Rakatzi Irini, Seipke Gerhard, Eckel Jürgen
Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, Düsseldorf, Germany.
Biochem Biophys Res Commun. 2003 Oct 24;310(3):852-9. doi: 10.1016/j.bbrc.2003.09.090.
Insulin receptor substrate (IRS)-2 has been implicated in the promotion of beta-cell survival. Here we tested the hypothesis that the novel analog [LysB3, GluB29] insulin (insulin glulisine, IG) might mediate an enhanced beta-cell protective effect due to its unique property of preferential IRS-2 phosphorylation. We assessed IRS activation by IG and its anti-apoptotic activity against cytokines or palmitic acid in comparison to insulin, insulin analogs, and insulin-like growth factor (IGF)-I using INS-1 cells. IG induced a prominent IRS-2 activation without significant IRS-1 stimulation. The marked cytokine- and fatty acid-induced apoptosis was strongly (55-60%) inhibited by IG both at the level of caspase 3 activation and nucleosomal release, with only 15% inhibition of apoptosis by regular insulin. At 1nM, insulin, insulin aspart, and insulin lispro were much less effective compared to IG. In conclusion, the prominent anti-apoptotic activity of insulin glulisine might serve to counteract autoimmune- and lipotoxicity-induced beta-cell destruction.
胰岛素受体底物（IRS）-2与促进β细胞存活有关。在此，我们检验了一种假说，即新型类似物[LysB3，GluB29]胰岛素（赖脯胰岛素，IG）因其优先磷酸化IRS-2的独特特性，可能介导增强的β细胞保护作用。我们使用INS-1细胞，评估了IG对IRS的激活作用及其与胰岛素、胰岛素类似物和胰岛素样生长因子（IGF）-I相比，对细胞因子或棕榈酸的抗凋亡活性。IG诱导了显著的IRS-2激活，而对IRS-1无明显刺激。在半胱天冬酶3激活和核小体释放水平上，IG强烈抑制（55 - 60%）细胞因子和脂肪酸诱导的明显凋亡，而常规胰岛素仅抑制15%的凋亡。在1nM时，与IG相比，胰岛素、门冬胰岛素和赖脯胰岛素的效果要差得多。总之，赖脯胰岛素突出的抗凋亡活性可能有助于对抗自身免疫和脂毒性诱导的β细胞破坏。
