Researchers from Washington University School of Medicine in St. Louis and the University of Washington in Seattle have found evidence of slight memory impairment in children receiving intensive therapy (IT) for insulin-dependent diabetes.
Reporting in the August 1999 edition of the journal Diabetes Care, the investigators said such children have three times the risk for severe hypoglycemia (low blood glucose) and a slight decline in performance on a test to measure spatial memory function. The research was supported in part by grants from the Juvenile Diabetes Foundation and the U.S. Public Health Service.
Most diabetes experts now recommend IT for patients with diabetes because the nationwide Diabetes Control and Complications Trial (DCCT) showed that intensive therapy could keep patients healthier longer. The DCCT concluded that by keeping blood glucose levels within a narrow window, intensive therapy could delay the onset of the major complications of diabetes: vision loss, nerve problems and kidney failure.
But the DCCT also found that as patients worked to keep glucose levels under tighter control, they increased the risk that those levels would fall too low. Adults and adolescents on IT had an increased risk of severe hypoglycemia, which can cause weakness, confusion and loss of consciousness and, in the worst cases, seizures or coma. This new study found a similar elevated risk in children.
Tracking hypoglycemic events
The Washington University investigators studied 25 children with insulin-dependent diabetes. Of those, 13 were randomly assigned to receive intensive therapy. They were expected to measure their blood glucose at least four times each day and use three to four insulin injections or an insulin pump to control their blood glucose levels.
The other 12 children received the older, conventional diabetes therapy. They checked blood glucose two to four times each day and used one or two insulin injections.
Those children--and 16 control subjects who did not have diabetes--were followed for two years. Every time a child in the study had a severe hypoglycemic episode, the parents were required to report it to the nurses. "At the end of two years, kids in the IT group had a three-fold higher rate of severe hypoglycemic incidents, though not every child had such an incident," said Tamara Hershey, Ph.D., the paper's lead author and a postdoctoral fellow in psychiatry at Washington University School of Medicine.
Because a person with diabetes is unlikely to check glucose levels in the midst of a hypoglycemic episode, the researchers couldn't define severe hypoglycemia according to measurable glucose levels. So they used the DCCT definition of severe hypoglycemia. An episode was severe if the patient needed outside assistance to stabilize blood glucose or if a doctor or parent or friend had to administer glucagon or help in some other way.
Memory testing
After two years of diabetes therapy, the children took a battery of tests to measure cognitive function. One test measured a brain function called spatial declarative memory. "They sat at a computer screen, and a dot would appear," Hershey explained. "After a certain period of time, they had to point to the screen where they remembered seeing the dot."
With assistance from a computer, the researchers determined the child's accuracy. As waiting times increased, children on IT showed greater impairment than children on conventional diabetes therapy. "Their impairment showed a particular pattern, but it was very slight," Hershey said. "You wouldn't have noticed as the children went about their daily routines."
But she believes the impairment may signal problems related to severe hypoglycemia. Past research has shown that hypoglycemia can damage neurons. And hypoglycemic episodes selectively, although not exclusively, impair neuronal function in the brain's hippocampus, a seahorse-shaped structure important in memory and learning. Hershey also says there can be damage in structures that surround the hippocampus in an area of the brain known as the medial-temporal region.
"Neurons there are affected by severe hypoglycemia, and they can die," she said. "If you have repeated insults, more and more neurons may die. Over time, there may be behavioral consequences."
Without more research, Hershey isn't ready to call the observed impairment in spatial declarative memory a consequence of severe hypoglycemia. But she was careful during the study to make sure that children were not hypoglycemic during the testing. She wanted to learn whether there are any long-term or permanent consequences related to hypoglycemia rather than whether the brain functions differently when a child is hypoglycemic.
"We really don't know how severe hypoglycemia may or may not affect cognitive functioning in children, but our data are so preliminary that we're very careful not to suggest that intensive therapy be ruled out for children because of potential cognitive effects," Hershey said. "I think IT has a lot of benefits for adults and adolescents, and it may have those benefits in children too."
On the other hand, Hershey and colleagues want to make sure the benefits outweigh the potential risks. Currently, she is studying a larger group of children with diabetes to learn both whether the effects on spatial declarative memory will be detectable in that larger group and whether certain effects might correspond with clinical symptoms--whether memory changes might relate to the number of severe hypoglycemic episodes a child has. That study will take another few years to complete.
Note: For more information, please refer to Hershey T, et al. "Conventional Versus Intensive Diabetes Therapy in Children with Type One Diabetes," Diabetes Care, vol. 22(8), pp. 1318-1324, Aug. 1999.
Journal
Diabetes Care