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


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


METHODS
Randomized crossover trial.


METHODS
Veterans Affairs hospital clinical research unit.


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


METHODS
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.


METHODS
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).


CONCLUSIONS
Moderate hyperinsulinemia can elevate inflammatory markers and Abeta42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.
Fishel
Mark A
MA
Department of Neurology, University of Washington, Seattle, WA 98108, USA.
Watson
G Stennis
GS
Montine
Thomas J
TJ
Wang
Qin
Q
Green
Pattie S
PS
Kulstad
J Jacob
JJ
Cook
David G
DG
Peskind
Elaine R
ER
Baker
Laura D
LD
Goldgaber
Dmitry
D
Nie
Wei
W
Asthana
Sanjay
S
Plymate
Stephen R
SR
Schwartz
Michael W
MW
Craft
Suzanne
S
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000032:analysis*; D001057:Apolipoproteins E / Q000097:blood / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000032:analysis*; D028441:F2-Isoprostanes / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D007328:Insulin / Q000097:blood / Q000134:cerebrospinal fluid; D007375:Interleukin-1 / Q000097:blood / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D009638:Norepinephrine / Q000097:blood / Q000134:cerebrospinal fluid; D011228:Prealbumin / Q000134:cerebrospinal fluid; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D016207:Cytokines; D028441:F2-Isoprostanes; D007328:Insulin; D007375:Interleukin-1; D015850:Interleukin-6; D011228:Prealbumin; D014409:Tumor Necrosis Factor-alpha; D009638:Norepinephrine