Rosiglitazone counteracts palmitate-induced β-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities
Rosiglitazone counteracts palmitate-induced β-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities
复制标题
DOI：
10.1007/s00018-008-8100-8
复制
发表时间：
2008-07-01
影响因子：
8
通讯作者：
Salehi, A.
中科院分区：
文献类型：
--
作者：
Abaraviciene, S. Meidute;Lundquist, I.;Salehi, A.
胰岛长期暴露于升高水平的棕榈酸导致β细胞功能障碍。我们研究了有丝分裂原活化蛋白激酶（MAPKs）和caspase-3在棕榈酸诱导的β细胞功能障碍中的可能参与，并测试了抗糖尿病药物罗格列酮（ROZ）的影响。在培养的胰岛中，棕榈酸盐放大了葡萄糖刺激的细胞内游离钙（[Ca 2 +]（i））和胰岛素分泌的增加。ROZ抑制这种扩增，而它适度增加葡萄糖诱导的这些事件的增加。ROZ抑制棕榈酸诱导的促凋亡MAPK的短期磷酸化，即，SAPK/JNK和p38。长期培养的胰岛与棕榈酸诱导诱导型一氧化氮合酶（iNOS）和激活SAPK/JNK-p38。ROZ抵消了这些影响。棕榈酸和细胞因子都激活了MIN 6c 4-细胞和分离的胰岛中的caspase-3。ROZ抑制棕榈酸酯-但不是苦参碱诱导的caspase-3激活。最后，在棕榈酸培养后，ROZ逆转了对葡萄糖刺激的胰岛素释放的抑制作用。我们认为ROZ通过抑制iNOS、促凋亡MAPK和caspase-3活性来抵消棕榈酸酯诱导的对β细胞功能的有害作用，如葡萄糖刺激的胰岛素释放的恢复所证明的。
Chronic exposure of pancreatic islets to elevated levels of palmitate leads to beta-cell dysfunction. We examined possible involvement of mitogenactivated protein kinases (MAPKs) and caspase-3 in palmitate-induced beta-cell dysfunction and tested the influence of the anti-diabetic drug rosiglitazone (ROZ). Palmitate amplified glucose-stimulated augmentation of intracellular free calcium ([Ca2+](i)) and insulin secretion in incubated islets. ROZ suppressed this amplification, whereas it modestly augmented glucose-induced increase in these events. ROZ suppressed short-term palmitate-induced phosphorylation of pro-apoptotic MAPKs, i.e., SAPK/JNK and p38. Long-term islet culturing with palmitate induced inducible nitric oxide synthase (iNOS) and activated SAPK/JNK-p38. ROZ counteracted these effects. Both palmitate and cytokines activated caspase-3 in MIN6c4-cells and isolated islets. ROZ suppressed palmitate- but not cytokine-induced caspase-3 activation. Finally, after palmitate culturing, ROZ reversed the inhibitory effect on glucose-stimulated insulin release. We suggest that ROZ counteracts palmitateinduced deleterious effects on beta-cell function via suppression of iNOS, pro-apoptotic MAPKs and caspase-3 activities, as evidenced by restoration of glucose-stimulated insulin release.