Inorganic arsenic exposure, measured as total urine arsenic concentrations in urine, was associated with diabetes prevalence in a sample of rural adults from Arizona, Oklahoma, and North and South Dakota who participated in the SHS in 1989–1991. The association remained after adjustment for diabetes risk factors, and although attenuated, it also remained after adjustment by region and after removal of urine creatinine from the models. The association between arsenic and diabetes, however, was restricted to participants with uncontrolled diabetes (HbA1c ≥8%). Consistent with this finding, the association between arsenic and glycated hemoglobin in participants with diabetes was stronger in participants with higher fasting glucose levels and in participants who were untreated or were taking oral hypoglycemic medications. We found no association between urine arsenic and glycated hemoglobin or insulin resistance among persons without diabetes. These findings suggest that urine arsenic could be associated with poorly controlled diabetes in this population.
A major source of exposure to inorganic arsenic in populations around the world is drinking water contaminated with natural mineral deposits (1
). In the United States, arsenic in water is a major concern for many small communities, especially in parts of the Southwest, Midwest, and Northeast (22
). Arsenic levels in public water systems measured by the Indian Health Service in the SHS communities during the 1990s and 2000s ranged from less than 10 to 61 µg/L in Arizona and from less than 1 to 21 µg/L in North and South Dakota (18
). For the Oklahoma communities, arsenic levels were generally less than 10 µg/L (33
). These arsenic measures in drinking water are consistent with urine arsenic levels measured in our study. Also, although concentrations of arsenobetaine, a common seafood arsenical, were lower in the SHS than in the US population (13
), total urine arsenic concentrations were markedly higher, especially in Arizona and North and South Dakota, which confirms that seafood intake was low and supports that total arsenic reflects inorganic arsenic exposure in this population. Although our study does not have environmental measurements of arsenic exposure, the US Environmental Protection Agency conducted a detailed study of routes of exposure to arsenic in Arizona (National Human Exposure Assessment Survey Phase I Arizona) in 1995–1998 (34
). Food, beverages, and water were primary routes of exposure (37
). In addition, there was spatial variation in arsenic exposures related to distance from mines (38
). Ambient air concentrations of arsenic were low and unlikely to be a primary route of exposure (1
Several epidemiologic studies have addressed the association of low-moderate arsenic exposure with diabetes (9
). The association between urine arsenic and prevalent diabetes in our study is consistent with the association found in a representative sample of the US population (9
) and in populations from Northern Mexico (39
). Two studies, one in the United States (9
) and one in Northern Mexico (39
), also reported a positive association between arsenic exposure and glycated hemoglobin, although neither evaluated the association in analyses stratified by diabetes status or medication use. Another cross-sectional study found no association between arsenic exposure and glycated hemoglobin in a population from Bangladesh with a low prevalence of diabetes (5
). Finally, one study evaluated the association between arsenic exposure and insulin resistance in individuals with and without diabetes from Northern Mexico (39
). In that study, inorganic arsenic exposure was positively associated with both diabetes and glycated hemoglobin but was negatively associated with the HOMA-IR (39
). In our study, we found no association between arsenic and HOMA-IR among participants without diabetes.
The association between arsenic and poor diabetes control has not been described previously. Poor diabetes control was a major problem in the SHS (41
). Younger participants, women, participants with a high-fat diet, and participants with diabetes who were taking oral medication or insulin had worse diabetes control, although insulin improved diabetes control over time (41
). High-fat diet could interact with arsenic to induce glucose intolerance with unaffected plasma insulin (7
). Poor diabetes control could be confounded by unmeasured characteristics, such as high-fat diet, that could interact with arsenic to produce diabetes. Our findings are also consistent with arsenic inducing a more severe form of diabetes. In our study, however, we could not determine if arsenic affected diabetes control or if poor diabetes control influenced arsenic metabolism and elimination into urine. Persons with poorly controlled diabetes also could have higher exposure to arsenic, possibly through polydipsia and increased consumption of liquids in areas with arsenic-contaminated drinking water. Interestingly, arsenic and diabetes share associations with several health outcomes, including bladder cancer (43
) and peripheral artery disease (45
). If poor diabetes control increases arsenic exposure, part of the association between diabetes and these health outcomes could be mediated by arsenic.
Our analyses were robust to adjustment for several sociodemographic and diabetes risk factors. Adjustment for region, however, attenuated the associations. This was related to the fact that arsenic levels were higher in regions with a higher burden of diabetes. Although the possibility of confounding by other environmental, social, or healthcare factors related to region cannot be ruled out, these findings also could indicate that long-term exposure to arsenic might influence population-wide diabetes burden in ways that cannot be captured by single determinations of arsenic in middle-aged participants.
Removing urine creatinine from the models markedly attenuated the associations of arsenic with diabetes and with HbA1c. It is known that persons with diabetes have lower urinary concentrations of creatinine (47
), possibly because of hyperfiltration (increased glomerular filtration rate) (48
), increased liquid intake due to polidypsia, or lower muscle mass (49
). In our study, urine creatinine concentrations were markedly lower among participants with HbA1c ≥8%, which suggests that diabetes control rather than diabetes itself was related to lower urine creatinine concentrations.
Our study has several limitations. First, the study was cross sectional, and we cannot separate the direction of the association of arsenic with diabetes and with diabetes control. Prospective studies to evaluate the role of arsenic in diabetes development, the role of arsenic in diabetes control, and the role of diabetes and diabetes control in urine arsenic levels are needed. Second, we used a single urine determination as a biomarker of arsenic exposure. In a pilot study in the SHS, urine arsenic concentrations remained relatively constant over a 10-year period (18
). Third, the unexpected association between arsenic and diabetes control was the result of a post hoc analysis and requires replication. Important strengths of this study include the standardized study protocols to determine diabetes, diabetes related-traits, and relevant confounders (27
); the rigorous laboratory procedures and the low limit of detection of our assay for urine arsenic (25
); the low seafood intake in the population, which simplifies the interpretation of urine arsenic; and the wide range of arsenic exposure at levels relevant to many populations in the United States.
In the SHS, a population from rural communities in the United States with a high burden of diabetes, arsenic was associated with poor diabetes control. Prospective studies to evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed. Furthermore, our findings could provide a potential explanation for some of the observed consequences of diabetes, including cancer (43
) and cardiovascular disease (43
), which could be related to increased arsenic concentrations in patients with poorly controlled diabetes.