Superfund Research Program

Role of Annexin II in Peripheral Vascular Disease

Project Leader: Richard R. Vaillancourt
Grant Number: P42ES004940
Funding Period: 2005-2010

Project-Specific Links

Final Progress Reports

Year:   2009 

Dr. Vaillancourt and his research team have been investigating the molecular mechanisms of arsenic-induced hyperglycemia using insulin-sensitive cells like adipocytes and myocytes. Cytokines like IL-6 are known to inhibit the insulin-signaling pathway in cells, thus causing insulin resistance in the targeted cells. In the researchers' studies, they tested the hypothesis that low levels of arsenite could induce cytokine expression using mouse-derived 3T3-L1 adipocytes. Using a cytokine array assay, researchers observed increases in IL-6 expression in adipocytes treated with 50 ppb arsenite for 24 hours. In addition, other cytokines were identified, which included IL-7 and neurotropin 3 (NT-3). NT-3 has not been associated with adipocytes cell biology, and for this reason experiments were designed to characterize the role of NT-3 on the insulin-signaling pathway. The researchers demonstrate that NT-3 activates the ERK MAP kinase and ribosomal S6 kinase in 3T3-L1 adipocytes, but not Akt. In addition, pretreatment of 3T3-L1 adipocytes with NT-3 and then treatment with insulin resulted in diminished ribosomal S6 kinase phosphorylation. This result suggests that NT-3 antagonizes the action of insulin in 3T3-L1 adipocytes and may provide a mechanism for arsenic-induced hyperglycemia in insulin-sensitive cells. Future studies will focus on the receptor and signaling pathways regulated by NT-3 as the relationship between the NT-3 receptor and the insulin receptor has not been characterized. In addition, the mechanism by which arsenite induces NT-3 expression in adipocytes will be explored further as the arsenic-induced secretion of neurotrophins has not been characterized previously and may help explain mechanisms for arsenic-induced diabetes.