Department of Metabolism, Nutrition and Hormones, IIS-Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain.
J Mol Endocrinol. 2012 Jan 25;48(1):37-47. doi: 10.1530/JME-11-0127. Print 2012 Feb.
Exendin-4 (Ex-4) mimics glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), being anti-diabetic and anorectic, in stimulating glucose and lipid metabolism in extrapancreatic tissues. We studied the characteristics of Ex-4 and GLP-1 action, during prolonged treatment, on GLUTs expression (mRNA and protein), glycogen content (GC), glucose transport (GT), glycogen synthase a (GSa), and kinase (PI3K and MAPKs) activity, in liver, muscle, and fat of insulin-resistant (IR, by fructose) and type 2 diabetic (T2D, streptozotocin at birth) rats compared with normal rats. In both IR and T2D, the three tissues studied presented alterations in all measured parameters. In liver, GLP-1 and also Ex-4 normalized the lower than normal Glut2 (Slc2a2) expression and showed a trend to normalize the reduced GC in IR, and GLP-1, like Ex-4, also in T2D, effects mediated by PI3K and MAPKs. In skeletal muscle, neither GLP-1 nor Ex-4 modified Glut4 (Slc2a4) expression in either experimental model but showed normalization of reduced GT and GSa, in parallel with the normalization of reduced PI3K activity in T2D and MAPKs in both models. In adipose tissue, the altered GLUT4 expression in IR and T2D, along with reduced GT in IR and increased GT in T2D, and with hyperactivated PI3K in both, became normal after GLP-1 and Ex-4 treatment; yet, MAPKs, that were also higher, became normal only after Ex-4 treatment. The data shows that Ex-4, as well as GLP-1, exerts a normalizing effect on IR and T2D states through a distinct post-receptor mechanism, the liver being the main target for Ex-4 and GLP-1 to control glucose homeostasis.
Exendin-4（Ex-4）模拟胰高血糖素样肽-1（GLP-1 或 HUGO 数据库中列出的 GCG），具有抗糖尿病和厌食作用，可刺激胰外组织的葡萄糖和脂质代谢。我们研究了 Ex-4 和 GLP-1 在延长治疗期间的作用特点，即在胰岛素抵抗（通过果糖）和 2 型糖尿病（出生时链脲佐菌素）大鼠的肝脏、肌肉和脂肪中，对葡萄糖转运体（GLUTs）表达（mRNA 和蛋白）、糖原含量（GC）、葡萄糖转运（GT）、糖原合酶 a（GSa）和激酶（PI3K 和 MAPKs）活性的影响，与正常大鼠相比。在 IR 和 T2D 中，所有研究的组织均改变了所有测量参数。在肝脏中，GLP-1 和 Ex-4 使低于正常的 Glut2（Slc2a2）表达正常化，并显示出使 IR 中降低的 GC 正常化的趋势，而 GLP-1 也像 Ex-4 一样，在 T2D 中，通过 PI3K 和 MAPKs 介导的作用。在骨骼肌中，GLP-1 和 Ex-4 均未改变任何实验模型中的 Glut4（Slc2a4）表达，但显示出降低的 GT 和 GSa 的正常化，与 T2D 中降低的 PI3K 活性和两种模型中的 MAPKs 正常化平行。在脂肪组织中，IR 和 T2D 中改变的 GLUT4 表达，以及 IR 中降低的 GT 和 T2D 中增加的 GT，以及两者中过度激活的 PI3K，在 GLP-1 和 Ex-4 治疗后变得正常；然而，MAPKs 也更高，仅在 Ex-4 治疗后才正常。这些数据表明，Ex-4 与 GLP-1 一样，通过一种独特的受体后机制对 IR 和 T2D 状态发挥正常化作用，肝脏是 Ex-4 和 GLP-1 控制血糖稳态的主要靶标。
