A Novel Mediator of Arsenic-Induced Pancreatic Beta-Cell Dysfunction

With up to 140 million people living above arsenic (AS)-contaminated groundwater, AS exposure presents a major health risk worldwide. Studies have revealed a positive correlation between AS exposure and diabetes, where those suffering from symptoms of chronic AS toxicity have 5-6 times the local rates of diabetes. Recent mouse models of AS exposure suggested that this form of diabetes may be mediated by pancreatic β-cell dysfunction. To evaluate this possibility, the MIN6-K8 mouse β-cell line was utilized as a model. Three days of physiologically-relevant AS exposure decreased glucose-induced insulin secretion (GIIS) without effects on basal secretion. Three days of exposure to 1 µM AS decreased GIIS more than 60% without effects on cell count, total protein, total DNA, mitochondrial mass, or O 2 consumption. RNAseq analysis of AS-exposed MIN6-K8 cells revealed 3 significantly regulated genes previously unassociated with β-cell function. Each gene was individually knocked down by siRNA in the presence of AS. Knockdown of one of these genes, UDP-glucuronosyltransferase 1a6a (Ugt1a6a), partially recovered GIIS in AS-exposed cells. Ugt1a6a is a phase 2 detoxification enzyme for the conjugation of small aromatic compounds. The precursor and rate-limiting factor for serotonin production, 5-hydroxytryptophan (5-HTP), a known target of Ugt1a6a and modulator of GIIS, was decreased following AS exposure. Therefore, the AS-mediated increase in Ugt1a6a expression may deplete serotonin, and secondarily 5-HTP, decreasing GIIS. This work introduces a gene with a novel role in β-cell physiology and arsenic-mediated pathology. Disclosure C.M. Carmean: None. N. Yokoi: None. A.G. Kirkley: Consultant; Self; AbbVie Inc., Takeda Pharmaceuticals U.S.A., Inc.. H. Takahashi: None. R.M. Sargis: Advisory Panel; Self; CVS/Caremark. S. Seino: Research Support; Self; Merck Sharp & Dohme Corp., MSD K.K., Novo Nordisk Inc., Poxel SA, Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K.. Speaker9s Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker9s Bureau; Self; Novartis Pharma K.K.. Research Support; Self; Taisho Pharmaceutical Co., Ltd..