AIMS/HYPOTHESIS: Type 2 diabetes has a well-established link to cognitive impairment in older adults; however, studies often do not control for adiposity and co-morbid conditions which might mediate this cognitive impairment. To overcome these limitations, we investigated the relation between prediabetes and cognition in youth with overweight/obesity while controlling for adiposity in a cross-sectional ancillary study to the Pathogenesis of Youth Onset Diabetes (PYOD) study. We reasoned that if glucose control directly impacts brain health, then cognitive function should be worse in youth with versus without prediabetes. We also predicted that this effect should be greater on tasks that depend on dopaminergic function, such as working memory and that it may be related to central insulin sensitivity.

METHODS

We evaluated 69 youth with overweight/obesity for anthropomorphic and metabolic measures, abdominal adiposity, comprehensive cognitive testing, and the effects of intranasal insulin on cognition, resting state brain activity, and functional connectivity. Oral glucose tolerance tests classified 22 participants as having prediabetes (preT2D+) and 44 participants as having normal glucose control (preT2D-).

RESULTS

Groups did not differ in age, sex, race, diet, or adiposity measures. IQ was significantly lower (p=0.032) in the preT2D+ group compared to the preT2D-group. The preT2D+ group performed worse than the preT2D-group in tasks of working memory (p<.0.001), reaction time (p=0.01), and visuospatial processing (p=0.02). After considering IQ as a model covariate, only spatial working memory showed a significant difference between groups (p=0.002). Insulin sensitivity across the entire sample was negatively correlated with processing speed in two tasks (reaction time index: p=0.022; and trail making test A: p=0.022) and with the sensitivity of the intraparietal sulcus to intranasal insulin administration. Administration of intranasal insulin showed no effect on cognition within or between groups. However, the extent to which intranasal insulin administration influenced caudate functional connectivity with the right intraparietal sulcus (p =0.018) and bilateral medial precuneus (p =0.03) was correlated with performance on the spatial working memory task.

CONCLUSIONS/INTERPRETATION: We find evidence for the presence of global cognitive impairment in youth with prediabetes that cannot be accounted for by adiposity, as well as a specific deficit in spatial working memory that is not attributable to global cognitive impairment. We identified associations between central insulin sensitivity and both cognition and peripheral insulin sensitivity; however, central insulin sensitivity did not appear to account for the effect of prediabetes on cognition. These findings show that the association between peripheral glucose intolerance and cognition exists early in the course of the disease, prior to the onset of significant comorbid conditions and independently of adiposity. It also suggests the involvement of both generalized and specific mechanisms contributing to cognitive change.

RESEARCH IN CONTEXT

Type 2 diabetes and prediabetes have been associated with an increased risk of dementia and cognitive impairment on dopaminergic tasksThe mechanism of this cognitive impairment and if it is dissociable from adiposity or comorbid conditions related to old age is unknownIt is unclear whether youth with prediabetes are at risk for cognitive impairment from impaired insulin sensitivity/glucose regulation Do youth with prediabetes show cognitive impairment independent of adiposity, and is this related to insulin sensitivity of dopaminergic systems? Youth with prediabetes show global cognitive impairment, as well as particular impairment of spatial working memory, independent of adiposityInsulin sensitivity of caudate functional connectivity with right intraparietal sulcus and bilateral precuneus is correlated with prior performance on a spatial working memory task These findings provide evidence that suggests that youth with prediabetes are at risk for cognitive impairment, indicating early detection and treatment of impaired insulin sensitivity is crucial.