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Toxicol Sci. 2019 Jan 1;167(1):116-125. doi: 10.1093/toxsci/kfy150.

miR-149 Negative Regulation of mafA Is Involved in the Arsenite-Induced Dysfunction of Insulin Synthesis and Secretion in Pancreatic Beta Cells.

Sun Q1,2, Yang Q1,2, Xu H1,2, Xue J1,2, Chen C1,2, Yang X3, Gao X4,5, Liu Q1,2.

Author information

1
Institute of Toxicology.
2
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.
3
School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, People's Republic of China.
4
Molecular Pathogenesis Group, National Toxicology Program Laboratory (NTPL), National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, North Carolina.
5
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211166, People's Republic of China.

Abstract

Chronic exposure to arsenic, a potent environmental oxidative stressor, is associated with the incidence of diabetes. However, the mechanisms for arsenite-induced reduction of insulin remain largely unclear. After CD1 mice were treated with 20 or 40 ppm arsenite in the drinking water for 12 months, the mice showed reduced fasting insulin levels, a depression in glucose clearance, and lower insulin content in the pancreas. The levels of glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells isolated from arsenite-exposed mice were low compared with those for control mice. Immunohistochemistry studies showed that arsenite exposure resulted a reduction of insulin content in the pancreas of mice. Exposure of Min6 cells, a pancreatic beta cell line, to low levels of arsenite led to lower GSIS in a dose- and time-dependent fashion. Since microRNAs (miRNAs) are involved in pancreatic β-cell function and the pathogenesis of diabetes, we hypothesized that arsenite exposure activates miR-149, decreases insulin transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (mafA), and induces an insulin synthesis and secretion disorder. In arsenite-exposed Min6 cells, mafA activity was lowered by the increase of its target miRNA, miR-149. Luciferase assays illustrated an interaction between miR-149 and the mafA 3' untranslated region. In Min6 cells transfected with an miR-149 inhibitor, arsenite did not regulate GSIS and mafA expression. In control cells, however, arsenite decreased GSIS or mafA expression. Our results suggest that low levels of arsenite affect β-cell function and regulate insulin synthesis and secretion by modulating mafA expression through miR-149.

PMID:
29905828
DOI:
10.1093/toxsci/kfy150

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