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

Background Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on β-amyloid (Aβ). 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 Aβ, 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 1α, interleukin 1β, interleukin 6, tumor necrosis factor α, F₂-isoprostane (CSF only), Aβ, norepinephrine, transthyretin, and apolipoprotein E. Results Insulin increased CSF levels of F₂-isoprostane and cytokines (bothP<.01), as well as plasma and CSF levels of Aβ42 (bothP<.05). The changes in CSF levels of Aβ42 were predicted by increased F₂-isoprostane and cytokine levels (bothP<.01) and reduced transthyretin levels (P = .02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (bothP<.05). Conclusion Moderate hyperinsulinemia can elevate inflammatory markers and Aβ42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease. Published online August 8, 2005 (doi:10.1001/archneur.62.10.noc50112).