The prevalence of obesity and type 2 diabetes is increasing at alarming rate and represents a growing burden on the health care system of the United States. Type 2 diabetes accounts for 90 to 95% of all diagnosed cases of diabetes mellitus and is characterized by the occurrence of insulin resistance and subsequent hyperglycemia. Until recently, an environmental mediator of type 2 diabetes had not been postulated. However, recent studies from retrospective analysis of data gathered by the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2001 have suggested that high serum concentrations of certain persistent organic pollutants, including the organochlorine compounds DDE and oxychlordane, are significantly correlated with increased prevalence of insulin resistance and diabetes. The current preliminary data suggest that exposure to DDE alters adipogenesis, promotes the release of both IL-6 and leptin from mature adipocytes, and prevents insulin-stimulated glucose transporter 4 translocation in skeletal muscle myotubules. Thus the following proposal seeks to determine if exposure to the organochlorine compounds DDE and oxychlordane promotes the occurrence of insulin resistance and type 2 diabetes through altering adipocyte maturation and inducing insulin resistance in the adipose tissue and skeletal muscle. To examine the molecular mechanisms involved in DDE-mediated decreases in adipocyte maturation, NIH3T3-L1 cells will be exposed to DDE prior to and during differentiation into mature adipocytes and the expression and DNA binding of adipogenic transcription factors will be assessed. Insulin stimulated glucose uptake following exposure to DDE or oxychlordane in mature NIH3T3-L1 adipocytes and L6 rat skeletal muscle myotubules will be used as in vitro cell culture models for the adipose tissue and skeletal muscle, respectively. In order to determine if exposure to DDE promotes the occurrence of type 2 diabetes in the whole animal, a high fat fed animal model of type 2 diabetes will be employed. Male C57BL/6J mice will be exposed to DDE weekly prior to and during consumption of either a normal or high fat diet for 16 weeks. Weight gain and insulin resistance will be monitored over the course of the dietary regimen to determine if exposure to DDE promotes the occurrence of hyperinsulinemia and hyperglycemia. Taken together, the current proposal seeks to empirically determine whether exposure to either DDE or oxychlordane, two prevalent bioaccumulative environmental contaminants, promotes the occurrence of type 2 diabetes. This line of investigation is of particular importance given that the origins of insulin resistance remain an enigma.
The presently proposal seeks to examine the effect of exposure to bioaccumulative organochlorine compounds that are present in the serum of a vast majority of the United States population on the development of insulin resistance and type 2 diabetes. This research will utilize cell culture models of adipose tissue and skeletal muscle as well as an animal model of type 2 diabetes to determine if exposure to these persistent compounds promotes the formation of insulin resistance. If so, the present study will provide mechanisms through which these compounds promote this disease and will establish exposure to certain organochlorine compounds as a risk factor for the development of type 2 diabetes.
| Mangum, Lauren H; Howell 3rd, George E; Chambers, Janice E (2015) Exposure to p,p'-DDE enhances differentiation of 3T3-L1 preadipocytes in a model of sub-optimal differentiation. Toxicol Lett 238:65-71 |
| Howell 3rd, George E; Mulligan, Charlee; Meek, Edward et al. (2015) Effect of chronic p,p'-dichlorodiphenyldichloroethylene (DDE) exposure on high fat diet-induced alterations in glucose and lipid metabolism in male C57BL/6H mice. Toxicology 328:112-22 |
| Howell 3rd, George E; Meek, Edward; Kilic, Jessica et al. (2014) Exposure to p,p'-dichlorodiphenyldichloroethylene (DDE) induces fasting hyperglycemia without insulin resistance in male C57BL/6H mice. Toxicology 320:6-14 |
| Howell 3rd, George; Mangum, Lauren (2011) Exposure to bioaccumulative organochlorine compounds alters adipogenesis, fatty acid uptake, and adipokine production in NIH3T3-L1 cells. Toxicol In Vitro 25:394-402 |
