Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), Leioa, Spain; Department of Molecular Biophysics, Fundación Biofísica Bizkaia, Leioa, Spain.
Int Rev Cell Mol Biol. 2021;359:357-402. doi: 10.1016/bs.ircmb.2021.02.013. Epub 2021 Mar 12.
Type 2 diabetes (T2D), a heterogeneous disorder derived from metabolic dysfunctions, leads to a glucose overflow in the circulation due to both defective insulin secretion and peripheral insulin resistance. One of the critical risk factor for T2D is obesity, which represents a global epidemic that has nearly tripled since 1975. Obesity is characterized by chronically elevated free fatty acid (FFA) levels, which cause deleterious effects on glucose homeostasis referred to as lipotoxicity. Here, we review the physiological FFA roles onto glucose-stimulated insulin secretion (GSIS) and the pathological ones affecting many steps of the mechanisms and modulation of GSIS. We also describe in vitro and in vivo experimental evidences addressing lipotoxicity in β-cells and the role of saturation and chain length of FFA on the potency of GSIS stimulation. The molecular mechanisms underpinning lipotoxic-β-cell dysfunction are also reviewed. Among them, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, inflammation, impaired autophagy and β-cell dedifferentiation. Finally therapeutic strategies for the β-cells dysfunctions such as the use of metformin, glucagon-like peptide 1, thiazolidinediones, anti-inflammatory drugs, chemical chaperones and weight are discussed.
2 型糖尿病（T2D）是一种源自代谢功能障碍的异质性疾病，由于胰岛素分泌缺陷和外周胰岛素抵抗，导致循环中葡萄糖溢出。T2D 的一个关键危险因素是肥胖，自 1975 年以来，肥胖几乎翻了三倍，成为一种全球性流行疾病。肥胖的特征是慢性升高的游离脂肪酸（FFA）水平，这对葡萄糖稳态产生有害影响，称为脂毒性。在这里，我们回顾了生理 FFA 对葡萄糖刺激胰岛素分泌（GSIS）的作用，以及影响 GSIS 机制和调节的许多步骤的病理作用。我们还描述了体外和体内实验证据，这些证据涉及β细胞中的脂毒性以及 FFA 的饱和度和链长对 GSIS 刺激效力的影响。还回顾了脂毒性-β细胞功能障碍的分子机制。其中包括内质网应激、氧化应激和线粒体功能障碍、炎症、自噬受损和β细胞去分化。最后，讨论了针对β细胞功能障碍的治疗策略，例如使用二甲双胍、胰高血糖素样肽 1、噻唑烷二酮类、抗炎药、化学伴侣和体重。
