PROJECT SUMMARY/ABSTRACT
Projected to afflict 642 million individuals globally by 2040, diabetes is a devastating metabolic disease that is
increasingly tied to environmental toxicants. One such pollutant of immense public health significance is
arsenic, which contaminates the drinking water for over 100 million individuals globally, including many living in
the United States. Epidemiological evidence links arsenic exposure with diabetes; however, the mechanisms
by which arsenic increases diabetes risk and the factors that modulate this risk remain incompletely known.
Interestingly, arsenic and the essential element selenium have been known to have opposing biological
functions for nearly 80 years. Selenium is incorporated into 25 unique proteins, selenoproteins, involved in
cellular processes such as immune function, cell division, thyroid hormone metabolism, and redox handling.
Built upon strengthening evidence that insulin-secreting pancreatic ß-cells are a primary target of arsenic's
metabolic toxicity and our preliminary studies demonstrating that selenoprotein deficiency augments arsenic's
adverse effects on glucose metabolism, we propose the following central hypothesis: selenoproteins play
an essential role in preserving glucose homeostasis by protecting insulin-secreting pancreatic ß-cells
from arsenic-induced dysfunction. To address this hypothesis, in Specific Aim 1 we will employ a novel ß-
cell-specific knockout of selenoproteins to examine the impact of this tissue-specific alteration on whole-body
energy physiology as well as pancreatic islet architecture. To understand how reducing exposure to arsenic
impacts diabetes risk, in Specific Aim 2 we will interrogate the conjecture that selenoproteins are required for
recovery from arsenic-induced impairments in glucose metabolism; moreover, we will employ synchrotron X-
ray fluorescence microscopy to perform tissue-level mapping of arsenic and selenium in pancreatic tissue to
test the hypothesis that selenoproteins promote metabolic recovery by protecting pancreatic islets from arsenic
accumulation and facilitating its clearance. In Specific Aim 3 we will expand upon our in vivo and cell line data
to define the cellular defects in ß-cell physiology induced by arsenic that are exacerbated by selenoprotein
deficiency. In particular, we will focus on aspects of cellular physiology for which evidence suggests arsenic
and selenium/selenoproteins have opposing actions, namely oxidative stress, AMP-activated protein kinase
activity, and ATP generation. Furthermore, this aim will narrow in on a specific selenoprotein implicated in
diabetes risk, glutathione peroxidase 1 (GPx1), to determine how this enzyme impacts arsenic-induced ß-cell
dysfunction and to ascertain whether common allelic variations in GPx1 account for differential sensitivity to
arsenic-induced diabetes risk in humans. Collectively, the proposed studies will provide new knowledge
regarding the essential role of selenoproteins in resisting arsenic-induced disruptions in glucose homeostasis,
including identification of populations at heightened risk due to coexisting selenium deficiency and endemic
arsenic exposure as well as those with polymorphisms in selenoproteins that enhance arsenic sensitivity.