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Hypothalamic-Pituitary-Adrenal Axis Dysregulation and Memory Impairments in Type 2 Diabetes

Department of Psychiatry (H.B., M.R., I.D., V.S., A.T., E.J., A.A., A.C.), New York University School of Medicine, New York, New York 10016; Department of Psychology (O.T.W.), University of Bielefeld, D-33501 Bielefeld, Germany; and Nathan Kline Institute for Psychiatric Research (A.C.), Orangeburg, New York 10962

Address all correspondence and requests for reprints to: Antonio Convit, M.D., Center for Brain Health, HN-400, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: antonio.convit{at}med.nyu.edu.

Context: There is evidence of both hypothalamic-pituitary-adrenocortical (HPA) axis and cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the exact nature and the associations between these abnormalities remain unclear.

Objectives: The aim of the study was to characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities.

Design: A cross-sectional study was performed, contrasting matched groups on HPA axis function and cognition by using the combined dexamethasone (DEX)/CRH test and a neuropsychological battery assessing declarative and working memory, attention, and executive function.

Setting: The study was conducted in a research clinic in an academic medical center.

Participants: Participants were volunteers functioning in the cognitively normal range. We studied 30 middle-aged individuals with T2DM, on average 7.5 yr since diabetes diagnosis, and 30 age-, gender-, and education-matched controls.

Main Outcome Measures: Basal cortisol levels, cortisol levels during the DEX/CRH test, and performance on neuropsychological tests were measured.

Results: Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after DEX suppression, and a larger response to CRH (all P 0.005). Among individuals with T2DM, cortisol levels during the DEX/CRH test were positively associated with glycosylated hemoglobin (P = 0.05), independent of age, body mass index, hypertension, and dyslipidemia. Diabetic subjects showed cognitive impairments restricted to declarative memory. Across all subjects, declarative memory was inversely associated with cortisol levels; however, these associations were subsumed by glycemic control (glycosylated hemoglobin).

Conclusions: HPA hyperactivity and declarative memory deficits are present in T2DM. Both alterations may reflect the negative impact of poor glycemic control on the hippocampal formation.