Evaluation of the association between arsenic and diabetes: a National Toxicology Program workshop review

Abstract

Background: Diabetes affects an estimated 346 million persons globally, and total deaths from diabetes are projected to increase > 50% in the next decade. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. In 2011, the National Toxicology Program (NTP) organized a workshop to assess the literature for evidence of associations between certain chemicals, including inorganic arsenic, and diabetes and/or obesity to help develop a focused research agenda. This review is derived from discussions at that workshop.

Objectives: Our objectives were to assess the consistency, strength/weaknesses, and biological plausibility of findings in the scientific literature regarding arsenic and diabetes and to identify data gaps and areas for future evaluation or research. The extent of the existing literature was insufficient to consider obesity as an outcome.

Data sources, extraction, and synthesis: Studies related to arsenic and diabetes or obesity were identified through PubMed and supplemented with relevant studies identified by reviewing the reference lists in the primary literature or review articles.

Conclusions: Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (≥ 150 µg arsenic/L in drinking water). The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 µg arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association. The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes.

Figure 1

Arsenic exposure and metabolism in the human body: from source to urine (modified from Navas-Acien et al. 2009a). ^aArsenic species measured in NHANES (Caldwell et al. 2009). Two other organic forms of arsenic considered to be minor contributors to arsenic in seafood were also measured in NHANES but were detected only in a small number of urine samples: arsenocholine (1.8%) and trimethylarsine oxide (0.3%). The predominant urinary metabolite of arsenocholine in rats, mice, and rabbits is arsenobetaine (Marafante et al. 1984).

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.

Figure 3

In vitro studies related to arsenic and diabetes. Abbreviations: Δ, cytotoxicity reported at specified concentration level; aP2, fatty acid-binding protein; As₂O₃, arsenic trioxide; AsIII, arsenite; AsV, arsenate; Ca, calcium; C/EBPα, CCAAT/enhancer binding protein (C/EBP alpha); DMAIII oxide, dimethylarsine oxide; DMAV, dimethylarsinate; HIF1a, hypoxia inducible factor, alpha; HO1, heme oxygenase 1; IUF1, insulin upstream factor 1 (also known as PDX1); KLF5, Kruppel-like factor 5; MAPKAP-K2, mitogen-activated protein kinase-activated protein kinase 2; MAsIII oxide, methylarsine oxide; MAsV, monosodium methylarsonate; Nrf2, transcription factor NF-E2–related factor 2; PDX1, pancreatic and duodenal homeobox 1 (also known as IUF1); PhAsO, oxophenylarsine; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species. *p < 0.05; doses at which statistically significant effects were observed.