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    The Role of Arsenite in the Induction of C-Reactive Protein and Aberrant Insulin Signaling

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    Author
    Druwe, Ingrid Leal
    Issue Date
    2012
    Keywords
    insulin resistance
    metabolic syndrome
    Pharmacology & Toxicology
    Arsenite
    C-reactive protein
    Advisor
    Vaillancourt, Richard R.
    
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    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Metabolic syndrome affects approximately 25% of the US population and increases risk for the development of cardiovascular disease, as well as, and Type 2 diabetes. Inorganic arsenite exposure has been associated with cardiovascular disease, insulin resistance and Type 2 diabetes. The mechanisms by which arsenic increases these health risks has not been fully elucidated. In this report we show two pathways by which arsenite may contribute to metabolic syndrome. First through induction of C-Reactive Protein (CRP) and secondly through inhibition of insulin stimulated glucose uptake. CRP is a clinical marker for metabolic syndrome and a predictive clinical marker for cardiovascular disease and type 2 diabetes. Treatment of HepG2 cells with arsenite resulted in elevated CRP production and secretion. In addition, treatment of FvB mice with 100 ppb sodium arsenite via drinking water for six months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-3), a mouse kidney cell line, were stimulated with CRP, which resulted in activation of NFkappaB. Pretreatment with Y27632, a Rho kinase inhibitor, prior to CRP stimulation attenuated NFkappaB activation. Additionally, L6 myocytes, an insulin responsive cell line, exposed to arsenite for 4 or 7 days showed decreased insulin-stimulated glucose uptake but no decrease in AKT activation. In addition, we found that ERK activity decreased, while p38 MAPK activity increased, in response to prolonged arsenite treatment. These data support the epidemiological evidence that chronic exposure to low physiologically relevant levels of arsenite can contribute to insulin resistance and type 2 diabetes. These data provide a novel pathway by which arsenic can contribute to metabolic syndrome, cardiovascular disease, insulin resistance and type 2 diabetes.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmacology & Toxicology
    Degree Grantor
    University of Arizona
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