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

Abstract

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.

• Authors: Mark A Fishel, G Stennis Watson, Thomas J Montine, Qin Wang, Pattie S Green, J Jacob Kulstad, David G Cook, Elaine R Peskind, Laura D Baker, Dmitry Goldgaber, Wei Nie, Sanjay Asthana, Stephen R Plymate, Michael W Schwartz, Suzanne Craft
• Journal: Archives of neurology (Arch Neurol) Vol. 62 Issue 10 Pg. 1539-44 (Oct 2005) ISSN: 0003-9942 [Print] United States
• PMID: 16216936 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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