Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Diabetes Obes Metab. 2010 Oct;12 Suppl 2:76-82. doi: 10.1111/j.1463-1326.2010.01279.x.
Pancreatic β-cell dysfunction is central to the pathogenesis of type 2 diabetes, and the loss of functional β-cell mass in type 2 diabetes is at least in part secondary to increased β-cell apoptosis. Accumulating evidence suggests that endoplasmic reticulum (ER) stress is present in β-cells in type 2 diabetes. Free fatty acids (FFAs) cause ER stress and are putative mediators of β-cell dysfunction and death. In this review, we discuss the molecular mechanisms underlying ER stress induced by saturated and unsaturated FFAs. Oleate and palmitate trigger ER stress through ER Ca(2+) depletion and build-up of unfolded proteins in the secretory pathway. Saturated and unsaturated FFAs elicit a differential signal transduction in the three branches of the ER stress response, resulting in different survival/apoptosis outcomes. The protection of β-cells against FFAs through the interference with ER stress signalling has opened novel therapeutic perspectives for type 2 diabetes. Chemical chaperones, salubrinal and glucagon-like peptide-1 (GLP-1) analogues have been used to protect β-cells from lipotoxic ER stress. Importantly, the pro- and antiapoptotic effects of these compounds are cell and context dependent.
胰岛β细胞功能障碍是 2 型糖尿病发病机制的核心，2 型糖尿病中功能性β细胞数量的减少至少部分是由于β细胞凋亡增加所致。越来越多的证据表明，内质网（ER）应激存在于 2 型糖尿病的β细胞中。游离脂肪酸（FFAs）可导致 ER 应激，是β细胞功能障碍和死亡的潜在介质。在这篇综述中，我们讨论了饱和和不饱和 FFAs 诱导 ER 应激的分子机制。软脂酸和硬脂酸通过 ER Ca（2+）耗竭和分泌途径中未折叠蛋白的积累引发 ER 应激。饱和和不饱和 FFAs 在 ER 应激反应的三个分支中引发不同的信号转导，导致不同的存活/凋亡结果。通过干扰 ER 应激信号转导来保护β细胞免受 FFAs 的侵害，为 2 型糖尿病开辟了新的治疗前景。化学伴侣、salubrinal 和胰高血糖素样肽-1（GLP-1）类似物已被用于保护β细胞免受脂肪毒性 ER 应激。重要的是，这些化合物的促凋亡和抗凋亡作用具有细胞和上下文依赖性。
