Arsenic exposure and type 2 diabetes: a systematic review of the experimental and epidemiological evidence

Abstract

Chronic arsenic exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes. We identified 19 in vitro studies of arsenic and glucose metabolism. Five studies reported that arsenic interfered with transcription factors involved in insulin-related gene expression: upstream factor 1 in pancreatic beta-cells and peroxisome proliferative-activated receptor gamma in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite or arsenate. These studies provide limited insight on potential mechanisms. We identified 10 in vivo studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval, 1.69-3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority.

Figure 1

Flow diagram of the experimental and epidemiologic study selection process.

Figure 2

Ratio of basal glucose uptake in peripheral cell lines comparing arsenite versus control. Lines represent the dose response for each independent study. Single points represent the effect for studies using a single dose (1 ppm = 13.35 μM; 0.75 ppm = 10 μM).

Figure 3

Risk of diabetes by cumulative arsenic exposure in drinking water in epidemiologic studies. Black lines represent the dose response for studies in Taiwan and Bangladesh compared with the baseline category of exposure. Gray lines represent the dose response in studies in the United States. Cumulative exposure: ∑ arsenic levels in drinking water_i × time of exposurei (i indicates specific village). For example, a cumulative exposure of 1 ppm-year is reached after 10 years of residence in a village with an arsenic concentration in drinking water of 0.1 ppm. In the study by Zierold et al. (2004), we assumed 20 years of exposure for all study subjects.