Evaluation of the Association Between Arsenic and Diabetes

A National Toxicology Program Workshop Review

Elizabeth A. Maull; Habibul Ahsan; Joshua Edwards; Matthew P. Longnecker; Ana Navas-Acien; Jingbo Pi; Ellen K. Silbergeld; Miroslav Styblo; Chin-Hsiao Tseng; Kristina A. Thayer; Dana Loomis

Disclosures

Environ Health Perspect. 2012;120(12):1658-1670. 

In This Article

Experimental Animal Studies

More than 20 animal studies published since 1979 were identified for this review, and they were primarily conducted with rats or mice (Figure 2). The existing studies are highly diverse, with considerable variation in the duration of treatment (1 day to 2 years), routes of administration, and in doses used in the studies. The most common routes of administration were oral, predominantly through drinking water or diet, or intraperitoneal injections. Other, less common forms of administration were gavage, oral capsules, or subcutaneous injection. Most of the studies treated animals with AsIII or arsenic trioxide, but other arsenicals have also been studied (Aguilar et al. 1997; Arnold et al. 2003; Hill et al. 2009; Paul et al. 2008). The studies also vary in experimental design and model systems used to assess end points relevant to diabetes as a health effect, ranging from urinary glucose in fasted animals (Pal and Chatterjee 2005), to blood glucose in nonfasted animals (Mitchell et al. 2000), to glucose tolerance test (Cobo and Castineira 1997; Ghafghazi et al. 1980; Hill et al. 2009; Paul et al. 2007b, 2008, 2011; Wang et al. 2009). Glucose was a commonly reported end point but findings were inconsistent across studies, which may stem from differences in the biological compartment assessed (urine, serum, plasma, whole blood) and fasting status of the animal (fasted, nonfasted, fasting status not reported) in addition to the differences in experimental design noted above related to arsenical tested, species, route of administration, and dose levels (Aguilar et al. 1997; Arnold et al. 2003; Biswas et al. 2000; Boquist et al. 1988; Ghafghazi et al. 1980; Hill et al. 2009; Izquierdo-Vega et al. 2006; Judd 1979; Mitchell et al. 2000; Pal and Chatterjee 2004a, 2004b, 2005; Paul et al. 2007b, 2008, 2011; Wang et al. 2009). Although the literature as a whole was judged inconclusive, findings from recent studies that were designed to focus more specifically on diabetes-relevant end points appear, at least qualitatively, to support a link between arsenic exposure and diabetes. Supportive findings include impaired glucose tolerance in studies with mice (Boquist et al. 1988; Hill et al. 2009; Paul et al. 2007b, 2011; Yen et al. 2007) or rats (Cobo and Castineira 1997; Ghafghazi et al. 1980; Izquierdo-Vega et al. 2006; Singh and Rana 2009; Wang et al. 2009). Measures of insulin regulation [i.e., HOMA-IR (homeostasis model assessment of insulin resistance), insulin sensitivity (Paul et al. 2011)], as well as pancreatic effects [including indicators of oxidative stress, degenerative changes in β-cells, and pancreatitis (Arnold et al. 2003; Boquist et al. 1988; Izquierdo-Vega et al. 2006; Mukherjee et al. 2006; Yen et al. 2007)], have also been reported to be affected. Results from several animal studies suggest that cotreatment with methyl donors or antioxidants (e.g., folic acid, vitamin B12, methionine, N-acetyl cysteine) may attenuate the effects of arsenic toxicity, including reductions in the degree of arsenic-induced pancreatic toxicity (Mukherjee et al. 2006) and arsenic-induced hyperglycemia (Pal and Chatterjee 2004a, 2004b, 2005). Although not directly assessing the potential diabetogenic effects of arsenic, Reichl et al. (1990) reported that cotreatment with glucose increased the survival rate in NMRI mice treated with a dose of AsIII oxide that resulted in 100% mortality when administered without the glucose (12.9 mg/kg by subcutaneous injection).

Figure 2.

Animal studies of arsenic and end points related to glucose homeostasis. Abbreviations: AsIII, arsenite; AsIII oxide, arsenic trioxide; AsV, arsenate; AsV oxide, arsenic pentoxide; GD, gestation day; GTT, glucose tolerance test; HFD, high-fat diet; HOMA-IR, homeostasis model assessment of insulin resistance; ip, intraperitoneal; LFD, low fat diet; MAsIII oxide, methylarsine oxide; MMA, monomethylarsonate; NR, not reported.
aBracketed information indicates that the dose was converted to mg/kg from a different dose unit presented in the publication; use of brackets can also indicate that experimental details were not explicitly stated in the paper but could be reasonably inferred. bNotes on Arnold et al. (2003) rat findings: Effects on blood glucose in rats were only observed at 1 year of age, not at study completion at 2 years of age; the occurrence of pancreatitis was not statistically different in the high-dose group compared to controls, but there was a significant dose-related trend (p > 0.001) in both male and female rats. *p < 0.05; doses at which statistically significant effects were observed.

These studies suggest that animal models can be relevant to understanding the effects of arsenic on glycemic control depending on experimental design. Mice may be less susceptible than humans to arsenic toxicity, partly due to a faster metabolism and clearance of arsenic, resulting in lower internal dose of inorganic arsenic species (Paul et al. 2007b, 2008). Rats, unlike mice or humans, sequester arsenic (specifically DMA) in erythrocytes (Lu et al. 2004, 2007, 2008). It is unclear how this binding affects target organ dose of inorganic arsenic and rats are generally not recommended as a model for assessing arsenic metabolism or toxicity (NRC 1999).

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