Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Pathology Department, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Cancer Metabolism and Epigenetics Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Experimental Biochemistry Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia; Cancer and Mutagenesis Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia.
Toxicol In Vitro. 2021 Feb;70:105015. doi: 10.1016/j.tiv.2020.105015. Epub 2020 Oct 8.
Environmental metals are believed to have diabetogenic effects without any clear underlying mechanisms. The study investigated the effects of metals, lead (Pb), mercury (Hg), cadmium (Cd), and molybdenum (Mo), on the bioenergetics of isolated pancreatic β-cells from CD-1 mice via different functional and structural techniques. The tested metals caused significant decrease in ATP production in concentration and exposure duration-dependent pattern; Cd was the most potent cytotoxic metal. In ATP assay estimated effective concentration 50 (EC50) (25, 40, 20, and 100 μM for Pb, Hg, Cd, and Mo, respectively), the metals also significantly inhibited the glucose-stimulated insulin secretion (GSIS), mitochondrial complexes activity, mitochondrial membranes potential, and oxygen consumption rates of the treated cells with parallel increases in their lactate production and in the mitochondrial swelling and permeation of their inner mitochondrial membranes to potassium (K) and hydrogen (H) ions. In addition, Cd, Pb, and Hg produced significant increases in mitochondrial membrane fluidity (MMF) with significant decreases in saturated/unsaturated fatty acid ratios. In 10 μM concentration, away from Mo, the three metals showed inhibitory effects on the mitochondrial functions to variable degrees. Only Cd showed significant effect on MMF and fatty acid ratios at a concentration of 10 μM. In conclusion, the tested metals significantly affected the bioenergetics of the pancreatic β-cells with significant effect on GSIS. Cd showed the most significant functional and structural effects on their mitochondria followed by Pb, then Hg, while Mo was almost safe up to 10 μM concentration. Hence, bioenergetic mitochondrial disruption can be considered as an underlying mechanism of the diabetogenic effects of the tested metals.
环境金属被认为具有致糖尿病作用，但没有明确的潜在机制。本研究通过不同的功能和结构技术，研究了金属（铅（Pb）、汞（Hg）、镉（Cd）和钼（Mo））对 CD-1 小鼠分离的胰岛β细胞生物能学的影响。测试金属以浓度和暴露时间依赖的方式导致 ATP 产生显著减少；Cd 是最有效的细胞毒性金属。在 ATP 测定中估计的有效浓度 50（EC50）（分别为 25、40、20 和 100 μM 的 Pb、Hg、Cd 和 Mo），这些金属还显著抑制葡萄糖刺激的胰岛素分泌（GSIS）、线粒体复合物活性、线粒体膜电位和处理细胞的耗氧量，同时平行增加细胞内乳酸产生以及线粒体肿胀和其内膜对内钾（K）和氢离子（H）的通透性。此外，Cd、Pb 和 Hg 导致线粒体膜流动性（MMF）显著增加，饱和/不饱和脂肪酸比例显著降低。在 10 μM 浓度下，远离 Mo，这三种金属对线粒体功能表现出不同程度的抑制作用。只有 Cd 在 10 μM 浓度下对 MMF 和脂肪酸比例表现出显著影响。总之，测试金属对胰岛β细胞的生物能学有显著影响，对 GSIS 有显著影响。Cd 对其线粒体的功能和结构影响最大，其次是 Pb，然后是 Hg，而 Mo 几乎在 10 μM 浓度下是安全的。因此，生物能学线粒体破坏可被认为是测试金属致糖尿病作用的潜在机制。
