c-Jun氨基末端激酶抑制剂减轻烫伤后胰岛素抵抗的实验研究

Amelioration of insulin resistance after scald by c-Jun N-terminal kinase inhibitor in rat

目的探讨c-Jun氨基末端激酶(JNK)抑制剂SP600125对烫伤后胰岛素抵抗的作用及机制。方法24只SD大鼠以表格随机法分为假伤组、烫伤对照组和烫伤+SP600125组。将大鼠制成30％TBSAⅢ度烫伤模型(其中假伤组以常温模拟烫伤过程)。伤后第4天进行葡萄糖钳夹实验(烫伤+SP600125组在实验开始前2 h给予拮抗剂SP600125),检测肌肉组织胰岛素受体底物(IRS)1磷酸化丝氨酸307(Ser307)和酪氨酸的活性变化,并比较各组磷酸化JNK表达水平。结果(1)葡萄糖钳夹实验:假伤组、烫伤对照组和烫伤+SP600125组100 g／L葡萄糖输注率分别为(12．33±0．42)、(6．61±0．27)、(11．11±0．68)mg·kg-1·min-1,各组间比较,差异有统计学意义(P< 0．01)。(2)烫伤对照组与假伤组比较,肌肉组织IRS-1磷酸化Ser307和磷酸化JNK活性明显升高, IRS-1磷酸化酪氨酸活性明显降低(P<0．05)。烫伤+SP600125组与烫伤对照组比较,肌肉组织中IRS-1磷酸化Ser307和磷酸化JNK活性降低而IRS-1磷酸化酪氨酸活性增加。结论SP600125通过抑制JNK磷酸化而降低IRS-1磷酸化Ser307活性,可部分减轻烫伤后胰岛素抵抗发生。

Objective To investigate the role and mechanism of c-Jun N-terminal kinase （JNk） in hibitor （SP600125） in amelioration of insulin resistance after scald. Methods Twenty-four Sprague-Daw ley rats were randomized into sham （ the process of scald was mimicked by water at room temperature） , scald, scald and SP600125 groups. The rats were inflicted with 30% TBSA full-thickness scald in the latter two groups. Euglycemic-hyperinsulinemic glucose clamp experiment was carried out 4 days after scald. SP600125 was administered to the rats in scald and SP600125 2 hrs before Euglycemic-hyperinsulinemic glucose clamp was performed. Changes in the phospho-Serine^307 and phospho-tyrosine of IRS-1 activity, as well as expression of phospho-JNK in muscles were determined. Results Euglycemic-Hyperinsulinemic Glucose Clamps experiment showed that the infusion rate of 100 g/L glucose in sham, scald, scald and SP600125 groups were （12.33±0.42）, （6.61±0.27）, （11.11 ±0.68） mg· kg^-1·min^-1, respectively （ P 〈0.01 ）. The level of IRS-1 Serine^307 phosphorylation and JNK activity in muscles were significantly increased, while insulin-induced tyrosine phosphorylation of IRS-1 decreased markedly after scald. Compared with scald group, the level of IRS-1 Serine^307 phosphorylation and JNK activity in scald and SP600125 group were decreased but tyrosine phosphorylation was elevated. Conclusion SP600125 can partially ameliorate insulin resistance after scald by inhibition of JNK activation, and decrease the level of IRS-1 phospho-serine^307 .