Department of Cell Physiology and Metabolism, Faculty Diabetes Center, University of Geneva Medical Center, 1206 Geneva, Switzerland.
Int J Mol Sci. 2021 Dec 28;23(1):324. doi: 10.3390/ijms23010324.
Over the last decades, lipotoxicity and glucotoxicity emerged as established mechanisms participating in the pathophysiology of obesity-related type 2 diabetes in general, and in the loss of β-cell function in particular. However, these terms hold various potential biological processes, and it is not clear what precisely they refer to and to what extent they might be clinically relevant. In this review, we discuss the basis and the last advances of research regarding the role of free fatty acids, their metabolic intracellular pathways, and receptor-mediated signaling related to glucose-stimulated insulin secretion, as well as lipid-induced β-cell dysfunction. We also describe the role of chronically elevated glucose, namely, glucotoxicity, which promotes failure and dedifferentiation of the β cell. Glucolipotoxicity combines deleterious effects of exposures to both high glucose and free fatty acids, supposedly provoking synergistic defects on the β cell. Nevertheless, recent studies have highlighted the glycerolipid/free fatty acid cycle as a protective pathway mediating active storage and recruitment of lipids. Finally, we discuss the putative correspondence of the loss of functional β cells in type 2 diabetes with a natural, although accelerated, aging process.
在过去的几十年中，脂毒性和糖毒性已被确立为参与肥胖相关 2 型糖尿病病理生理学的机制，特别是在β细胞功能丧失方面。然而，这些术语具有各种潜在的生物学过程，目前尚不清楚它们具体指的是什么，以及在多大程度上具有临床相关性。在这篇综述中，我们讨论了游离脂肪酸及其代谢细胞内途径、与葡萄糖刺激胰岛素分泌相关的受体介导信号，以及脂诱导的β细胞功能障碍方面的研究基础和最新进展。我们还描述了慢性高血糖（即糖毒性）的作用，其促进β细胞衰竭和去分化。糖脂毒性结合了暴露于高葡萄糖和游离脂肪酸的有害影响，推测对β细胞会产生协同缺陷。然而，最近的研究强调了甘油磷脂/游离脂肪酸循环作为一种保护途径，介导活跃的脂质储存和募集。最后，我们讨论了 2 型糖尿病中功能性β细胞的丧失与自然（尽管加速）衰老过程之间的可能对应关系。
