Bikhazi A B, Azar S T, Birbari A E, El-Zein G N, Haddad G E, Haddad R E, Bitar K M
Department of Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Eur J Pharm Sci. 2000 Oct;11(4):299-306. doi: 10.1016/s0928-0987(00)00110-x.
Insulin-resistance is associated with a number of disease states such as diabetes, syndrome X, and hypertension. These situations may be coupled to insulin-resistance through the insulin signaling system as a common pathway. The purpose of this study was to investigate the receptor binding alterations in streptozotocin-induced diabetic rats, spontaneously hypertensive rats and aortocaval shunted rats (eccentric cardiac hypertrophy). A physical model describing a 1:1 stoichiometry of ligand binding with its receptor is proposed describing reversible binding of [(125)I]insulin or [(125)I]IGF-1 at the microvascular endothelial as well as with the cardiac myocytes after CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function which allowed the calculation of the forward binding constants (k(n)), the reversible constants (k(-n)), the dissociation constants (k(d)) and the residency time constants (tau). The results showed that streptozotocin-induced diabetic rats showed insulin-resistance through alterations in the kinetics of insulin receptor binding. The normotensive controls of the spontaneously hypertension rats (SHR) carry themselves insulin-resistant receptors whose binding to insulin worsens in the hypertensive SHR. Negative cooperativity between insulin-like growth factor IGF-1 and insulin receptors could be a causative factor predisposing for insulin-resistance in the aortocaval shunted rats to insulin resistance. The defects may be occurring at the receptor level in insulin-dependent diabetes mellitus, Wistar-Kyoto rats and spontaneously hypertensive rats. In conclusion, alterations in the kinetics of insulin binding to its receptor seem to play a central role for the initiation of insulin-resistance during the various pathophysiological states.
胰岛素抵抗与多种疾病状态相关，如糖尿病、X综合征和高血压。这些情况可能通过胰岛素信号系统作为共同途径与胰岛素抵抗相关联。本研究的目的是调查链脲佐菌素诱导的糖尿病大鼠、自发性高血压大鼠和主动脉腔静脉分流大鼠（离心性心肌肥大）中受体结合的改变。提出了一个描述配体与其受体1:1化学计量比结合的物理模型，该模型描述了经CHAPS处理后，[(125)I]胰岛素或[(125)I]IGF-1在微血管内皮细胞以及心肌细胞上的可逆结合。对收集的流出物进行分析，用守恒方程和一阶贝塞尔函数进行曲线拟合，从而可以计算正向结合常数（k(n)）、可逆常数（k(-n)）、解离常数（k(d)）和驻留时间常数（tau）。结果表明，链脲佐菌素诱导的糖尿病大鼠通过胰岛素受体结合动力学的改变表现出胰岛素抵抗。自发性高血压大鼠（SHR）的血压正常对照组本身携带胰岛素抵抗受体，在高血压的SHR中，这些受体与胰岛素的结合会恶化。胰岛素样生长因子IGF-1和胰岛素受体之间的负协同作用可能是主动脉腔静脉分流大鼠易患胰岛素抵抗的一个致病因素。在胰岛素依赖型糖尿病、Wistar-Kyoto大鼠和自发性高血压大鼠中，缺陷可能发生在受体水平。总之，胰岛素与其受体结合动力学的改变似乎在各种病理生理状态下胰岛素抵抗的起始过程中起着核心作用。
