Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes

J Clin Endocrinol Metab. 2007 Jul;92(7):2439-45. doi: 10.1210/jc.2006-2540. Epub 2007 Apr 10.


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 <or= 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Cognition
  • Cognition Disorders / diagnosis
  • Cognition Disorders / etiology
  • Cognition Disorders / physiopathology
  • Cross-Sectional Studies
  • Dexamethasone
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Female
  • Glucocorticoids
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Male
  • Memory Disorders / diagnosis
  • Memory Disorders / etiology
  • Memory Disorders / physiopathology*
  • Middle Aged
  • Neuropsychological Tests
  • Pituitary-Adrenal System / physiopathology*


  • Glucocorticoids
  • Dexamethasone
  • Hydrocortisone