Early Evidence of Brain Complications With Type 2 Diabetes in Obese Adolescents

From Medscape Medical News

Megan Brooks

August 10, 2010 — In a small study of obese adolescents, those with type 2 diabetes performed worse on several cognitive function tests than their equally obese peers without diabetes or prediabetes. Subtle brain abnormalities on magnetic resonance imaging (MRI) were also seen only in the type 2 diabetes group.

"This is the first report of brain and cognitive abnormalities among obese adolescents with type 2 diabetes," the study team notes in the journal Diabetologia, published online July 30. "We demonstrate that, in the absence of clinically significant vascular disease, there may be clear brain complications among adolescents with type 2 diabetes.

"There is good evidence to believe that it is the insulin resistance itself that causes the cognitive dysfunction," study author Antonio Convit, MD, professor of psychiatry and medicine at New York University Langone Medical Center and the Nathan S. Kline Institute for Psychiatric Research in New York City noted in a telephone interview with Medscape Medical News.

The study included 18 obese adolescents with type 2 diabetes (mean age, 16.4 years) and 18 obese adolescents without type 2 diabetes or marked insulin resistance (mean age, 17.1 years). In addition to age, the 2 groups were "very well matched," Dr. Convit said; they were comparable in sex, school grade, ethnicity, socioeconomic status, body mass index, waist circumference, and ratings of sleep apnea. During 2 clinic visits, all of the subjects underwent comprehensive medical, endocrine, psychiatric, neuropsychological, and brain MRI assessments.

Consistently Worse Cognitive Function

According to Dr. Convit and colleagues, the adolescents who had been diagnosed as having type 2 diabetes for 2.61 years on average (range, 5 months to 7.50 years) consistently scored lower than obese nondiabetic controls on all cognitive tests administered. "They scored significantly lower in 6 of 13 cognitive tests and we had trends in others, so this is not a type 1 error," Dr. Convit said.

More specifically, the adolescents with type 2 diabetes had significantly lower overall intellectual functioning, lower verbal memory scores, and lower psychomotor efficiency (all P < .05) and tended to have lower executive function ability (P = .06). All of these measures showed "medium-large to large effect sizes," the study authors note.

Despite being in the same grade and socioeconomic status, the adolescents with type 2 diabetes also posted lower scores on standard reading (P = .09) and spelling (P = .07) tests, "both trending toward significance and with medium effect sizes."

The difference in estimated full-scale IQ between the diabetic and nondiabetic teens (87.8 vs 103.6; P < .001) "could be a hot button," Dr. Convit noted. "But it's not that they are less smart than the other kids, it's just that they are not performing as well on the tasks and therefore their measured IQ is going to be lower."

IQ Difference Potentially Concerning

In an email to Medscape Medical News, Claude Messier, MD, PhD, who was not involved in the study, noted that the IQ difference of roughly 15 points "would suggest a significant intellectual impairment.

"A larger study will be needed to confirm this observation, particularly one with enough participants to allow to verify developmental delay as a possible explanation for the results. It will also help to determine if the reduction is equal at all IQ levels," said Dr. Messier, who is with the School of Psychology and Behavioral Neuroscience Specialization Coordinator at University of Ottawa in Ontario, Canada.

Prior studies by Dr. Messier and colleagues, and others, have documented significant cognitive slowing and learning and memory deficits in older adults with type 2 diabetes.

The findings in the current study of obese adolescents with type 2 diabetes were "not really expected since otherwise healthy type 2 diabetes patients (with no important cerebrovascular disease or hypertension) only have very mild cognitive changes before the age of 70," Dr. Messier added.

Subtle but Significant Differences on MRI

MRI-based automated brain structural analyses showed reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular but no obvious reduction in the volume of gray matter.

Diffusion-tensor imaging revealed reduced white and gray matter microstructural integrity.

"Particularly worrisome," Dr. Messier said, "is the cerebral ventricle enlargement, which is usually associated with many brain diseases. If ventricular enlargement was not present, the other reductions in brain volume or density could still be explained by development delay, particularly since anatomical changes in the frontal cortex (a late-developing region) and functional changes associated with the frontal cortex were prominent in the study. The presence of ventricular enlargement makes this possibility less likely," he said.

"The fact that large IQ differences and anatomical changes were found in the Convit study," Dr. Messier said, "suggest that type 2 diabetes is more damaging to the brain during development possibly with the combination of obesity (and associated health problems such as sleep apnea and depression, which may also be associated with brain anatomical and functional changes)."

This study, Dr. Messier added, "suggests that brain-related impairments are yet another reason to change the societal conditions that lead to obesity and type 2 diabetes. Although reduced intelligence and brain functions may pale in comparison to heart attacks and limb amputation as a consequence of early type 2 diabetes, as a society, a reduction in the intellectual abilities of significant proportion of its youth is definitely not a good trend," he said.

Strengths, Shortcomings and a Cautionary Note

Roger A. Dixon, MD, professor of psychology and Canada Research Chair in Cognition and Aging at the University of Alberta in Canada, told Medscape Medical News this new study provides "preliminary evidence for brain complications that could be associated with type 2 diabetes in adolescents.

"It is preliminary for methodological reasons," Dr. Dixon noted, "in that the study has a very small sample size and only 1 wave of measurement." Still, it is a very promising direction of research, because it examines markers of both brain and cognitive functioning, and such findings can help researchers and clinicians link the better-known effects of type 2 diabetes in older adults with those of the growing population of children and younger adults acquiring this disease, he said.

"The inclusion of a measure of depression," added Dr. Messier, "could have been informative since obesity is associated with a higher risk of depression and depression is associated with anatomical changes and cognitive deficits, although most studies linking depression and brain anatomical or functional changes have been done in adults."

Future Directions

Dr. Convit and colleagues say studies are needed to determine the underlying pathophysiologic mechanisms of cognitive impairment and brain changes in obese adolescents with type 2 diabetes. They propose that the negative impact of type 2 diabetes on the adolescent brain "may result from a combination of functional vascular changes and glucose and lipid metabolism abnormalities in the absence of overt vascular disease."

"By conducting longitudinal studies, we need to see whether some of these deficits are reversible on reversal of insulin resistance," Dr. Convit said. The diabetes study participants had a mean hemoglobin A1c of 8.3%, indicating intermediate glycemic control.

In just completed (unpublished) research, Dr. Convit's team found that obese kids who have insulin resistance short of diabetes also have cognitive impairment relative to lean kids. "So there is a stepwise function with higher levels of insulin resistance leading to greater and greater cognitive dysfunction," he noted.

The study was supported by grants from the National Institutes of Health and the National Center for Research Resources and the Pollock-Nguyen Charitable Fund. The study authors, as well as Dr. Messier and Dr. Dixon, have disclosed no relevant financial relationships.

Diabetologia. Published online July 30, 2010.