Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults

Arch Neurol. 2005 Oct;62(10):1539-44. doi: 10.1001/archneur.62.10.noc50112.


Background: Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on beta-amyloid (Abeta). Hyperinsulinemia induces inflammation and is a risk factor for Alzheimer disease. Thus, insulin abnormalities may contribute to Alzheimer disease pathophysiology through effects on the inflammatory network.

Objectives: To determine the effects of induced hyperinsulinemia with euglycemia on Abeta, transthyretin, and inflammatory markers and modulators in plasma and cerebrospinal fluid (CSF).

Design: Randomized crossover trial.

Setting: Veterans Affairs hospital clinical research unit.

Participants: Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2 years).

Interventions: On separate mornings, fasting participants received randomized infusions of saline or insulin (1.0 mU.kg(-1).min(-1)) with variable dextrose levels to maintain euglycemia, achieving plasma insulin levels typical of insulin resistance. Plasma and CSF were collected after an approximately 105-minute infusion.

Main outcome measures: Plasma and CSF levels of interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, F2-isoprostane (CSF only), Abeta, norepinephrine, transthyretin, and apolipoprotein E.

Results: Insulin increased CSF levels of F2-isoprostane and cytokines (both P<.01), as well as plasma and CSF levels of Abeta42 (both P<.05). The changes in CSF levels of Abeta42 were predicted by increased F2-isoprostane and cytokine levels (both P<.01) and reduced transthyretin levels (P = .02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both P<.05).

Conclusion: Moderate hyperinsulinemia can elevate inflammatory markers and Abeta42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Amyloid beta-Peptides / analysis*
  • Apolipoproteins E / blood
  • Apolipoproteins E / cerebrospinal fluid
  • Cytokines / analysis*
  • F2-Isoprostanes / cerebrospinal fluid
  • Female
  • Humans
  • Hyperinsulinism / physiopathology*
  • Inflammation / physiopathology*
  • Insulin / blood
  • Insulin / cerebrospinal fluid
  • Interleukin-1 / blood
  • Interleukin-1 / cerebrospinal fluid
  • Interleukin-6 / blood
  • Interleukin-6 / cerebrospinal fluid
  • Male
  • Norepinephrine / blood
  • Norepinephrine / cerebrospinal fluid
  • Prealbumin / cerebrospinal fluid
  • Tumor Necrosis Factor-alpha / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Cytokines
  • F2-Isoprostanes
  • Insulin
  • Interleukin-1
  • Interleukin-6
  • Prealbumin
  • Tumor Necrosis Factor-alpha
  • Norepinephrine