Department of Nutrition, Nutrition Research Institute, CB# 74612, University of North Carolina at Chapel Hill School of Public Health, Chapel Hill, NC, 27599-7461, USA.
Department of Nutrition, CB# 74612, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, 27599-7461, USA.
Arch Toxicol. 2020 Jun;94(6):1955-1972. doi: 10.1007/s00204-020-02729-y. Epub 2020 Apr 10.
Inorganic arsenic (iAs) is an environmental diabetogen, but mechanisms underlying its diabetogenic effects are poorly understood. Exposures to arsenite (iAs) and its methylated metabolites, methylarsonite (MAs) and dimethylarsinite (DMAs), have been shown to inhibit glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated pancreatic islets. GSIS is regulated by complex mechanisms. Increase in ATP production through metabolism of glucose and other substrates is the ultimate trigger for GSIS in β-cells. In the present study, we used metabolomics to identify metabolites and pathways perturbed in cultured INS-1 832/13 rat insulinoma cells and isolated murine pancreatic islets by exposures to iAs, MAs and DMAs. We found that the exposures perturbed multiple metabolites, which were enriched primarily in the pathways of amino acid, carbohydrate, phospholipid and carnitine metabolism. However, the effects of arsenicals in INS-1 832/13 cells differed from those in the islets and were exposure specific with very few overlaps between the three arsenicals. In INS-1 832/13 cells, all three arsenicals decreased succinate, a metabolite of Krebs cycle, which provides substrates for ATP synthesis in mitochondria. Acetylcarnitine was decreased consistently by exposures to arsenicals in both the cells and the islets. Acetylcarnitine is usually found in equilibrium with acetyl-CoA, which is the central metabolite in the catabolism of macronutrients and the key substrate for Krebs cycle. It is also thought to play an antioxidant function in mitochondria. Thus, while each of the three trivalent arsenicals perturbed specific metabolic pathways, which may or may not be associated with GSIS, all three arsenicals appeared to impair mechanisms that support ATP production or antioxidant defense in mitochondria. These results suggest that impaired ATP production and/or mitochondrial dysfunction caused by oxidative stress may be the mechanisms underlying the inhibition of GSIS in β-cells exposed to trivalent arsenicals.
无机砷（iAs）是一种环境致糖尿病物，但人们对其致糖尿病作用的机制知之甚少。已有研究表明，亚砷酸盐（iAs）及其甲基化代谢物甲基砷酸盐（MAs）和二甲基砷酸盐（DMAs）的暴露会抑制胰岛β细胞和分离的胰岛中的葡萄糖刺激胰岛素分泌（GSIS）。GSIS 受复杂机制的调节。通过代谢葡萄糖和其他底物来增加 ATP 的产生是β细胞中 GSIS 的最终触发因素。在本研究中，我们使用代谢组学方法来鉴定暴露于 iAs、MAs 和 DMAs 后培养的 INS-1 832/13 大鼠胰岛素瘤细胞和分离的鼠胰岛中受到干扰的代谢物和途径。我们发现，这些暴露物扰乱了多种代谢物，这些代谢物主要富集在氨基酸、碳水化合物、磷脂和肉碱代谢途径中。然而，砷化合物在 INS-1 832/13 细胞中的作用与胰岛中的作用不同，并且具有暴露特异性，三种砷化合物之间很少有重叠。在 INS-1 832/13 细胞中，三种砷化合物均降低了琥珀酸，这是三羧酸循环的一种代谢物，可为线粒体中 ATP 合成提供底物。乙酰肉碱在细胞和胰岛中受到砷化合物暴露的一致降低。乙酰肉碱通常与乙酰辅酶 A 处于平衡状态，乙酰辅酶 A 是分解代谢的关键代谢物，是三羧酸循环的关键底物。它也被认为在粒体中具有抗氧化功能。因此，虽然三种三价砷化合物都扰乱了特定的代谢途径，但这些途径可能与 GSIS 相关，也可能不相关，但所有三种砷化合物似乎都损害了支持线粒体中 ATP 产生或抗氧化防御的机制。这些结果表明，暴露于三价砷化合物的β细胞中 GSIS 受到抑制的机制可能是由于 ATP 产生受损和/或线粒体功能障碍引起的氧化应激。
