Abstract 405: Central IKKß Inhibition Prevents Air Pollution--Mediated Peripheral Inflammation and Exaggeration of Type 2 Diabetes
Objective: Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development and the underlying mechanism.
Approach and results: KKay mice, which are susceptible to Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4-8 weeks via a versatile aerosol concentrator and exposure system (n=7-8 for each group). PM2.5 exposure led to hyperglycemia and insulin resistance, which were accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and increased microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor (IMD-0354, n=8 for each group), but not TNFα blockade with infliximab (n=6) for each group), improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchanging ratio and heat generation) and reduced peripheral inflammation in response to PM2.5.
Conclusions: Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.
Author Disclosures: C. Liu: None. X. Sun: None. L.K. Fonken: None. X. Xu: None. Y. Bai: None. S. Maurya: None. M. Morishita: None. J. Harkema: None. Z. Ying: None. Q. Sun: None. R. Nelson: None. S. Rajagopalan: None.
- © 2014 by American Heart Association, Inc.