Context: There is both evidence of 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.

Objective: To characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities.

Design: Cross-sectional study, contrasting matched groups on HPA axis function and cognition by employing the combined DEX/CRH test and a neuropsychological battery assessing declarative and working memory, attention and executive function.

Setting: Research clinic in an academic medical center.

Participants: Volunteers functioning in the cognitively normal range. Thirty middle-aged individuals with T2DM, on average 7.5 years since diabetes diagnosis, and 30 age-, gender-, and education-matched controls.

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

Results: Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after dexamethasone suppression, and a larger response to CRH (all p .005). Among individuals with T2DM, cortisol levels during the DEX/CRH were positively associated with HbA1c (p=.05), independent of age, BMI, 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 (HbA1c).

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.