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的葡萄糖溢出。T2D 的关键风险因素之一是肥胖，这是一种全球流行病，自 1975 年以来几乎增加了两倍。肥胖的特点是游离脂肪酸 (FFA) 水平长期升高，这对称为脂毒性的葡萄糖稳态造成有害影响。在这里，我们回顾了生理 FFA 对葡萄糖刺激的胰岛素分泌 (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解决了 β 细胞中的脂毒性以及 FFA 的饱和度和链长对 GSIS 刺激效力的作用。还回顾了支持脂毒性β细胞功能障碍的分子机制。其中，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、抗炎药、化学伴侣和体重。