Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues
Enhanced protection against cytokine- and fatty acid-induced apoptosis in pancreatic beta cells by combined treatment with glucagon-like peptide-1 receptor agonists and insulin analogues
复制标题
DOI：
10.1055/s-2008-1042426
复制
发表时间：
2008-03-01
影响因子：
2.2
通讯作者：
Eckel, J.
中科院分区：
文献类型：
--
作者：
Tews, D.;Werner, U.;Eckel, J.
我们最近发现胰岛素类似物具有β细胞保护功能。本研究的目的是检测GLP-1激动剂和胰岛素类似物的抗凋亡活性是否由不同途径介导，以及联合治疗是否可以增强对β细胞死亡的保护。INS-1细胞与细胞因子或脂肪酸的孵育增加了凋亡细胞的数量和半胱天冬酶3的活性，而GLP-1及其受体激动剂exendin-4和AVE 0010预处理使其降低了50- 60%。用几种胰岛素类似物预处理后观察到类似的效果（约40%降低）。联合治疗显示出相加活性，并导致细胞因子和脂肪酸诱导的细胞凋亡的预防高达80%。未观察到GLP-1受体激动剂引起的急性Akt磷酸化，但在刺激24小时后可检测到。Akt 2的基因沉默使马槟榔诱导的细胞凋亡增加2倍。在这些条件下，AVE 0010的β细胞保护活性保持完全不变。我们在此表明，GLP-1及其受体激动剂AVE 0010和exendin-4的抗凋亡活性通过添加胰岛素类似物而增强，并且GLP-1模拟物的抗凋亡作用大多与Akt 2信号传导无关。这表明GLP-1受体激动剂与胰岛素类似物（特别是甘精胰岛素）联合治疗可能代表了2型糖尿病患者β细胞群保护的一种新治疗选择。
We recently showed that insulin analogues exhibit a beta-cell protective function. The aim of this study was to test if the anti-apoptotic activity of GLP-1 agonists and insulin analogues is mediated by different pathways and if combined treatment may provide augmented protection against beta-cell death. incubation of INS-1 cells with cytokines or fatty acids increased the number of apoptotic cells and caspase 3 activity, which was reduced by pretreatment with GLP-1 and its receptor agonists exendin-4 and AVE0010 by 50-60%. Similar effects (about 40% reduction) were observed after pretreatment with several insulin analogues. Combined treatment revealed additive activity and resulted in prevention of both cytokine- and fatty acid-induced apoptosis by up to 80%. No acute Akt-phosphorylation in response to GLP-1 receptor agonists could be observed, however, it became detectable after 24-hour stimulation. Gene silencing of Akt2 increased cytokine-induced apoptosis 2-fold. Under these conditions the beta-cell protective activity of AVE0010 remained completely unaltered. We show here that the anti-apoptotic activity of GLP-1 and its receptor agonists AVE0010 and exendin-4 is enhanced by addition of insulin analogues and that the anti-apoptotic action of GLP-1 mimetics is mostly unrelated to Akt2 signaling. It is suggested that combination of GLP-1 receptor agonists and insulin analogues, specifically insulin glargine, may represent a new therapeutic option for preservation of beta-cell mass in type 2 diabetic patients.