Type 1 diabetes is associated with chronic hyperglycemia and exposure to intermittent severe hypoglycemia. The long-term cerebral effects of these consequences of diabetes are ill defined. In this study, the history of preceding severe hypoglycemia and the presence of background retinopathy were examined in relation to cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging) in a cross-sectional evaluation of 74 young people with type 1 diabetes. Participants differed by their severe hypoglycemia exposure and degree of diabetic retinopathy and none had previous neuropsychological pathology. Severe hypoglycemia did not influence cognitive ability or brain structure. Background diabetic retinopathy was associated with small focal white-matter hyperintensities in the basal ganglia (33.3 vs. 4.7%, after correction for age, P ‫؍‬ 0.005) and significant cognitive disadvantage, affecting fluid intelligence (P ‫؍‬ 0.008, Eta 2 ‫؍‬ 0.14), information processing (P ‫؍‬ 0.001, Eta 2 ‫؍‬ 0.22), and attention and concentration ability (P ‫؍‬ 0.03, Eta 2 ‫؍‬ 0.09). In conclusion, recurrent exposure to severe hypoglycemia alone in young people with type 1 diabetes had no detrimental impact on brain structure or function over the duration of diabetes examined. Chronic hyperglycemia (inferred by the presence of background diabetic retinopathy) may affect brain structure and function. Diabetes 52: 149 -156, 2003

OBJECTIVE -Children who develop type 1 diabetes before age 7 years (early-onset diabetes; EOD) have comparatively poorer cognitive abilities. Whether this relates to psychosocial consequences of chronic illness or organic factors related to diabetes and its complications remains unresolved. We hypothesized that if differences in neuroradiological structure and cognitive ability coexisted in those who had EOD, then an organic component to their etiology was likely. RESEARCH DESIGN AND METHODS-A cohort of 71 young adults with longduration type 1 diabetes diagnosed during childhood or adolescence participated in a crosssectional evaluation of cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging). Diabetes onset age, preceding severe hypoglycemia exposure, retinopathy status, and diabetes duration were examined as potential correlates of cognitive and neuroradiological differences. No participants had previous neuropsychological pathology.RESULTS -In EOD participants (n ϭ 26), current intellectual ability (Wechsler Adult Intelligence ScaleϪRevised performance IQ; P ϭ 0.03) and information processing ability (Choice Reaction Time; P ϭ 0.006) were comparatively poorer than was observed in those with lateronset diabetes (n ϭ 45). Furthermore, lateral ventricular volumes were 37% greater (P ϭ 0.002) and ventricular atrophy was more prevalent (61 vs. 20%; P ϭ 0.01) in the EOD group than in those who had later-onset type 1 diabetes.CONCLUSIONS -An early childhood onset of type 1 diabetes was associated with mild central brain atrophy and significant differences in intellectual performance in adulthood, implying that neurodevelopment may be adversely affected by EOD. The differences observed in brain structure support an organic contribution to their etiology but do not exclude a coexistent contribution of psychosocial factors. Diabetes Care 28:1431-1437, 2005O ptimal intellectual development may be compromised by early childhood onset type 1 diabetes. The diabetes-related factor most consistently related to later intellectual ability is the onset age of type 1 diabetes; children developing the disorder in early childhood are more likely to score relatively poorly on cognitive tests, independent of diabetes duration. Ack et al.(1) first identified an association between early-onset type 1 diabetes (EOD) and comparatively lower general intelligence test scores; children with diabetes averaged 10 IQ points lower than their siblings. Subsequent studies identified small-tomoderate permanent differences in nonverbal (2-5) and verbal (6) intelligence, information processing (3,7-9), visuospatial ability (3-5), attention (7-11), executive function (7,9,12), and learning and memory ability (2,3,7). Prospective evaluation has confirmed that EOD independently influences verbal and nonverbal intelligence, attention, psychomotor speed, and executive functions (6,9). Some researchers have suggested that the differences in intellectual ability may reflect chronic hyperglycemia, severe hypog...

OBJECTIVE -Experimentally induced hypoglycemia in humans causes progressive but reversible cognitive dysfunction, but it is not known to what extent neuropsychological tests index abilities of cognitive functioning that are important in everyday life. This study examines the effects of acute insulin-induced hypoglycemia on attention and intelligence in nondiabetic humans. RESULTS -Hypoglycemia induced a significant deterioration in tests sensitive to both visual and auditory selective attention. During hypoglycemia, attentional flexibility deteriorated and speed of information processing was delayed. Sustained attention was preserved and intelligence scores did not deteriorate during hypoglycemia. RESEARCH DESIGN AND METHODSCONCLUSIONS -During hypoglycemia, a significant deterioration occurs in attentional abilities, whereas fluid intelligence is preserved. On the basis of these results, it can be surmised that many complex attention tasks relevant to everyday life are impaired during moderate hypoglycemia.

In individuals with type 1 diabetes, who have impaired awareness of hypoglycaemia, treatment with insulin lispro may be associated with a lower incidence of severe hypoglycaemia manifested predominantly through less frequent nocturnal episodes. Insulin lispro may have a beneficial role in the management of patients with diabetes at risk of severe hypoglycaemia, although a larger study is required to confirm these findings.

The epsilon4 allele of the apolipoprotein-E (APOE) gene is associated with poor outcome following various cerebral insults. The relationship between APOE genotype and cognitive function in patients with type 1 diabetes is unknown. In a cross-sectional study of 96 people with type 1 diabetes, subjects were APOE genotyped, previous exposure to severe hypoglycemia was estimated by questionnaire, and cognition was assessed by neuropsychological testing. Cognitive abilities were compared using multivariate general linear modeling (multiple analysis of covariance, MANCOVA) in those with (n = 21) and without (n = 75) the APOE epsilon4 allele. APOE epsilon4 selectively influenced cognitive ability in a sex-specific manner (F = 2.3, P = 0.044, Eta(2) = 0.15); women with APOE epsilon4 performed less well on tests of current, nonverbal intellectual ability (Wechsler Adult Intelligence Scale-Revised performance test score, P = 0.001, Eta(2) 0.26) and frontal lobe and executive function (Borkowski verbal fluency, P = 0.016, Eta(2) = 0.15). Previous exposure to severe hypoglycemia did not interact with APOE epsilon4 to produce cognitive disadvantage. The APOE epsilon4 genotype is associated with specific cognitive disadvantage in young women with type 1 diabetes. APOE epsilon4 is unlikely to mediate susceptibility to hypoglycemia-induced cognitive disadvantage.