C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c h O R I G I N A L A R T I C L E Morning Cortisol Levels and Cognitive Abilities in People With Type 2 Diabetes The Edinburgh Type 2 Diabetes Study REBECCA M. REYNOLDS, PHD1 MARK W.J. STRACHAN, MD2 JAVIER LABAD, MD1 AMANDA J. LEE, PHD3 BRIAN M. FRIER, MD4,5 F. GERALD FOWKES, PHD6 RORY MITCHELL, PHD6 JONATHAN R. SECKL, PHD1,5 IAN J. DEARY, PHD5,7 BRIAN R. WALKER, MD1 JACKIE F. PRICE, MD5,6 ON BEHALF OF THE EDINBURGH TYPE 2 DIABETES STUDY INVESTIGATORS OBJECTIVE — People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes. RESEARCH DESIGN AND METHODS — This was a cross-sectional study of 1,066 men and women aged 60 –75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, infor- mation processing speed, executive function, and mental ﬂexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relation- ships between fasting morning plasma cortisol levels and cognitive ability and estimated cogni- tive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables. RESULTS — In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and car- diovascular disease (P 0.05). CONCLUSIONS — High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes. Diabetes Care 33:714–720, 2010 T cognitive impairments, including ype 2 diabetes is associated with deﬁcits in processing speed, execu- tive function and declarative memory, and with structural changes in the brain including reductions in hippocampal and amygdalar volumes, which are key areas inﬂuencing learning and long-term mem- ory (1,2). Hyperglycemia, cerebral micro- vascular disease, and recurrent severe ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, U.K.; the 2Metabolic Unit, Western General Hospital, Edinburgh, U.K.; the 3Section of Population Health, University of Aberdeen, Aberdeen, U.K.; the 4Department of Diabetes, Royal Inﬁrmary of Edinburgh, Edinburgh, U.K.; the 5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, U.K.; the 6Centre for Population Health Sciences, University of Edinburgh, Edinburgh, U.K.; and the 7Department of Psychology, University of Edinburgh, Edinburgh, U.K. Corresponding author: Rebecca Reynolds, r.reynolds@ed.ac.uk. Received 24 September 2009 and accepted 16 January 2010. Published ahead of print at http://care. diabetesjournals.org on 22 January 2010. DOI: 10.2337/dc09-1796. © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. See http://creativecommons. org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 714 DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 hypoglycemic episodes have all been im- plicated as potential causative factors of cognitive decline (3) but are unlikely to explain the entire effect of diabetes on cognition. Increasing evidence supports a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and ele- vated endogenous glucocorticoids (as occurs in Cushing’s syndrome) are asso- ciated with cognitive impairment in ani- mals and humans. More subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function have also been linked with cognitive function, with higher plasma cortisol levels at 0900 h being associated with poorer age-related cognitive ability in a small group of elderly, healthy male volunteers (4). Conversely, manipula- tions that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing in rodents (5,6). Elevated glu- cocorticoid levels have widespread effects within the central nervous system, in- cluding deleterious effects on the struc- ture and function of the hippocampus, a key locus for cognitive function, which also highly expresses glucocorticoid re- ceptors (7,8). Several studies have demonstrated that people with type 2 diabetes have ac- tivation of the HPA axis, manifested by elevated basal plasma cortisol levels (9,10), higher late-night salivary cortisol levels (11), elevated ACTH levels (12), in- creased cortisol levels following overnight dexamethasone suppression (13,14), and impaired habituation of cortisol levels to repeated stress (15). These ﬁndings are consistent with a central dysregulation of the HPA axis in type 2 diabetes. The ele- vated plasma cortisol levels are associated with metabolic abnormalities in diabetes (16) and with complications of diabetes, including retinopathy, neuropathy, and nephropathy (17). Investigators have started to explore whether altered HPA axis activity contrib- utes to cognitive impairment in diabetes. Impaired central negative feedback con- trol of the HPA axis, as indicated by care.diabetesjournals.org