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

Persistent Link:
http://hdl.handle.net/10150/247276
Title:
The Role of Arsenite in the Induction of C-Reactive Protein and Aberrant Insulin Signaling
Author:
Druwe, Ingrid Leal
Issue Date:
2012
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
Keywords:
insulin resistance; metabolic syndrome; Pharmacology & Toxicology; Arsenite; C-reactive protein
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Vaillancourt, Richard R.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe Role of Arsenite in the Induction of C-Reactive Protein and Aberrant Insulin Signalingen_US
dc.creatorDruwe, Ingrid Lealen_US
dc.contributor.authorDruwe, Ingrid Lealen_US
dc.date.issued2012-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.abstractMetabolic 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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectinsulin resistanceen_US
dc.subjectmetabolic syndromeen_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectArseniteen_US
dc.subjectC-reactive proteinen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorVaillancourt, Richard R.en_US
dc.contributor.committeememberBrooks, Heddwenen_US
dc.contributor.committeememberCamenisch, Todden_US
dc.contributor.committeememberHenricksen, Eriken_US
dc.contributor.committeememberRegan, Johnen_US
dc.contributor.committeememberVaillancourt, Richard R.en_US
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