Question

explaim the mechanisms amd toxological effects if type 1 diabetes in this article

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes. We previously reported an association of diabetes and urinary concentration of dimethylarsinite (DMAS"), a toxic product of arsenic methylation by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Here we examine associations between AS3MT polymorphism, arsenic metabolism and diabetes. Fasting blood glucose, oral glucose tolerance and self-reported diagnoses were used to identify diabetic individuals. Inorganic arsenic and its metabolites were measured in urine. Genotyping analysis focused on six polymorphic sites of AS3MT. Individuals with M287T and G4965C polymorphisms had higher levels of urinary DMAS" and were more frequently diabetic than the respective wild-type carriers, although the excess was not statistically significant. Odds ratios were 11.4 (95% confidence interval (CI) 2.2-58.8) and 8.8 (95% CI 1.6-47.3) for the combined effects of arsenic exposure > 75th percentile and 287T and 4965C genotypes, respectively. Carriers of 287T and 4965C may produce more DMAS" and be more likely to develop diabetes when exposed to arsenic. Journal of Exposure Science and Environmental Epidemiology (2013) 23, 151-155; doi:10.1038/jes.2012.103; published online 24 October 2012 Keywords: biomonitoring: disease; emerging contaminants; metals INTRODUCTION Chronic exposure to inorganic arsenic (As) in drinking water has been associated with cancer and it is suspected to cause other chronic diseases, including diabetes. There is, however, a high degree of inter-individual variation in As metabolism and disease manifestation. Arsenic (+3 oxidation state) methyltransferase (AS3MD is the key enzyme in the pathway for the methylation of iAs.? AS3MT polymorphism has been shown to account in part for inter-individual differences in iAs metabolism. The presence of variant alleles in intronic G12390C (3740393), C14215T (rs3740390) and G35991A (rs10748835) SNPs were shown to be significantly associated with the second methylation step in indigenous women in northern Argentina, that is, with lower percentage of total As (tAs) in urine represented by monomethylarsenic (MAs) and higher percentage represented by dimethylarsenic (DMAs). These polymorphisms were in a strong linkage and with higher allelic frequencies than those previ- ously reported for other populations. In addition, variation in the percentage of MAs in urine was linked to the presence of 3740393 SNP in AS3MT gene and to individual cancer susceptibility. A lower percentage of DMAs and a lower DMA/ MAs ratio was detected in urine of Vietnamese carriers of variant alleles for G35991 A (rs10748835) SNP in AS3MT. Multiple studies showed that the most common exonic AS3MT SNP Met287Thr (rs11191439) is associated with higher percentage of MAs in urine of subjects exposed to iAs. In addition, iAs-exposed carriers of the AS3MT(Met287Thr) variant have increased prevalence of DNA damage and skin lesions characteristic of IAs exposure. Wood and associates reported differences in variable number of tandem repeats (VNTRs) in 5-UTR region of AS3MT: transfection of HepG2 cells with a reporter gene constructs containing the VNTR variants (AB, A2B and A3B) indicated that the shorter VNTR (AB) was associated with higher activity of the reporter gene." To investigate the role of AS3MT polymorphism in the metabolism of iAs and the development of diabetes, we conducted a cross-sectional study in the Zimapan and Lagunera regions in Mexico where levels of iAs in ground water were historically high. We focused on variation in the production of toxic methylated trivalent metabolites of iAs, methylarsonite (MAS) and dimethylarsinite (DMAS") and associations of diabetes indicators with AS3MT polymorphism. Six polymorphic sites (12390C, rs3740393; C14215T, rs3740390; 635991A, rs 10748835; Met287Thr, rs11191439; G4965C, rs17881215; VNTR) previously linked to differences in As metabolism or susceptibility to iAs toxicity"-16 were examined. MATERIALS AND METHODS Details of population recruitment, data collection and analytical methods have been published elsewhere. Briefly, we recruited individuals >5 years old who had resided in either region for 2 years and those giving consent were invited for an interview during which they completed a questionnaire on consumption and sources of drinking water, health history and potential occupational exposures to arsenic, Pregnant women, alcoholics and individuals with urinary tract diseases or occupational exposures to arsenic were excluded. Eligible subjects provided a sample of the water typically used for drinking at home and a spot urine sample. Department of Nutrition, University of North Carolina at Chapel Hill Chapel Hill, North Carolina, USA Departamento de Toxicologia, Centro de Investigación y de Estudios Avanzados del Instituto Politecnico Nacional, México, DF, Mexico: Facultad de Medicina, Universidad Audrer del Estado de Durango, Gómez Palacio, Durango, Mexico and PARC Monographs Section, IARC WHO, Lyon Cedex, France. Correspondence Professor Dana Loomis, ARC Monographs Section, IARC WHO, 150 Cours Albert Thomas, 69372 Lyon Cedex o, France Tel: +33 (0)4 72 73 8909. Fax +33 014 72 73 8575 E-mail: loomisdaar Received 10 February 2012; accepted 9 August 2012, published online 24 October 2012

Answer 1

We have recently reported that exposure of IAs to drinking water is associated with increased risk of diabetes among Zimapan and Langunera residents. Here we provide evidence that individuals with variant AS3MT/287T and 4965C genotypes have higher level of 2HBG and FBG, and suggest they are more likely to be classified as common clinical criteria. Taken together this findings suggest that carrier of the 287T and 4965C variant genotypes are more likely to develop diabetes when exposed to IAs possibly due to enhanced production of its toxic metabolite DMA.