Environmental arsenic and diabetes mellitus

Summary

Principal Investigator: M Styblo
Affiliation: University of North Carolina
Country: USA
Abstract: Millions of people in various geographical regions, including the US, are exposed to unsafe levels of inorganic arsenic (iAs) in drinking water. The research of the effects of chronic exposure to iAs has commonly focused on its carcinogenic potency. However, epidemiologic studies indicate that iAs exerts other adverse effects that do not involve cancer. Several studies in arseniasis-endemic areas of Taiwan, Bangladesh, and Mexico have linked chronic exposures to high or moderate levels of iAs in drinking water to an increased risk for type 2 diabetes mellitus (T2D). Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research shows that exposures to iAs can produce symptoms that are consistent with T2D. In our preliminary studies, mice chronically exposed to iAs in drinking water developed impaired glucose tolerance. The major fraction of arsenic retained in tissues of these mice, including liver, pancreas, adipose and skeletal muscle tissues, was represented by methylated arsenicals, the products of the methylation of iAs by arsenic (3+ oxidation state) methyltransferase (AS3MT). Our in vitro studies showed that methylated trivalent arsenicals are more potent than iAs as inhibitors of insulin signaling and insulin-stimulated glucose uptake in cultured adipocytes. Notably, concentrations of arsenicals that inhibit glucose uptake by adipocytes and arsenic concentrations in tissues of mice that developed impaired glucose tolerance after exposure to iAs in drinking water are similar to arsenic concentrations in livers of residents in the arseniasis areas of Bangladesh. These results suggest that the formation of methylated trivalent arsenicals in the course of iAs metabolism may be a determining factor for development of T2D in individuals exposed to iAs in drinking water and that insulin-activated signal transduction pathway is the key target for these arsenicals. Based on these findings, we propose a translational research project that will examine diabetogenic effects of iAs in cultured cells, laboratory mice, and in humans. The main goals of this project are (i) to further characterize the association between iAs exposure and T2D, (ii) to identify molecular mechanisms for the diabetogenic effects of iAs exposure, (iii) to evaluate the roles specific metabolites of iAs play in these effects, and (iv) to characterize AS3MT polymorphisms that are associated with the increased production of these metabolites. Results of this project will advance knowledge in the area of environmental toxicology of As that has not been systematically studied, providing novel information that will improve the risk assessment of diabetes in arseniasis-endemic areas and the identification of individuals with increased susceptibility to the diabetogenic effects of chronic exposures to iAs. PUBLIC HEALTH RELEVANCE: Millions of people worldwide are exposed to arsenic in drinking water. Previous epidemiologic studies have linked chronic exposures to arsenic to an increased risk for type 2 diabetes mellitus. We propose a translational research project that will examine diabetogenic effects of arsenic in cultured cells, laboratory mice, and in humans. The goals of this project are to identify mechanisms by which exposures to arsenic induce diabetes and to characterize genetic polymorphisms that are associated with increased risk of diabetes for individuals exposed to arsenic in drinking water.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes
    David S Paul
    Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Toxicol Appl Pharmacol 222:305-14. 2007
  2. pmc Methylation of arsenic by recombinant human wild-type arsenic (+3 oxidation state) methyltransferase and its methionine 287 threonine (M287T) polymorph: Role of glutathione
    Lan Ding
    Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7461, USA
    Toxicol Appl Pharmacol 264:121-30. 2012
  3. pmc Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico
    Zuzana Drobna
    Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    J Expo Sci Environ Epidemiol 23:151-5. 2013
  4. pmc Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets
    Christelle Douillet
    Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7461, USA
    Toxicol Appl Pharmacol 267:11-5. 2013
  5. pmc Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet
    David S Paul
    Department of Nutrition, University of North Carolina Chapel Hill, Chapel Hill, North Carolina 27599 7461, USA
    Environ Health Perspect 119:1104-9. 2011
  6. pmc Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico
    Luz M Del Razo
    Departamento de Toxicologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico DF, Mexico
    Environ Health 10:73. 2011
  7. pmc Identification of the GST-T1 and GST-M1 null genotypes using high resolution melting analysis
    Zuzana Drobna
    Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina 27599 7461, United States
    Chem Res Toxicol 25:216-24. 2012

Scientific Experts

  • M Styblo
  • Zuzana Drobna
  • David S Paul
  • Felecia S Walton
  • Christelle Douillet
  • Lan Ding
  • R Jesse Saunders
  • Luz M Del Razo
  • Tomás Matousek
  • Wanda M Bodnar
  • Jenna Currier
  • Jesse Saunders
  • Pencheng Xun
  • David J Thomas
  • Dana Loomis
  • Erika Hernández Castellanos
  • Luz C Sánchez-Peña
  • Gonzalo G Garcia-Vargas
  • Olga L Valenzuela
  • Jenna M Currier
  • Blakely M Adair
  • Jirí Dĕdina
  • Araceli Hernández-Zavala

Detail Information

Publications9

  1. pmc Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes
    David S Paul
    Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Toxicol Appl Pharmacol 222:305-14. 2007
    ..These data suggest that mice are less susceptible than humans to the diabetogenic effects of chronic exposure to iAs due to a more efficient clearance of iAs or its metabolites from target tissues...
  2. pmc Methylation of arsenic by recombinant human wild-type arsenic (+3 oxidation state) methyltransferase and its methionine 287 threonine (M287T) polymorph: Role of glutathione
    Lan Ding
    Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7461, USA
    Toxicol Appl Pharmacol 264:121-30. 2012
    ....
  3. pmc Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico
    Zuzana Drobna
    Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    J Expo Sci Environ Epidemiol 23:151-5. 2013
    ..6-47.3) for the combined effects of arsenic exposure >75th percentile and 287T and 4965C genotypes, respectively. Carriers of 287T and 4965C may produce more DMAs(III) and be more likely to develop diabetes when exposed to arsenic...
  4. pmc Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets
    Christelle Douillet
    Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7461, USA
    Toxicol Appl Pharmacol 267:11-5. 2013
    ....
  5. pmc Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet
    David S Paul
    Department of Nutrition, University of North Carolina Chapel Hill, Chapel Hill, North Carolina 27599 7461, USA
    Environ Health Perspect 119:1104-9. 2011
    ..Growing evidence suggests that chronic exposure to inorganic arsenic (iAs) also produces symptoms consistent with diabetes. Thus, iAs exposure may further increase the risk of diabetes in obese individuals...
  6. pmc Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico
    Luz M Del Razo
    Departamento de Toxicologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico DF, Mexico
    Environ Health 10:73. 2011
    ..Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico...
  7. pmc Identification of the GST-T1 and GST-M1 null genotypes using high resolution melting analysis
    Zuzana Drobna
    Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina 27599 7461, United States
    Chem Res Toxicol 25:216-24. 2012
    ....