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Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and -Amyloid in Normal Adults

Mark A. Fishel, MD; G. Stennis Watson, PhD; Thomas J. Montine, MD, PhD; Qin Wang, PhD; Pattie S. Green, PhD; J. Jacob Kulstad, BS; David G. Cook, PhD; Elaine R. Peskind, MD; Laura D. Baker, PhD; Dmitry Goldgaber, PhD; Wei Nie, MD, PhD; Sanjay Asthana, MD; Stephen R. Plymate, MD; Michael W. Schwartz, MD; Suzanne Craft, PhD

Arch Neurol. 2005;62:1539-1544. Published online August 8, 2005 (doi:10.1001/archneur.62.10.noc50112).

Background  Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on -amyloid (A). 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 A, 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 1, interleukin 1, interleukin 6, tumor necrosis factor , F₂-isoprostane (CSF only), A, 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 A42 (both P<.05). The changes in CSF levels of A42 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 A42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

Author Affiliations: Departments of Neurology (Dr Fishel), Psychiatry and Behavioral Sciences (Drs Watson, Peskind, Baker, and Craft), Pathology (Drs Montine and Wang), Medicine (Drs Green, Cook, Plymate, and Schwartz), Psychology (Mr Kulstad), and Pharmacology (Dr Cook), University of Washington School of Medicine, Seattle; Geriatric Research, Education, and Clinical Center (Drs Fishel, Watson, Cook, Baker, Plymate, and Craft) and Mental Illness Research, Education, and Clinical Center and Veterans Affairs Puget Sound Health Care System (Dr Peskind), Seattle; Department of Psychiatry, State University of New York, Stony Brook (Drs Goldgaber and Nie); and Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Hospital, and Department of Medicine, University of Wisconsin School of Medicine, Madison (Dr Asthana).

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