Faculdade de Medicina da Universidade de São Paulo, Laboratório de Endocrinologia Celular e Molecular LIM-25, São Paulo, Brazil.
Diabetes Metab Res Rev. 2013 May;29(4):296-307. doi: 10.1002/dmrr.2390.
Loss of β-cell function hastens deterioration of metabolic control in type 2 diabetes patients. Besides amyloid deposit and glucolipotoxicity, advanced glycation end products (AGEs) acting through their receptors (RAGE) seem to contribute to this process by promoting islet apoptosis. In order to investigate the role of AGEs in β-cell deterioration, we evaluated the temporal and dose effects of AGE compounds on apoptosis rate, reactive oxygen species generation and expression of pro-apoptotic and anti-apoptotic genes in cultured islets.
Rat pancreatic islets were exposed or not for 24, 48, 72 and 96 h to albumin modified by glycoaldehyde. Apoptosis, reactive oxygen species and superoxide content and NADPH oxidase activity were evaluated as well as RNA expression of the genes Ager (codes for RAGE), Bax, Bcl2 and Nfkb1.
In 24 and 48 h, glycoaldehyde elicited a decrease in apoptosis rate in comparison with the control condition concomitantly with a reduction in Bax/Bcl2 RNA ratio and in Nfkb1 RNA expression. In contrast, after 72 and 96 h, glycoaldehyde promoted an increase in apoptosis rate concomitantly with an increase in Bax/Bcl2 RNA ratio and in Nfkb1 RNA expression. In 24 h, glycoaldehyde elicited a decrease in the islet content of reactive oxygen species, whereas after 48 and 72 h, it promoted an opposite effect, increasing superoxide generation. The NADPH oxidase inhibitor VAS2870 attenuated superoxide production, implicating NADPH oxidase as an important source of reactive oxygen species in islets exposed to AGEs.
Albumin modified by glycoaldehyde exerted a dual effect in cultured pancreatic islets, being protective against apoptosis after short exposure but pro-apoptotic after prolonged exposure.
β细胞功能的丧失会加速 2 型糖尿病患者代谢控制的恶化。除了淀粉样沉积和糖脂毒性外，通过其受体 (RAGE) 起作用的晚期糖基化终产物 (AGEs) 似乎通过促进胰岛细胞凋亡而促进这一过程。为了研究 AGEs 在 β细胞恶化中的作用，我们评估了 AGE 化合物对培养的胰岛细胞凋亡率、活性氧生成和促凋亡及抗凋亡基因表达的时间和剂量效应。
将大鼠胰岛分别暴露于或不暴露于甘醛修饰的白蛋白 24、48、72 和 96 小时。评估凋亡、活性氧和超氧阴离子含量以及 NADPH 氧化酶活性，以及基因 Ager（编码 RAGE）、Bax、Bcl2 和 Nfkb1 的 RNA 表达。
在 24 和 48 小时，与对照条件相比，甘醛降低了凋亡率，同时降低了 Bax/Bcl2 RNA 比值和 Nfkb1 RNA 表达。相比之下，在 72 和 96 小时后，甘醛促进了凋亡率的增加，同时增加了 Bax/Bcl2 RNA 比值和 Nfkb1 RNA 表达。在 24 小时，甘醛降低了胰岛中活性氧的含量，而在 48 和 72 小时后，它促进了相反的效果，增加了超氧阴离子的产生。NADPH 氧化酶抑制剂 VAS2870 减弱了超氧阴离子的产生，表明 NADPH 氧化酶是暴露于 AGE 后胰岛中活性氧的重要来源。
甘醛修饰的白蛋白对培养的胰腺胰岛有双重作用，在短时间暴露时具有抗凋亡作用，但在长时间暴露时则具有促凋亡作用。
