Cnop Miriam, Welsh Nils, Jonas Jean-Christophe, Jörns Anne, Lenzen Sigurd, Eizirik Decio L
Laboratory of Experimental Medicine, Faculty of Medicine, Erasmus Hospital, Université Libre de Bruxelles (ULB), Route de Lennik 808, CP-618, 1070 Brussels, Belgium.
Diabetes. 2005 Dec;54 Suppl 2:S97-107. doi: 10.2337/diabetes.54.suppl_2.s97.
Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
1型和2型糖尿病的特征是β细胞进行性衰竭。细胞凋亡可能是这两种类型疾病中β细胞死亡的主要形式。有人提出，分别导致2型和1型糖尿病中营养物质和细胞因子诱导的β细胞死亡的机制，共享一条涉及白细胞介素（IL）-1β、核因子（NF）-κB和Fas的最终共同途径的激活。我们在此回顾1型和2型糖尿病中β细胞死亡机制之间的异同。在1型糖尿病的胰岛炎病变中，侵入的免疫细胞产生细胞因子，如IL-1β、肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ。IL-1β和/或TNF-α加IFN-γ通过在转录因子NF-κB和STAT-1控制下激活β细胞基因网络来诱导β细胞凋亡。NF-κB激活导致一氧化氮（NO）和趋化因子的产生以及内质网（ER）钙的耗竭。β细胞死亡的执行通过丝裂原活化蛋白激酶的激活、ER应激的触发以及线粒体死亡信号的释放而发生。长期暴露于高水平的葡萄糖和游离脂肪酸（FFA）会导致β细胞功能障碍，并可能在2型糖尿病中诱导β细胞凋亡。暴露于高葡萄糖有双重作用，最初通过不同机制触发“葡萄糖超敏反应”，随后诱导凋亡。然而，高葡萄糖在体外或体内的大鼠或肥胖沙鼠的β细胞中不会诱导或激活IL-1β、NF-κB或诱导型一氧化氮合酶。FFA可能通过ER应激导致β细胞凋亡，而ER应激不依赖于NF-κB和NO。因此，细胞因子和营养物质通过根本不同的机制触发β细胞死亡，即细胞因子通过最终导致半胱天冬酶-3激活的NF-κB依赖性机制，而营养物质则通过NF-κB非依赖性机制。这反对了1型和2型糖尿病中β细胞死亡机制的统一假说，并表明预防1型和2型糖尿病中β细胞死亡需要不同的方法。
