only have a high prevalence of hypertension and dyslipidemia, but a high incidence of autoantibody positivity as well, investigators reported at the annual scientific sessions of the American Diabetes Association.
The findings add to those of other studies suggesting that a significant number of children with apparent type 2 diabetes mellitus also may have diabetes autoimmunity consistent with type 1 diabetes, reported Dr. Georgeanna J. Klingensmith, director of pediatric clinics at the Barbara Davis Center for Childhood Diabetes in Aurora, Colo.
Approximately 18% of the 535 children screened for inclusion thus far in the 15-center, National Institutes of Health-sponsored Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study were found to be positive for diabetes autoimmunity. The children, who were racially and ethnically diverse, were considered by their pediatric endocrinologists to have type 2 diabetes.
The number of youth with diabetes autoimmunity in conjunction with characteristics of type 2 diabetes is likely much higher, however, because some potential study participants were locally prescreened for autoantibodies and were not even sent to the TODAY study investigators. The presence of islet cell autoimmunity is an exclusion criterion for the study, Dr. Klingensmith said.
Indeed, other studies have reported higher rates of what some physicians and investigators are now calling “double,” “hybrid,” or “type 3” diabetes.
Investigators of a large British study, for instance, reported almost 10 years ago that 33% of 157 young adults with type 2 diabetes were found to be positive for diabetes-associated antibodies. And, just this year, investigators of a German study reported that 36% of 128 children thought to have type 2 diabetes also had diabetes-associated antibodies, Dr. Klingensmith said.
Dr. Ingrid M. Libman of the Children's Hospital in Pittsburgh said in another presentation that the “spectrum” of diabetes now presenting in youth presents treatment dilemmas.
“If insulin therapy preserves B-cell function, should all patients that phenotypically look like type 2 but have antibodies be treated with insulin?” she asked. “And should patients [with type 1 and obesity] be treated with insulin sensitizers?”
There have been few studies on treatment for “double” diabetes, she continued. Children who are registered in the Allegheny County Registry for diabetes and the Children's Hospital Registry who have characteristics of both type 1 (antibodies and/or ketones and diabetic ketoacidosis, for instance) and type 2 (obesity and/or acanthosis nigricans) are being treated in their communities with either insulin alone or with insulin and an oral agent, mainly metformin, she said.
It is possible that obesity and insulin resistance may accelerate the presentation of type 1 diabetes in patients with type 2, said Dr. Libman.
The children being enrolled in the TODAY study, in addition to having an absence of islet cell autoimmunity, must have had diabetes for 2 years or less, be 10–17 years of age, and have a fasting C-peptide greater than 0.6 ng/mL and a body mass index at the 85th percentile or above. Participants will be randomized to receive metformin alone, metformin and rosiglitazone, or metformin and intensive lifestyle therapy.
Of the 535 children who were screened for inclusion in the TODAY study, approximately 5% had only glutamic acid decarboxylase (GAD) autoantibodies and 6% had only IA-2 autoantibodies. Approximately 7% had both GAD and IA-2 autoantibodies. All told, 18% were positive for one or both of the antibodies measured.
Dr. Klingensmith and her coinvestigators also looked at the number of children who had very high titer antibody levels. They found that 12% of the children screened—and 65% of all antibody-positive children—were either positive for both autoantibodies or had antibody titers that were more than 300% above normal (above the cut-off point for positivity).
They found that there were no differences between the groups in age, gender, or duration of diabetes. Children with both antibodies, however, had lower C-peptide levels, BMI and triglyceride levels, as well as higher HDL cholesterol and HbA1c levels, and greater insulin use than did children with no antibodies, Dr. Klingensmith said.
According to Dr. Neil H. White, director of the division of pediatric endocrinology and metabolism at St. Louis University who is also a TODAY study investigator, approximately 12% of the children were receiving insulin alone at the time of screening for the study, and almost 50% were receiving metformin only. Approximately 25% were receiving both. The remaining children were receiving other medications or no treatment at all.