Kumar Rahul, Chinala Ashwin, Grandhe Dhruv, Endicott S Joseph, Garcia Marcus A, Campen Matthew J, Gullapalli Rama R
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA; Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM, 87131, USA.
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
Environ Pollut. 2025 Jul 17;383:126844. doi: 10.1016/j.envpol.2025.126844.
Insulin resistance is a major pathophysiological process underlying a variety of human metabolic disorders such as type II diabetes, obesity and metabolic (dysfunction) associated steatotic liver disease (MASLD). The etiology of insulin resistance and human metabolic disorders is complex, involving an interplay of genetics, gut microbiome, dietary intake, sedentary behavior, and environmental exposures. Of these, the role of environmental exposures is perhaps the least explored in the pathophysiology of insulin resistance. Due to a multitude of causal factors implicated in the etiopathogenesis of insulin resistance, it has been difficult to delineate specific roles of individual risk factors. However, from a biochemical and pathophysiological perspective, there are common cellular drivers that are universally accepted as key drivers of insulin resistance. These include-altered cell signaling, abnormal reactive oxygen species (ROS) production, mitochondrial dysfunction, and sustained bioenergetic imbalances. Target cell dysfunction is a common theme driving insulin resistance irrespective of the organ (e.g., liver, muscle and adipose tissue). While humans are exposed to numerous chemicals on a routine basis, some of the most potent environmental exposures implicated in chronic disease causation fall into the category of heavy metals. This review explores the role of sustained, low-dose heavy metal exposures in the specific context of hepatic insulin resistance. Despite being a major site for heavy metal accumulation with decades-long half-lives, our understanding of the long-term impacts of these heavy metals on human liver health remains minimal at the current time.
胰岛素抵抗是多种人类代谢紊乱（如2型糖尿病、肥胖症和代谢（功能障碍）相关脂肪性肝病（MASLD））背后的主要病理生理过程。胰岛素抵抗和人类代谢紊乱的病因复杂，涉及遗传、肠道微生物群、饮食摄入、久坐行为和环境暴露之间的相互作用。其中，环境暴露在胰岛素抵抗病理生理学中的作用可能是研究最少的。由于胰岛素抵抗的病因涉及多种因果因素，因此很难确定各个风险因素的具体作用。然而，从生化和病理生理学角度来看，存在一些普遍被认为是胰岛素抵抗关键驱动因素的共同细胞驱动因素。这些因素包括细胞信号改变、活性氧（ROS）产生异常、线粒体功能障碍和持续的生物能量失衡。无论器官（如肝脏、肌肉和脂肪组织）如何，靶细胞功能障碍都是导致胰岛素抵抗的一个共同主题。虽然人类日常会接触到多种化学物质，但一些与慢性病病因相关的最具潜在影响的环境暴露属于重金属类别。本综述探讨了在肝脏胰岛素抵抗这一特定背景下持续低剂量重金属暴露的作用。尽管肝脏是重金属蓄积的主要部位，其半衰期长达数十年，但目前我们对这些重金属对人类肝脏健康的长期影响的了解仍然很少。
