In their recent article, Cukierman-Yaffe et al. (1) performed a cross-sectional study comparing the relationship of A1C and fasting plasma glucose (FPG) levels with performance on four cognitive tests of subjects from the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. These authors showed that a chronic marker of hyperglycemia, A1C, was associated with significantly lower cognitive performance, whereas FPG did not have any effect. These findings extend those from previous reports regarding the progressive relationship between the degree of chronic hyperglycemia and cognitive dysfunction. However, over the last few years, postprandial hyperglycemia (PPG) has also been known to trigger cellular mechanisms leading to diabetic complications, which in turn may also explain an increased susceptibility to cognitive decline (2). Indeed, FPG or A1C alone cannot thoroughly explain the glycemic disorders occurring in diabetes, and a suggestive body of evidence for the harmful effect of PPG on diabetes complications has been sufficient to influence guidelines from key professional bodies (3).
We previously reported a potential role of PPG on cognitive decline over time in older patients with type 2 diabetes in therapy with different oral antidiabetic agents (2). We performed clinical testing and a neuropsychological battery that included the Mini-Mental State Examination (MMSE), Trail Making Test Parts A and B, Digit Span forward and backward, and verbal fluency at baseline and at 3-month intervals for 12 months in 156 older persons with type 2 diabetes who were randomly assigned to undergo treatment with either repaglinide or glibenclamide. We did not find any significant correlations between A1C and MMSE or a composite score of executive and attention functioning after adjusting for multiple confounders at baseline. However, exaggerated PPG excursions were associated with a derangement of both global, executive, and attention functioning over time. In particular, coefficient variation of PPG (CV-PPG) was associated with MMSE scores (r = −0.3410, P < 0.001) and a composite score of executive and attention functioning (r = −0.3744, P < 0.001) after adjusting for multiple confounders. Both groups showed a significant decline in A1C and FPG, but only the repaglinide group demonstrated a significant decline of CV-PPG over time. In models investigating the change in cognitive functioning over time, adjusted for A1C and CV-FPG, a decline in cognitive functioning was observed only in the glibenclamide group (P < 0.001). After adjusting for CV-PPG, a decline was no longer found in executive and attention functioning composite score (P = 0.085) or the MMSE (P = 0.080) with glibenclamide.
Considering the limits of the cross-sectional design of the study by Cukierman-Yaffe et al., an important role played by PPG should not be ruled out. PPG could be the cause of cognitive impairment either by direct neuronal damage mediated by the advanced glycosylated end products (4), by an indirect neuronal damage due to micro- and macrovascular atherosclerotic damage, or through a worsening degree of insulin resistance, which is also known to have an important role in cognition (5). Therefore, our results suggest that PPG represents an important target on cognitive decline during diabetes.
Acknowledgments
No potential conflicts of interest relevant to this article were reported.
