Improving Metabolic Control Leads to Better Working Memory in Adults With Type 2 Diabetes

Abstract

OBJECTIVE -The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such improvements are mediated by changes in circulating insulin or insulin resistance. RESEARCH DESIGN AND METHODS -This randomized double-blind trial enrolled145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery.RESULTS -Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1-2.3 mmol/l). Working memory improved with both rosiglitazone (P Ͻ 0.001) and glyburide (P ϭ 0.017). Improvement (25-31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r ϭ 0.30) with improved glycemic control as measured by FPG.CONCLUSIONS -Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control. Diabetes Care 29:345-351, 2006O lder adults with type 2 diabetes have an increased risk of cognitive dysfunction. Memory and mental processing speed are the cognitive domains most often compromised, whereas other cognitive skills (e.g., attention, problem-solving, and general intelligence) tend to be unaffected (1-3). Whether cognitive deterioration is a direct consequence of chronically elevated blood glucose levels or whether it reflects diabetes-associated hyperinsulinemia has not yet been determined, but increasing evidence suggests that elevated insulin levels may be associated with adverse effects on cognition (4 -6) and an increased risk of Alzheimer's dementia (7).If chronically elevated glucose and/or insulin levels are linked to poorer cognitive performance, one might predict that efforts to improve glycemic control or reduce hyperinsulinemia would ameliorate cognitive function or attenuate its decline. Results from three small studies provide only limited support for that possibility. Gradman et al. (8) treated 23 diabetic adults with glipizide for up to 7 months and found both a reduction in fasting plasma glucose (FPG) levels and marked improvement on a verbal learning test; other cognitive skills were unaffected. By comparison, no changes in either FPG or cognition were seen in an untreated group of 13 nondiabetic control subjects. Circumscribed improvements in cognition have also been reported in 16 diabetic adults over a 7-month period (9) and in two gr...

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