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

Abstract

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 ab-normalitiesmaycontributetoAlzheimerdiseasepathophysiology 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 ␣, F 2 -isoprostane (CSF only), A␤, norepinephrine, transthyretin, and apolipoprotein E.Results: Insulin increased CSF levels of F 2 -isoprostane and cytokines (both PϽ.01), as well as plasma and CSF levels of A␤42 (both PϽ.05). The changes in CSF levels of A␤42 were predicted by increased F 2 -isoprostane and cytokine levels (both PϽ.01) and reduced transthyretin levels (P=.02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both PϽ.05).Conclusion: Moderate hyperinsulinemia can elevate inflammatory markers and A␤42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

“…156 Insulin resistance also leads to a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, again consistent with the hypothesis that hyperinsulinemia 157 or insulin resistance 158 may potentiate the risk of AD. A pathological feedback mechanism may occur between increased Ab generation and high insulin levels characteristic of insulin resistance, accelerating the pathological process.…”

Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

“…Chronic hyperinsulinaemia and peripheral insulin resistance may impair insulin signalling by reducing cerebral insulin uptake [30] and insulin action [31], respectively. They may also impair memory function and precede Alzheimer's disease by increasing the levels of inflammatory factors and β-amyloid in the brain [32].…”

Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

“…Moreover, TTR is found to be stored in the secretory vesicles in pancreatic islets, thus it is likely that part of the plasma TTR is derived from the pancreas (29)(30)(31)(32). Furthermore, TTR is known to be inducible by insulinlike growth factor-1, and an insulin-responsive element has also been identified in the TTR promoter region (59). Therefore, while it is possible that TTR expression is upregulated under high-insulin conditions (T2D), the converse is true in T1D.…”