Hennige A M, Sartorius T, Tschritter O, Preissl H, Fritsche A, Ruth P, Häring H-U
Department of Internal Medicine IV, University of Tübingen, 72076 Tübingen, Germany.
Diabetologia. 2006 Jun;49(6):1274-82. doi: 10.1007/s00125-006-0192-9. Epub 2006 Mar 29.
AIMS/HYPOTHESIS: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo.
C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection.
The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir.
CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.
目的/假设：重组DNA技术是一种有用的工具，可用于创建具有改变吸收动力学的胰岛素类似物，以改善1型和2型糖尿病患者的血糖控制。在通常通过氨基酸交换产生的传统胰岛素类似物中，地特胰岛素是第一种用脂肪酸酰化以实现可逆白蛋白结合的类似物。在本研究中，我们在胰岛素受体（IR）和IR底物（Irs）磷酸化水平以及下游信号元件如磷脂酰肌醇3激酶和Akt水平上，测定了地特胰岛素对IR信号级联的激活，并在体内进行了硬膜外脑电图检查。
给C57Bl/6小鼠静脉注射地特胰岛素或人胰岛素，并对肝脏、肌肉、下丘脑和大脑皮质组织进行蛋白质印迹分析。此外，在清醒小鼠中通过脑电图检测大脑皮质活动，并在注射人胰岛素和地特胰岛素后测量脑内胰岛素浓度。
与人类胰岛素相比，地特胰岛素治疗后外周组织中IR磷酸化的时间进程和程度相似，但由IR和Irs2蛋白的酪氨酸磷酸化所确定的下丘脑和大脑皮质组织中的胰岛素信号传导发生得更快，并且由于脑中地特胰岛素浓度较高而增强。此外，使用地特胰岛素时小鼠的硬膜外脑电图显示皮质活动增加。
结论/解读：综上所述，这些数据表明地特胰岛素具有组织选择性作用，与外周组织相比，对脑具有相对偏好。
