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Diabetes NewsOctober 2011

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Cognitive Function in Type 1 Diabetic Adults with Early Exposure to Severe Hypoglycemia

Diabetes Care • September, 2010

Early-onset diabetes is associated with reduced cognition, possibly due to the effects of severe hypoglycemia (SH) on the developing brain. Although moderate, this cognition defect seems to be enduring. The researchers hypothesized that the earlier the age at SH occurrence would entail more pronounced effects on cognition. In this 16-year follow–up study of diabetic subjects, cognitive function was investigated in relation to early exposure to SH.

Research Design and Methods - Sixteen years subsequent to the study of cognitive function in 28 diabetic children and 28 matched control subjects, the same subjects were reexamined with a 96% participation rate. Diabetic subjects were classified as with (n = 9) or without (n = 18) early (≤10 years of age) SH, which was defined as convulsions or loss of consciousness. The study entailed cognitive function and electroencephalograms in diabetic children attending Trondheim University Hospital, the only referral center for diabetic children in the region. All 15 children who had experienced SH and 13 diabetic children of the same age without previous SH. For each subject a sex-and-age matched control subject was included, 20 of whom were schoolmates of the diabetic subjects.

In 2008, the participants were invited to participate in a follow-up at mean age of 28 years: 27 of the 28 diabetic subjects (96%) and the control group participated. Information on the SHs (i.e. episodes with convulsions or loss of consciousness), A1C levels and comorbidity was obtained from hospital records and personal interviews.

As in the baseline study, neuro-psychological tests were grouped into seven cognitive domains. For each domain, a relative score was computed, expressing the difference between diabetic subject and matched control subject, with the SD among control subjects as the unit of measure (e.g. a relative score of -1.0 implied that the diabetic subjects scored on average 1.0 SD poorer than the control subjects within that domain). By averaging these scores, an overall relative score was obtained as a measure of overall cognition. Relative mean scores for diabetic subjects were estimated with and without early SH and examined whether relative scores differed between diabetic groups.

Data from the baseline study was used to estimate childhood cognitive function and change in cognition from childhood to adulthood. For this analysis, neuro-psychological tests were excluded that had no equivalent baseline.

Researchers studied whether age at which first SH occurred (≤5 years of age, n = 4; 6-10 years of age, n = 5; or no early SH, n = 18) was associated with overall adulthood cognition, and overall cognition was assessed in relation to the total number of SHs and lifetime mean A1C (the average A1c since diabetes onset, weighted for the frequency of recordings).    

Results - Overall, cognitive scores were 0.9 SDs lower in subjects with early SH compared with subjects without early SH. Diabetic adults without early SH had similar cognitive function as control subjects (overall relative score -0.1 SD), whereas subjects with early SH scored on average 1.0 SD lower than control subjects. The diabetic groups particularly differed in problem solving, verbal function and psychomotor efficiency. They also tended to differ in memory. All results were adjusted for parental education and work at baseline, but even before this adjustment the overall relative score was 0.9 SD lower in subjects with early SH compared with subjects without early SH.

Subjects with early SH already had reduced cognitive function in childhood (overall relative score -0.7 SD). They also tended to have a less favorable development in cognitive function during follow-up compared with control subjects (relative score -0.3 SD). This adverse tendency was driven by a reduced problem-solving ability.

Earlier age at first SH was associated with poorer cognitive function in adulthood. Overall, diabetic subjects with first SH before 6 years of age scored 1.3 SD lower than control subjects, whereas subjects with first SH 6-10 years of age scored 0.7 SD lower than control subjects. Overall cognition in adulthood was not related to the total number of SHs or to the mean lifetime A1C.

Conclusions - In this 16-year follow-up study, diabetes with early SH was associated with ~1.0 SD poorer cognitive function in adulthood, which is considered a large effect size. The deficit was found across several cognitive domains and was most pronounced in subjects exposed to SH before 6 years of age.

Most, but not all studies indicate cognitive effects from SH occurring in childhood. Possibly the developing brain is particularly vulnerable to the effects of SH. Unlike previous long-term studies, the diabetic subjects were included when exposed to SH in early childhood. This could explain why the data suggest larger persistent cognitive decline than previously reported in the studies of early-onset diabetes or SH in childhood.

The subjects with early SH were younger at diabetes onset than subjects without early SH (average 5 years vs. 10 years of age). Even though an association was not found between lifetime A1C and cognition, the possibility of hyperglycemia in early childhood, or a synergism between hyperglycemia and the occurrence of SH, may underlie the cognitive defects demonstrated.

The study presented a nearly complete follow-up of diabetic subjects and matched control subjects from childhood to adulthood. Participants were enrolled in childhood and any effects from diabetes on cognitive abilities later did not bias the selection. Influence from recall bias is not likely since early SHs were contemporarily documented in hospital records. Potential confounding parental cognition is possible: however, adjustment for parental education and work did not change the results. In conclusion, the findings suggest that early exposure to SH may have lasting and clinically relevant effects on cognition. 

Reprinted with permission from the American Diabetes Association

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