Cortisol and cognition in type 2 diabetes Figure 1—Association between general cognitive ability factor (g) and fasting cortisol levels in quartiles. Signiﬁcant decline in general cognitive ability, g, in association with higher fasting cortisol levels, particularly among those with subclinical atherosclerosis, as indicated by a lower ABI score ( 0.8) (P 0.05 in multiple regression analysis model 4 after adjustment for sex, age, MHVS, other covariates, and interactions). abolic and cardiovascular status, suggest- ing that there may be a direct link between cortisol and the brain. Mechanis- tically, the hippocampus is highly vulner- able to both age-related and metabolic insults and is particularly susceptible to the damaging effects of elevated cortisol. Glucocorticoids exert direct effects on hippocampal neurons, inhibiting long- term synaptic potentiation (the process thought to play a role in memory and learning) and also causing neuronal dam- age and reducing de novo neurogenesis (21). Glucocorticoids also have indirect effects, sensitizing neurons to metabolic and neurochemical challenges such as glutamate excess, oxidative stress, and disrupted calcium homeostasis. How- ever, the direction of causality remains unknown as prospective studies of cogni- tive function in subjects without diabetes have suggested that hippocampal dys- function potentially causes elevated corti- sol levels (22). The blood samples in our study were collected under carefully timed condi- tions in the morning, with all of the sub- jects in the fasting state. These fasting cortisol levels in our subjects were high (mean 730 nmol/l), but high fasting cor- tisol levels, associated with cognitive de- cline, were also reported in the much smaller published studies (1,18). The mechanisms underlying the high cortisol levels in diabetes are not known. Cortico- steroid-binding globulin levels are not el- evated in diabetes. Thus, these cortisol concentrations might reﬂect a stress re- sponse due to the combination of fasting, venesection, and the novel clinic setting in which the samples were obtained. However, we did not formally assess for current stress levels. It may be that people with diabetes are more susceptible to the effects of stress on plasma cortisol such that repeated cortisol elevations damage the hippocampus. Our own studies of im- paired habituation of cortisol responses to venepuncture (15) would be consistent with activation of the HPA axis from higher centers in type 2 diabetes. Whether subjects with type 2 diabetes have impaired central 718 DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 negative feedback sensitivity of the HPA axis that contributes to high cortisol levels is not clear, with reports of both impaired (13,14) and enhanced (23) feedback re- sponses. Further detailed studies including examining both the glucocorticoid and mineralocorticoid receptor components of central negative feedback sensitivity, as has recently been described in obesity (24), are required. The strengths of this study include the large sample size and the application of a battery of seven psychometric tests, which provides a relatively comprehensive and validated assessment of cognitive domains and mood states. There was also detailed phenotyping for potential confounding or mediating factors. The study population had a veriﬁed clinical diagnosis of type 2 diabetes and was representative of the wider type 2 diabetic population (elderly, com- munity-dwelling men and women with the full spectrum of severity of type 2 diabetes, from diet controlled to insulin treated). Many large-scale studies on people with di- abetes are restricted to those attending hos- care.diabetesjournals.org