Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes

Abstract

Previous epidemiologic studies found increased prevalences of type 2 diabetes mellitus in populations exposed to high levels of inorganic arsenic (iAs) in drinking water. Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research has shown that exposures to iAs can produce effects that are consistent with type 2 diabetes. The current paper reviews the results of laboratory studies that examined the effects of iAs on glucose metabolism and describes new experiments in which the diabetogenic effects of iAs exposure were reproduced in a mouse model. Here, weanling male C57BL/6 mice drank deionized water with or without the addition of arsenite (25 or 50 ppm As) for 8 weeks. Intraperitoneal glucose tolerance tests revealed impaired glucose tolerance in mice exposed to 50 ppm As, but not to 25 ppm As. Exposure to 25 and 50 ppm As in drinking-water resulted in proportional increases in the concentration of iAs and its metabolites in the liver and in organs targeted by type 2 diabetes, including pancreas, skeletal muscle and adipose tissue. Dimethylarsenic was the predominant form of As in the tissues of mice in both 25 and 50 ppm groups. Notably, the average concentration of total speciated arsenic in livers from mice in the 50 ppm group was comparable to the highest concentration of total arsenic reported in the livers of Bangladeshi residents who had consumed water with an order of magnitude lower level of iAs. 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.

Fig. 1

Water consumption by mice in the treatment groups: (A) Changes in the daily water consumption by mice exposed to 25 ppm As (●) and 50 ppm As (■) and by control mice (□). (B) The average daily consumption of water by mice in the control, 25 ppm, and 50 ppm groups. (C) Estimated average intake of As by mice in the 25 ppm and 50 ppm groups. (Mean and SD, n = 5.) *Value is significantly different (P < 0.05) from that in the control group.

Fig. 2

Body weights of mice in the treatment groups: (A) Changes in the body weights of mice exposed to 25 ppm As (●) and 50 ppm As (■) and control mice (□) (Mean ± SD, n = 5). (B) The average body weights of mice in the control, 25 ppm, and 50 ppm groups at the beginning (□) and the end (■) of the study. (Mean and SD, n = 5.)

Fig. 3

Glucose concentrations in the blood of mice before and during the intraperitoneal glucose tolerance test: Mice exposed to 25 ppm As (●) and 50 ppm As (■) and control mice (□). (Mean ± SD, n = 5.) *Value is significantly different (P < 0.05) from that in the control group.

Fig. 4

Dose-dependent increases in the total speciated As (iAs^V + MAs^V + DMAs^V) levels in adipose tissue (◆), pancreas (■), skeletal muscle (●), and liver (▲) of mice exposed to 25 ppm and 50 ppm As. (Mean ± SD, n = 5.)

Fig. 5

Arsenic species in adipose tissue, skeletal muscle, pancreas, and livers of control mice (A) and mice exposed to 25 ppm As (B) and 50 ppm As (C): iAs^V (■), MAs^V (□) and DMAs^V (▨). (Mean; n = 5 for adipose tissue, skeletal muscle, and liver; n = 3 for pancreas.)