Urinary Metals and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a major global health concern. Most epidemiologic studies of diabetes risk factors to date have focused on genetics, unhealthy diets, and physical inactivity. The potential contributions of environmental chemicals, specifically metals, to the epidemic of diabetes have received less attention. The general population is exposed to a myriad of metals through food, drinking water and ambient air. Biological evidence suggests that exposure to metals may play a role in the development of diabetes. Selected metals, especially arsenic, have been examined in relation to diabetes risk in human populations but little is known about the role of other metals in diabetes risk. This dissertation examined exposures to multiple metals and their impacts on diabetes risk in midlife women who may experience unfavorable changes in glucose metabolism over menopausal transition using data from the Study of Women’s Health Across the Nation (SWAN). In aim 1, we examined the distributions of 21 urinary metal concentrations, identified subgroups of women with different exposure patterns to metal mixtures, and evaluated associations of demographic, socioeconomic, lifestyle, dietary characteristics with each urinary metal, as well as with exposure patterns to metal mixtures, in 1335 SWAN participants. We found that Asian women, both Chinese and Japanese, had higher urinary concentrations of arsenic, cadmium, copper, mercury, molybdenum, lead and thallium, compared with other race/ethnic groups, independent of all other factors. Two distinct overall exposure patterns to metal mixtures- “high” vs. “low” -- were identified using the k-means clustering method. Women in the “high” overall exposure pattern were more likely to be Asians, current smokers, and to report high intake of seafood and rice. In aim 2, we evaluated associations of individual metals measured in urine and overall exposure patterns as metal mixtures with incident diabetes over 16 years of follow-up in 1237 SWAN participants. After multivariable adjustment, the hazard ratios (HR) (95%CI) of diabetes associated with each doubling increase in urinary metal concentrations were 1.24 (1.14, 1.35) for arsenic and 1.23 (1.08, 1.40) for lead, in Cox proportional hazards models. A doubling in urinary excretion of zinc was associated with higher diabetes risks (HR=1.31, 95%CI 1.11, 1.55). The multivariable adjusted HR of diabetes associated with the “high” exposure pattern to metal mixtures compared with the “low”, which were generated by k-means clustering, was 1.46 (1.11, 1.91). In aim 3, we further examined associations between metal mixtures and longitudinal changes in insulin resistance and β-cell dysfunction, important etiopathogenic underlying mechanisms of diabetes, among 1262 SWAN participants. Using adaptive elastic-net models, urinary copper, lead, and zinc were associated with higher homeostatic model assessments for insulin resistance (HOMA-IR) at baseline, whereas molybdenum was associated with lower baseline HOMA-IR. Urinary zinc was also associated with a faster rate of increase in HOMA-IR. Urinary arsenic and zinc were associated with lower baseline HOMA β-cell function (HOMA-β), whereas cobalt was associated with higher baseline HOMA-β. Arsenic was also associated with a faster rate of decline in HOMA-β. Overall, this dissertation suggests that metal exposures differ by race/ethnicity, as well as by sociodemographic, lifestyle, and dietary factors, and that metal exposures may influence diabetes risk, possibly through effects on insulin resistance and β-cell dysfunction, even decades before its onset. Future studies need to confirm these findings to strengthen the foundation of knowledge on environmental chemicals as risk factors of diabetes.PhDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155168/1/xwangsph_1.pd