Epidemiologic studies have reported an increased prevalence of type 2 diabetes mellitus in populations exposed to high levels of inorganic arsenic (iAs) in drinking-water. Laboratory research suggests that arsenicals may interfere with processes related to glucose metabolism. This dissertation describes research that: (1) Examines the mechanisms responsible for the inhibition of insulin-stimulated glucose uptake (ISGU) in cultured adipocytes and (2) Establishes an in vivo model for arsenic-induced diabetes using C57BL/6 mice.
We examined the effects of arsenite (iAsIII) and its trivalent metabolites, methylarsonous acid (MAsIII), and dimethylarsinous acid (DMAsIII) on components of the insulin-activated signal transduction pathway that regulate ISGU in murine 3T3-L1 adipocytes. We demonstrated that subtoxic concentrations of iAsIII and MAsIII inhibit ISGU in adipocytes through a mechanism that involves the inhibition of phosphoinositide dependent kinase-1 (PDK-1) catalyzed phosphorylation of protein kinase B (PKB/Akt). The mechanisms responsible for the inhibition of ISGU by DMAsIII were found to be independent of PKB/Akt activation.
Male C57BL/6 mice were used to establish an in vivo model for arsenic-induced diabetes. Mice were exposed to 25 and 50 ppm of iAsIII in drinking-water for 8 weeks. Subsequent intraperitoneal glucose tolerance tests demonstrated that glucose tolerance was impaired in mice exposed to 50 ppm arsenic, but not 25 ppm arsenic. Exposures to 25 and 50 ppm arsenic in drinking-water resulted in proportional increases in the concentration of iAs and its metabolites in tissues responsible for glucose metabolism and homeostasis, including the liver, pancreas, skeletal muscle and adipose tissue. Notably, the average concentration of total speciated arsenic in livers of mice in the 50 ppm group was comparable to the highest concentration of total arsenic reported in livers of Bangladeshi residents who had consumed water with an order of magnitude lower concentration of iAs. These data suggest that mice are less susceptible than humans to the diabetogenic effects of chronic exposures to iAs in drinking-water, possibly due to the more efficient clearance of arsenic from target tissues.
This dissertation demonstrates the capacity of iAs and its metabolites to disrupt insulin signaling and insulin-dependent glucose metabolism in a manner that is consistent with diabetes mellitus.
|Commitee:||Coleman, Rosalind, Combs, Terry P., Lund, Pauline K., Thomas, David J.|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 68/06, Dissertation Abstracts International|
|Keywords:||Arsenic, Diabetes, Drinking water, Glucose|
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