Khaldi M Z, Elouil H, Guiot Y, Henquin J C, Jonas J C
Endocrinology and Metabolism, Université catholique de Louvain, Ave. Hippocrate, 55-UCL 55.30, B-1200 Brussels, Belgium.
Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E137-46. doi: 10.1152/ajpendo.00145.2005. Epub 2006 Feb 7.
We previously showed that the stimulation of heme oxygenase-1 expression by high glucose and hydrogen peroxide (H(2)O(2)) in cultured rat islets is prevented by antioxidants and suggested that this effect of high glucose results from an oxidative stress. However, the role of oxidative stress in high-glucose-induced beta-cell dysfunction is unclear. We therefore compared the preventative effects of N-acetyl-l-cysteine (NAC), a free radical scavenger, and manganese(III)tetrakis (4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase/catalase mimetic agent, on the alteration of stimulus-secretion coupling induced in rat islets by overnight exposure to hydrogen peroxide (H(2)O(2)-treated islets) or 1-wk culture in 30 vs. 10 mmol/l glucose (High-glucose vs. Control islets). The features of beta-cell dysfunction differed between the two groups: reduced glucose-induced insulin secretion without changes in glucose sensitivity in H(2)O(2)-treated islets; increased sensitivity to glucose with parallel reductions in insulin content and maximal rate of glucose-induced insulin secretion in High-glucose islets. The latter alterations were accompanied by a decrease in preproinsulin without changes in pancreatic and duodenal homeobox gene 1 mRNA levels. The functional alterations induced by H(2)O(2) were significantly prevented by addition of NAC or MnTBAP in the culture medium. In contrast, neither NAC nor MnTBAP affected the functional alterations induced by high glucose. These results suggest that beta-cell dysfunction induced by 1-wk culture in high glucose does not result from an increase in oxidative stress.
我们之前发现，在培养的大鼠胰岛中，抗氧化剂可抑制高糖和过氧化氢（H₂O₂）对血红素加氧酶-1表达的刺激作用，并提示高糖的这种作用源于氧化应激。然而，氧化应激在高糖诱导的β细胞功能障碍中的作用尚不清楚。因此，我们比较了自由基清除剂N-乙酰-L-半胱氨酸（NAC）和超氧化物歧化酶/过氧化氢酶模拟剂锰（III）四（4-苯甲酸）卟啉（MnTBAP）对大鼠胰岛刺激-分泌偶联改变的预防作用，这些改变是由过夜暴露于过氧化氢（H₂O₂处理的胰岛）或在30 mmol/l与10 mmol/l葡萄糖中培养1周（高糖组与对照组胰岛）诱导产生的。两组β细胞功能障碍的特征有所不同：在H₂O₂处理的胰岛中，葡萄糖诱导的胰岛素分泌减少，但葡萄糖敏感性无变化；在高糖组胰岛中，对葡萄糖的敏感性增加，同时胰岛素含量和葡萄糖诱导的胰岛素分泌最大速率平行降低。后者的改变伴随着胰岛素原前体的减少，而胰腺和十二指肠同源盒基因1 mRNA水平无变化。在培养基中添加NAC或MnTBAP可显著预防H₂O₂诱导的功能改变。相比之下，NAC和MnTBAP均未影响高糖诱导的功能改变。这些结果表明，高糖培养1周诱导的β细胞功能障碍并非由氧化应激增加所致。
